More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\n
Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n
“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\n
Additionally, each book published by IntechOpen contains original content and research findings.
\\n\\n
We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\n
Simba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\n
IntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\n
Since the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\n
Our breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n
“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\n
Additionally, each book published by IntechOpen contains original content and research findings.
\n\n
We are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n
\n\n
\n'}],latestNews:[{slug:"intechopen-signs-new-contract-with-cepiec-china-for-distribution-of-open-access-books-20210319",title:"IntechOpen Signs New Contract with CEPIEC, China for Distribution of Open Access Books"},{slug:"150-million-downloads-and-counting-20210316",title:"150 Million Downloads and Counting"},{slug:"intechopen-secures-indefinite-content-preservation-with-clockss-20210309",title:"IntechOpen Secures Indefinite Content Preservation with CLOCKSS"},{slug:"intechopen-expands-to-all-global-amazon-channels-with-full-catalog-of-books-20210308",title:"IntechOpen Expands to All Global Amazon Channels with Full Catalog of Books"},{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"}]},book:{item:{type:"book",id:"577",leadTitle:null,fullTitle:"Assistive Technologies",title:"Assistive Technologies",subtitle:null,reviewType:"peer-reviewed",abstract:"This book offers the reader new achievements within the Assistive Technology field made by worldwide experts, covering aspects such as assistive technology focused on teaching and education, mobility, communication and social interactivity, among others. Each chapter included in this book covers one particular aspect of Assistive Technology that invites the reader to know the recent advances made in order to bridge the gap in accessible technology for disabled or impaired individuals.",isbn:null,printIsbn:"978-953-51-0348-6",pdfIsbn:"978-953-51-5570-6",doi:"10.5772/1089",price:119,priceEur:129,priceUsd:155,slug:"assistive-technologies",numberOfPages:246,isOpenForSubmission:!1,isInWos:1,hash:"a96647e24e8f72a97a6df1368e625ebc",bookSignature:"Fernando A. Auat Cheein",publishedDate:"March 16th 2012",coverURL:"https://cdn.intechopen.com/books/images_new/577.jpg",numberOfDownloads:31972,numberOfWosCitations:51,numberOfCrossrefCitations:73,numberOfDimensionsCitations:103,hasAltmetrics:0,numberOfTotalCitations:227,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"March 9th 2011",dateEndSecondStepPublish:"April 6th 2011",dateEndThirdStepPublish:"August 11th 2011",dateEndFourthStepPublish:"September 10th 2011",dateEndFifthStepPublish:"January 8th 2012",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6,7",editedByType:"Edited by",kuFlag:!1,editors:[{id:"78273",title:"Dr.",name:"Fernando",middleName:null,surname:"Auat Cheein",slug:"fernando-auat-cheein",fullName:"Fernando Auat Cheein",profilePictureURL:"https://mts.intechopen.com/storage/users/78273/images/2354_n.jpg",biography:"Dr. Fernando A. Auat Cheein is an Assistant Professor with the Universidad Técnica Federico Santa María, Valparaíso, Chile, since 2011. He received the Electronics Engineer degree -with honors- by the Universidad Nacional de Tucumán, Argentina, in 2002, the M. Sc. and the Doctorate degree from the Universidad Nacional de San Juan, Argentina, in 2005 and 2009 respectively, obtaining in both, the excellence grade. His Master degree thesis concerned the development of Brain-Computer Interfaces (BCI) for controlling robotic devices (robot manipulators, mobile robots and robotic wheelchairs). His doctorate thesis was focused in SLAM (Simultaneous Localization and Mapping) algorithms applied to mobile vehicles, including robotic wheelchairs. He has several publications within both: the robotics field and the rehabilitation field. Several of his publications have been awarded as selected or best papers. He is currently a reviewer of numerous indexed journals, conferences and part of the editorial board of the International Journal of Advanced Robotic Systems (Intech).\r\n\r\nDr. Auat Cheein has also won the doctorate and postdoctoral grant by the CONICET, Argentina (2004 and 2009 respectively), and an ALFA grant by the European Union (2006). His current research interests include: autonomous systems and planning, human-robot interaction and agricultural robotics.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Federico Santa María Technical University",institutionURL:null,country:{name:"Chile"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1361",title:"Assistive Technologies",slug:"assistive-technologies"}],chapters:[{id:"31901",title:"How to Use Low-Cost Devices as Teaching Materials for Children with Different Disabilities",doi:"10.5772/30479",slug:"application-of-interactive-design-as-teaching-materials",totalDownloads:8650,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Chien-Yu Lin",downloadPdfUrl:"/chapter/pdf-download/31901",previewPdfUrl:"/chapter/pdf-preview/31901",authors:[{id:"82737",title:"Prof.",name:"Chien-Yu",surname:"Lin",slug:"chien-yu-lin",fullName:"Chien-Yu Lin"}],corrections:null},{id:"31902",title:"Disabled Pupils` Use of Assistive ICT in Norwegian Schools",doi:"10.5772/30798",slug:"pupils-use-of-assistive-ict-in-norwegian-primary-school-",totalDownloads:1875,totalCrossrefCites:2,totalDimensionsCites:2,signatures:"Sylvia Söderström",downloadPdfUrl:"/chapter/pdf-download/31902",previewPdfUrl:"/chapter/pdf-preview/31902",authors:[{id:"84282",title:"Dr.",name:"Sylvia",surname:"Soederstroem",slug:"sylvia-soederstroem",fullName:"Sylvia Soederstroem"}],corrections:null},{id:"31903",title:"Inclusion Through the Internet of Things",doi:"10.5772/31929",slug:"inclusion-through-the-internet-of-things",totalDownloads:2330,totalCrossrefCites:14,totalDimensionsCites:14,signatures:"Louis Coetzee and Guillaume Olivrin",downloadPdfUrl:"/chapter/pdf-download/31903",previewPdfUrl:"/chapter/pdf-preview/31903",authors:[{id:"89372",title:"Dr.",name:"Louis",surname:"Coetzee",slug:"louis-coetzee",fullName:"Louis Coetzee"},{id:"89812",title:"Mr.",name:"Guillaume",surname:"Olivrin",slug:"guillaume-olivrin",fullName:"Guillaume Olivrin"}],corrections:null},{id:"31904",title:"An Implementation of Intelligent HTMLtoVoiceXML Conversion Agent for Text Disabilities",doi:"10.5772/37615",slug:"an-implementation-of-intelligent-htmltovoicexml-conversion-agent-for-text-disabilities",totalDownloads:1995,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Young Gun Jang",downloadPdfUrl:"/chapter/pdf-download/31904",previewPdfUrl:"/chapter/pdf-preview/31904",authors:[{id:"113531",title:"Dr.",name:"Young Gun",surname:"Jang",slug:"young-gun-jang",fullName:"Young Gun Jang"}],corrections:null},{id:"31905",title:"Touch Screens for the Older User",doi:"10.5772/38302",slug:"touch-screens-for-the-older-user",totalDownloads:4784,totalCrossrefCites:48,totalDimensionsCites:76,signatures:"Niamh Caprani, Noel E. O’Connor and Cathal Gurrin",downloadPdfUrl:"/chapter/pdf-download/31905",previewPdfUrl:"/chapter/pdf-preview/31905",authors:[{id:"1479",title:"Dr.",name:"Cathal",surname:"Gurrin",slug:"cathal-gurrin",fullName:"Cathal Gurrin"},{id:"116543",title:"Ms.",name:"Niamh",surname:"Caprani",slug:"niamh-caprani",fullName:"Niamh Caprani"},{id:"116548",title:"Prof.",name:"Noel",surname:"E. O'Connor",slug:"noel-e.-o'connor",fullName:"Noel E. O'Connor"}],corrections:null},{id:"31906",title:"Universal Design or Modular-Based Design Solutions - A Society Concern",doi:"10.5772/30152",slug:"universal-design-or-modular-based-design-solutions-",totalDownloads:2139,totalCrossrefCites:2,totalDimensionsCites:2,signatures:"Evastina Björk",downloadPdfUrl:"/chapter/pdf-download/31906",previewPdfUrl:"/chapter/pdf-preview/31906",authors:[{id:"81092",title:"Dr.",name:"Evastina",surname:"Bjoerk",slug:"evastina-bjoerk",fullName:"Evastina Bjoerk"}],corrections:null},{id:"31907",title:"Proposal for a New Development Methodology for Assistive Technology Based on a Psychological Model of Elderly People",doi:"10.5772/30407",slug:"proposal-for-a-new-development-methodology-for-assistive-technology-based-on-the-psychological-model",totalDownloads:1805,totalCrossrefCites:4,totalDimensionsCites:5,signatures:"Misato Nihei and Masakatsu G. Fujie",downloadPdfUrl:"/chapter/pdf-download/31907",previewPdfUrl:"/chapter/pdf-preview/31907",authors:[{id:"82435",title:"Dr.",name:"Misato",surname:"Nihei",slug:"misato-nihei",fullName:"Misato Nihei"},{id:"113281",title:"Prof.",name:"Masakatsu",surname:"Fujie",slug:"masakatsu-fujie",fullName:"Masakatsu Fujie"}],corrections:null},{id:"31908",title:"New Strategies of Mobility and Interaction for People with Cerebral Palsy",doi:"10.5772/31214",slug:"new-strategies-of-mobility-and-interaction-for-people-with-cerebral-palsy",totalDownloads:2335,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"R. Raya, E. Rocon, R. Ceres, L. Calderón and J. L. Pons",downloadPdfUrl:"/chapter/pdf-download/31908",previewPdfUrl:"/chapter/pdf-preview/31908",authors:[{id:"1384",title:"Dr.",name:"Eduardo",surname:"Rocon",slug:"eduardo-rocon",fullName:"Eduardo Rocon"},{id:"27959",title:"Mr.",name:"Ramon",surname:"Ceres",slug:"ramon-ceres",fullName:"Ramon Ceres"},{id:"27960",title:"Dr.",name:"José Luis",surname:"Pons",slug:"jose-luis-pons",fullName:"José Luis Pons"},{id:"86077",title:"BSc.",name:"Rafael",surname:"Raya",slug:"rafael-raya",fullName:"Rafael Raya"},{id:"123534",title:"Dr.",name:"Leopoldo",surname:"Calderón",slug:"leopoldo-calderon",fullName:"Leopoldo Calderón"}],corrections:null},{id:"31909",title:"Brazilian Assistive Technology in Bath or Shower Activity for Individuals with Physical Disability",doi:"10.5772/31242",slug:"assistive-technology-in-bath-activity-for-individuals-with-physical-disability",totalDownloads:2242,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Fabiola Canal Merlin Dutra, Alessandra Cavalcanti de Albuquerque e Souza, Cláudia Regina Cabral Galvão, Valéria Sousa de Andrade, Daniel Marinho Cezar da Cruz, Daniel Gustavo de Sousa Carleto and Letícia Zanetti Marchi Altafim",downloadPdfUrl:"/chapter/pdf-download/31909",previewPdfUrl:"/chapter/pdf-preview/31909",authors:[{id:"86190",title:"Ms.",name:"Fabiola",surname:"Dutra",slug:"fabiola-dutra",fullName:"Fabiola Dutra"},{id:"89576",title:"Ms.",name:"Alessandra",surname:"Souza",slug:"alessandra-souza",fullName:"Alessandra Souza"},{id:"89577",title:"Ms.",name:"Claudia",surname:"Galvao",slug:"claudia-galvao",fullName:"Claudia Galvao"},{id:"89578",title:"Ms.",name:"Valeria",surname:"Andrade",slug:"valeria-andrade",fullName:"Valeria Andrade"},{id:"89579",title:"Dr.",name:"Reidson",surname:"Gouvinhas",slug:"reidson-gouvinhas",fullName:"Reidson Gouvinhas"}],corrections:null},{id:"31910",title:"Imaging Systems in Assistive Technology",doi:"10.5772/31519",slug:"electronic-imaging-systems-in-assistive-technology",totalDownloads:1895,totalCrossrefCites:1,totalDimensionsCites:2,signatures:"Miloš Klíma and Stanislav Vítek",downloadPdfUrl:"/chapter/pdf-download/31910",previewPdfUrl:"/chapter/pdf-preview/31910",authors:[{id:"87601",title:"Prof.",name:"Milos",surname:"Klima",slug:"milos-klima",fullName:"Milos Klima"},{id:"87615",title:"Dr.",name:"Stanislav",surname:"Vitek",slug:"stanislav-vitek",fullName:"Stanislav Vitek"}],corrections:null},{id:"31911",title:"Soft and Noiseless Actuator Technology Using Metal Hydride Alloys to Support Personal Physical Activity",doi:"10.5772/31032",slug:"soft-and-noiseless-actuator-technology-using-metal-hydride-alloys-to-support-personal-physical-activ",totalDownloads:1922,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Shuichi Ino and Mitsuru Sato",downloadPdfUrl:"/chapter/pdf-download/31911",previewPdfUrl:"/chapter/pdf-preview/31911",authors:[{id:"2467",title:"Dr.",name:"Shuichi",surname:"Ino",slug:"shuichi-ino",fullName:"Shuichi Ino"},{id:"89119",title:"Prof.",name:"Mitsuru",surname:"Sato",slug:"mitsuru-sato",fullName:"Mitsuru Sato"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"314",title:"Regenerative Medicine and Tissue Engineering",subtitle:"Cells and Biomaterials",isOpenForSubmission:!1,hash:"bb67e80e480c86bb8315458012d65686",slug:"regenerative-medicine-and-tissue-engineering-cells-and-biomaterials",bookSignature:"Daniel Eberli",coverURL:"https://cdn.intechopen.com/books/images_new/314.jpg",editedByType:"Edited by",editors:[{id:"6495",title:"Dr.",name:"Daniel",surname:"Eberli",slug:"daniel-eberli",fullName:"Daniel Eberli"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"872",title:"Organic Pollutants Ten Years After the Stockholm Convention",subtitle:"Environmental and Analytical Update",isOpenForSubmission:!1,hash:"f01dc7077e1d23f3d8f5454985cafa0a",slug:"organic-pollutants-ten-years-after-the-stockholm-convention-environmental-and-analytical-update",bookSignature:"Tomasz Puzyn and Aleksandra Mostrag-Szlichtyng",coverURL:"https://cdn.intechopen.com/books/images_new/872.jpg",editedByType:"Edited by",editors:[{id:"84887",title:"Dr.",name:"Tomasz",surname:"Puzyn",slug:"tomasz-puzyn",fullName:"Tomasz Puzyn"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"47331",slug:"correction-to-the-cultural-reinforcers-of-child-abuse",title:"Correction to: The Cultural Reinforcers of Child Abuse",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/47331.pdf",downloadPdfUrl:"/chapter/pdf-download/47331",previewPdfUrl:"/chapter/pdf-preview/47331",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/47331",risUrl:"/chapter/ris/47331",chapter:{id:"37763",slug:"the-cultural-reinforcers-of-child-abuse",signatures:"Essam Al-Shail, Ahmed Hassan, Abdullah Aldowaish and Hoda Kattan",dateSubmitted:"November 8th 2011",dateReviewed:"June 14th 2012",datePrePublished:null,datePublished:"July 11th 2012",book:{id:"2663",title:"Child Abuse and Neglect",subtitle:"A Multidimensional Approach",fullTitle:"Child Abuse and Neglect - A Multidimensional Approach",slug:"child-abuse-and-neglect-a-multidimensional-approach",publishedDate:"July 11th 2012",bookSignature:"Alexander Muela",coverURL:"https://cdn.intechopen.com/books/images_new/2663.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"138437",title:"Dr.",name:"Alexander",middleName:null,surname:"Muela Aparicio",slug:"alexander-muela-aparicio",fullName:"Alexander Muela Aparicio"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"85712",title:"Dr.",name:"Ahmed",middleName:"M.",surname:"Hassan",fullName:"Ahmed Hassan",slug:"ahmed-hassan",email:"amh_64@hotmail.com",position:null,institution:{name:"King Faisal Specialist Hospital & Research Centre",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"139594",title:"Prof.",name:"Essam",middleName:null,surname:"Al-Shail",fullName:"Essam Al-Shail",slug:"essam-al-shail",email:"shail@kfshrc.edu.sa",position:null,institution:{name:"Alfaisal University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"149745",title:"Dr.",name:"Hoda",middleName:null,surname:"Kattan",fullName:"Hoda Kattan",slug:"hoda-kattan",email:"hoda@kfshrc.edu.sa",position:null,institution:null},{id:"149746",title:"Dr.",name:"Abdullah",middleName:null,surname:"Aldowaish",fullName:"Abdullah Aldowaish",slug:"abdullah-aldowaish",email:"dowaish@kfshrc.edu.sa",position:null,institution:null}]}},chapter:{id:"37763",slug:"the-cultural-reinforcers-of-child-abuse",signatures:"Essam Al-Shail, Ahmed Hassan, Abdullah Aldowaish and Hoda Kattan",dateSubmitted:"November 8th 2011",dateReviewed:"June 14th 2012",datePrePublished:null,datePublished:"July 11th 2012",book:{id:"2663",title:"Child Abuse and Neglect",subtitle:"A Multidimensional Approach",fullTitle:"Child Abuse and Neglect - A Multidimensional Approach",slug:"child-abuse-and-neglect-a-multidimensional-approach",publishedDate:"July 11th 2012",bookSignature:"Alexander Muela",coverURL:"https://cdn.intechopen.com/books/images_new/2663.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"138437",title:"Dr.",name:"Alexander",middleName:null,surname:"Muela Aparicio",slug:"alexander-muela-aparicio",fullName:"Alexander Muela Aparicio"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"85712",title:"Dr.",name:"Ahmed",middleName:"M.",surname:"Hassan",fullName:"Ahmed Hassan",slug:"ahmed-hassan",email:"amh_64@hotmail.com",position:null,institution:{name:"King Faisal Specialist Hospital & Research Centre",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"139594",title:"Prof.",name:"Essam",middleName:null,surname:"Al-Shail",fullName:"Essam Al-Shail",slug:"essam-al-shail",email:"shail@kfshrc.edu.sa",position:null,institution:{name:"Alfaisal University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"149745",title:"Dr.",name:"Hoda",middleName:null,surname:"Kattan",fullName:"Hoda Kattan",slug:"hoda-kattan",email:"hoda@kfshrc.edu.sa",position:null,institution:null},{id:"149746",title:"Dr.",name:"Abdullah",middleName:null,surname:"Aldowaish",fullName:"Abdullah Aldowaish",slug:"abdullah-aldowaish",email:"dowaish@kfshrc.edu.sa",position:null,institution:null}]},book:{id:"2663",title:"Child Abuse and Neglect",subtitle:"A Multidimensional Approach",fullTitle:"Child Abuse and Neglect - A Multidimensional Approach",slug:"child-abuse-and-neglect-a-multidimensional-approach",publishedDate:"July 11th 2012",bookSignature:"Alexander Muela",coverURL:"https://cdn.intechopen.com/books/images_new/2663.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"138437",title:"Dr.",name:"Alexander",middleName:null,surname:"Muela Aparicio",slug:"alexander-muela-aparicio",fullName:"Alexander Muela Aparicio"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"7199",leadTitle:null,title:"Charged Particles",subtitle:null,reviewType:"peer-reviewed",abstract:"A charged particle is a particle that carries an electric charge and can be discussed in many aspects. This book focuses on cutting-edge and important research topics such as flavor physics to search for new physics via charged particles that appear in different extensions of the standard model, as well as the analysis of ultra-high energy muons using the pair-meter technique. Also included in this book are the idea of the Eloisatron to PeVatron, the important research field of electrostatic waves in magnetized electron/positron plasmas, and the application of charge bodies.",isbn:"978-1-78985-396-4",printIsbn:"978-1-78985-395-7",pdfIsbn:"978-1-83962-035-5",doi:"10.5772/intechopen.73999",price:119,priceEur:129,priceUsd:155,slug:"charged-particles",numberOfPages:104,isOpenForSubmission:!1,hash:"c456f670b68b3512e9e9866f9837fd98",bookSignature:"Malek Maaza and Mahmoud Izerrouken",publishedDate:"February 20th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/7199.jpg",keywords:null,numberOfDownloads:2725,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 9th 2018",dateEndSecondStepPublish:"May 23rd 2018",dateEndThirdStepPublish:"July 22nd 2018",dateEndFourthStepPublish:"October 10th 2018",dateEndFifthStepPublish:"December 9th 2018",remainingDaysToSecondStep:"3 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:"Edited by",kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"192286",title:"Prof.",name:"Malek",middleName:null,surname:"Maaza",slug:"malek-maaza",fullName:"Malek Maaza",profilePictureURL:"https://mts.intechopen.com/storage/users/192286/images/system/192286.jpg",biography:"Prof. M. Maaza, holds a DESS in Solid State Physics from the University of Oran-Algeria, an MSC in Lasers & Photonics & a PhD in Quantum wave matter Optics from the University of Pierre-Marie Curie& the Commissariat a l’Energie Atomique respectively. He is currently a permanent joint staff member of the\r\nNational Research Foundation of South Africa (NRF) and the University of South Africa\r\n(UNISA). Prof. Maaza is the current UNESCO UNISA Africa Chair in Nanosciences &\r\nNanotechnology via a trilateral partnership between UNESCO, NRF and the University of\r\nSouth Africa (UNISA). Among other positions held, he was the Southern Africa representative\r\nof the International Commission of Optics, He is the chair of the ICTP/AU supported official Nanosciences African Network. \r\nHe is a fellow of the African European Academy of Sciences, Royal Society of Chemistry, New York Academy ofSciences & the Islamic Academy of Sciences.Recently, ProfM. Maaza has been elected as\r\nFellow of the American Association for Advancement of Sciences. His expertise is in the multidisciplinary field of nanosciences, photonics and solar energy. Prof. M. Maaza has published more than 300 ISI International publications and supervised several postgraduates from all over Africa & the South.",institutionString:"University of South Africa",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of South Africa",institutionURL:null,country:{name:"South Africa"}}}],coeditorOne:{id:"251161",title:"Dr.",name:"Mahmoud",middleName:null,surname:"Izerrouken",slug:"mahmoud-izerrouken",fullName:"Mahmoud Izerrouken",profilePictureURL:"https://mts.intechopen.com/storage/users/251161/images/7175_n.png",biography:"Mahmoud Izerrouken joined Nuclear Research Centre of Draria in 1996 and currently holds the position of the head of the Nuclear Techniques Department, Nuclear Research Center of Draria, Algiers, Algeria. He has co-authored over 30 publications in SCI journals and supervised several Master and PhD students. His research interests are focused on Ion and Neutron induced damage in materials. He obtained his PhD at Ferhat Abbas University, Faculty of Sciences, Setif, Algeria.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"229",title:"Plasma Physics",slug:"plasma-physics"}],chapters:[{id:"64835",title:"Introductory Chapter: Charged Particles",slug:"introductory-chapter-charged-particles",totalDownloads:584,totalCrossrefCites:0,authors:[{id:"204045",title:"Dr.",name:"Ishaq",surname:"Ahmad",slug:"ishaq-ahmad",fullName:"Ishaq Ahmad"}]},{id:"64221",title:"Analysis of Ultra-High Energy Muons at INO-ICAL Using Pair Meter Technique",slug:"analysis-of-ultra-high-energy-muons-at-ino-ical-using-pair-meter-technique",totalDownloads:366,totalCrossrefCites:0,authors:[null]},{id:"63295",title:"From the Eloisatron to the Pevatron",slug:"from-the-eloisatron-to-the-pevatron",totalDownloads:377,totalCrossrefCites:0,authors:[null]},{id:"64112",title:"Flavor Physics and Charged Particle",slug:"flavor-physics-and-charged-particle",totalDownloads:475,totalCrossrefCites:0,authors:[null]},{id:"63654",title:"Electrostatic Waves in Magnetized Electron-Positron Plasmas",slug:"electrostatic-waves-in-magnetized-electron-positron-plasmas",totalDownloads:539,totalCrossrefCites:0,authors:[null]},{id:"63057",title:"Biological Effects of Negatively Charged Particle-Dominant Indoor Air Conditions",slug:"biological-effects-of-negatively-charged-particle-dominant-indoor-air-conditions",totalDownloads:386,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"194667",firstName:"Marijana",lastName:"Francetic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/194667/images/4752_n.jpg",email:"marijana@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6861",title:"Plasmonics",subtitle:null,isOpenForSubmission:!1,hash:"e33a5b5eaffb8edd2de62ce2a21486ea",slug:"plasmonics",bookSignature:"Tatjana Gric",coverURL:"https://cdn.intechopen.com/books/images_new/6861.jpg",editedByType:"Edited by",editors:[{id:"212653",title:"Prof.",name:"Tatjana",surname:"Gric",slug:"tatjana-gric",fullName:"Tatjana Gric"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7393",title:"Atmospheric Pressure Plasma",subtitle:"from Diagnostics to Applications",isOpenForSubmission:!1,hash:"1e06b02c1a2008b06370a0ed2f36521c",slug:"atmospheric-pressure-plasma-from-diagnostics-to-applications",bookSignature:"Anton Nikiforov and Zhiqiang Chen",coverURL:"https://cdn.intechopen.com/books/images_new/7393.jpg",editedByType:"Edited by",editors:[{id:"176861",title:"Dr.",name:"Anton",surname:"Nikiforov",slug:"anton-nikiforov",fullName:"Anton Nikiforov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6735",title:"Plasma Science and Technology",subtitle:"Basic Fundamentals and Modern Applications",isOpenForSubmission:!1,hash:"6438c65002222003fa8943fe40ebdb7b",slug:"plasma-science-and-technology-basic-fundamentals-and-modern-applications",bookSignature:"Haikel Jelassi and Djamel Benredjem",coverURL:"https://cdn.intechopen.com/books/images_new/6735.jpg",editedByType:"Edited by",editors:[{id:"233397",title:"Dr.",name:"Haikel",surname:"Jelassi",slug:"haikel-jelassi",fullName:"Haikel Jelassi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8856",title:"Electrostatic Discharge",subtitle:"From Electrical breakdown in Micro-gaps to Nano-generators",isOpenForSubmission:!1,hash:"bc66d347ac7bb73c1ae552a0dcbc976c",slug:"electrostatic-discharge-from-electrical-breakdown-in-micro-gaps-to-nano-generators",bookSignature:"Steven H. Voldman",coverURL:"https://cdn.intechopen.com/books/images_new/8856.jpg",editedByType:"Edited by",editors:[{id:"207997",title:"Dr.",name:"Steven",surname:"Voldman",slug:"steven-voldman",fullName:"Steven Voldman"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8490",title:"Selected Topics in Plasma Physics",subtitle:null,isOpenForSubmission:!1,hash:"0fe936bfad77ae70ad96c46de8b7730d",slug:"selected-topics-in-plasma-physics",bookSignature:"Sukhmander Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8490.jpg",editedByType:"Edited by",editors:[{id:"282807",title:"Dr.",name:"Sukhmander",surname:"Singh",slug:"sukhmander-singh",fullName:"Sukhmander Singh"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"41743",title:"Fetal and Environmental Basis for the Cause of Parkinson’s Disease",doi:"10.5772/54071",slug:"fetal-and-environmental-basis-for-the-cause-of-parkinson-s-disease",body:'
1. Introduction
In Parkinson’s disease (PD) dopamine producing neurons in the substantia nigra, pars compacta of the midbrain and with their axons projecting to the neostriatum degenerate. PD is classified as being familiar when it is known to be the result of genetic abnormalities, and this represents about 5 to 10 percent of all cases. The other cases are idiopathic, represent 90 – 95 percent of all cases of PD and the causes are unknown. The expression of the specific symptoms of idiopathic PD vary among individuals, and may be accompanied with other brain disorders, including Alzheimer’s type dementia, depression and amyotrophic lateral sclerosis (ALS). The common relationship among all of the degenerative disorders is that all are caused by failure of specific functions that are under the control of identifiable neuronal sets, with relatively low population number of larger neurons that usually occur in clusters and with far reaching axons. These neurons are well represented by the nigrostriatal dopamine neurons, and the degeneration of the neuronal set represents the major pathology of PD. They are also represented by the basal nucleus of Meynert acetylcholine neurons with major projections to the cerebral cortex that degenerate in Alzheimer’s disease (AD), and by the upper and lower motor neurons with projections to the brainstem, spinal cord or motor-end plate, that degenerate in ALS. These neuronal sets have specific prenatal and fetal periods for their neurogenesis, migration and axonal extension during which they acquire their specific phenotype that can be influenced by internally and externally derived biochemical forces, including toxins and excesses and deficiency of regulatory factors that will shape the physiological and functional destiny of these neuronal sets. If the influence is of a positive or enhancing nature, the neuronal set will turn out to be functionally superior or with exceptional resilience and longevity and will impart an enhanced character to the individual. However, if the influence is deleterious it will cause harm to the neuronal set and likewise will influence the character of the individual. For the latter, deficiencies may occur at sub-threshold level, may continue in a subliminal and a graded way and may compromise resilience and functional longevity, finally serving as the ‘weak link’ and pairing with deteriorating changes that occur during aging to cause diseases, such as Parkinson’s disease. Whereas the gene has inherent command over the variation of biological forms and some biological outcomes, it is the interacting entities derived from the environment that really sway functional outcomes. Toxins, that may be endogenous or exogenous, represent a set of these environmental factors and quite likely are responsible for the cause of idiopathic PD and other degenerative disorders. So, this chapter will discuss the idea, supported by experimental findings, that the substantia nigra dopamine neurons that deteriorate to the point of causing idiopathic PD were impaired early in life at a sub-threshold level. This occurs during the vulnerable stage of neurogenesis, neuronal development and neuronal migration. The exposures of the substantia nigra dopamine neurons to toxic or harmful influences early in life cause sub-threshold harm, and further exposures to stress during aging cause additive insults that precipitate the symptoms of PD. The early insults, the naturally low population of nigrostriatal neurons, the continuous functional demands placed on the few nigrostriatal DA neurons and the far-reaching nature of the axonal projections render the nigrostriatal DA neurons vulnerable. The high content of cytoskeleton and their kinases seen as pathological markers for various degenerative disorders (McGee and Steele, 2011) indicate that axonal damage to far-reaching neurons is a preeminent occurrence in PD.
2. Major symptoms and the proposed causes for Parkinson’s disease
The major clinical symptoms of Parkinson’s disease (PD), an age-related disorder, are resting tremors, hypokinesia, rigidity and postural instability (Tetriakoff, 1919: Foix and Nicolesco, 1925) caused by the degeneration of the nigrostriatal (NS) dopaminergic pathway and the depletion of dopamine (DA) (Greenfield and Bosanquet, 1953; Hornykiewicz, 1966). The pathological features include extensive (about 70% or more) loss of dopaminergic neurons in the pars compacta of the substantia nigra, the presence of inter-cytoplasmic inclusions known as Lewy’s bodies and gliosis. It was reported also that norepinephrine (NE) (Erhinger and Hornykiewicz, 1960) and serotonin (5-HT) Bernheimer et al., 1961) levels are decreased and that acetylcholine neurotransmission (Yahr, 1968) is increased. A small population of PD cases is caused by genetic abnormalities, involving alpha–synuclein (Polymeropoulos et al, 1997; Papadimitrior et al, 1999 and Kruger et al,1998, Dauer et al, 2002), ubiquitin (Leroy et al, 1998) and apolipoprotein E (APOE), (Kruger et al, 1999). Changes in chromosome 2p13 (Gasser et al, 1998), cyp2D6 (Kruger et al, 1999; Christensen et al, 1998; Kosel et al, 1996; Bon et al, 1999, Sabbagh et al, 1999) as well as mitochondria tRNA (A4336G) (Epensperger et al, 1997) have also been reported. The mutation of the parkin gene is closely associated with juvenile PD (Kitada et al, 1998), which has about eight variants (Lansbury and Brice, 2002). It should be noted however, that multiple other PD cases have been screened and they did not harbor mutations (Giasson et al, 2000), but gene mutations may serve as vulnerable markers, superimposed by environmental factors and age-related wear-and–tear. The root-cause of idiopathic PD is unknown, but various factors are implicated, including the oxidation of dopamine, free radical-mediated oxidative injury, mitochondrial abnormalities, excitotoxins, over exposure to manganese (Chu et al, 1995; Hochberg et al, 1996) and carbon monoxide, the intake of beta-methylaminoalanine (Spencer, 1987), benzyl-tetra-hydroisoquinolines and tetra-hydroprotoberines (Caparros-Lefebvre and Steele, 2005), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Davis et al, 1979), methanol (Guggenheim et al, 1971). As well as the potent methylating agent, methylazoxymethanol (Ince and Codd, 2005) and excess methylation via high utilization of the endogenous S-adenosyl-L- methionine in the brain (Charlton and Way, 1978; Charlton et al, 1992; Charlton and Mack, 1994).
2.1. Aberrations in non-basal ganglia systems.
In PD the basal ganglia is the primary affected structure, but lesions have been identified in the locus ceruleus (Selby, 1968; Alvord et al, 1974), the hypothalamus (Jagar and Bethlem, 1969; Ohama and Ikuta, 1976; Langston and Forno, 1978), the dorsal motor nucleus of vagus (Eadie, 1963; Vanderhaegen et al 1970), the sympathetic ganglia (Jagar and Bethlem, 1960; Vanderhaeghen et al., 1970; Rajput and Rozdilsky, 1970 and Forno and Norvill, 1976) and in the adrenal medulla (Jager, 1969) as well. Furthermore, Lewy’s bodies, the standard marker for PD, have been seen in the cerebral cortex, anterior thalamus, hypothalamus, amygdala, basal forebrain, dorsal motor nucleus of vagus, adrenal medulla and locus ceruleus. The clearly un-circumscribed localization of lesions in the patients or victims of PD means that the changes or the incidents that cause the dopaminergic cell loss in the nigrostriatal system may not specifically target the basal ganglia, but instead the nigrostriatal dopaminergic neurons may be more vulnerable or sensitive. In other words, the factors that are involved in the cause of, at least, some cases of PD may also cause harm to other cell populations, but the basal ganglia neurons are more vulnerable and will die when other neuronal sets remain alive and function normally. This means that a state of vulnerability or sensitization may exists for PD and that the occurrence of damage to other neuronal pool may help to explain the variation in the expression of the PD syndrome.
3. The fetal basis hypothesis for Parkinson’s disease.
PD is age-related but a large percentage of the older population does not suffer from the disorder, although aging is accompanied with pronounced and progressing reduction in motor and other functions. The age-dependent increase in the frequency of essential tremor (Elble 1995; Koller and Huber, 1989), the occurrence of kyphotic posture, diminished arm swing, shorter strides (Murray et al, 1969; Elble et al, 1992; Elble et al, 1991, bradykinesia (Waite et al, 1996) and slowed reaction time (Weiss 1965; Welford, 1977) are signs found to be associated with aging, but the abnormalities are distinguishable from the changes that occur in PD. This suggests that, during normal aging and as a rule, the nigrostriatal DA neurons do not deteriorate to the point of causing PD. Therefore, it is very possible that for PD symptoms to be expressed in the aged, some primary changes that render the nigrostriatal DA neurons vulnerable occur during the earlier life of the PD patients and serve as the underpinning for the deleterious age-related changes that normally occur. So, the functional age-related changes pair with the early predispositions to precipitate the symptoms of PD. Furthermore, there is the high probability that the causes of the vulnerability that occur early in life are based on chance and occur during a critical period when nigrostriatal dopamine neurons are structurally responsive to endogenous and exogenous toxic type of interventions.
3.1. Chance encounter of the nigrostriatal neurons with harmful factors.
It is proposed that chance encounter of factors with the NS DA neurons at critical times during their development eventually shape the long-term outcome of the neuronal pool. If the encounter decreases the longevity of the neurons idiopathic PD will occur. This will underlie the sporadic feature of idiopathic PD, and the nature of the early encounter will determine the pathological characteristics. So, the cluster of PD cases caused by the outbreak of the epidemic encephalitis lethargic in 1919 that killed about one million people worldwide and left millions more ‘frozen’ with the symptoms of PD and which decline rapidly after 1925 (Ravenholt et al, 1982) represent a special but a typical set of parkinsonism. The Guam Parkinson’s dementia complex (PDC)-amyotrophic lateral sclerosis (ALS) syndrome proposed to be caused by the toxins contained in flour prepared from the cycad plant (Spencer et al, 1987) suggests a syndrome that is caused by long–term exposures that target the nigrostriatal neurons, motor neurons and basal nucleus of Meynert acetlycholinergic neurons. In these cases the diversity in the character of the syndrome is a reflection of the neuronal sets that were harmed. So, the individuals that develop idiopathic Parkinson\'s disease, and likely other neurodegenerative disorders, were marked early in life for the disorder. The early process may be synonymous to natural selection that occurs by chance, and helps to define the variation of phenotypes among a population. In the case of PD, the variation may be defined by the magnitude of the reduction in the number of nigrostriatal dopaminergic neurons, and/or deficiencies in the metabolic capability or resilience of the neurons. Therefore, the nigrostriatal DA neurons of the PD patients may have experienced early exposure to environmental, nutritional and/or metabolic toxic interventions. This early exposures may result in DA neurons that lack the reserve capacity to survive during the natural life of the individual, but they function at a level of output that is above the threshold at which the symptoms of PD occur (pre-threshold). During the progression of time or during aging, however, subtle but accumulative changes occur that further damage the nigrostriatal DA neurons and the additive effects precipitate PD-like symptoms. Thus, the fetal basis hypothesis proposes that by chance early interventions render the nigrostriatal neurons sensitive, susceptible or vulnerable, characteristics that enable changes involving the wear-and-tear of living or the exposure to toxins or traumatic events later in life to take a toll on the vulnerable NS neurons and cause PD.
3.2. High workload may explain the vulnerability of the nigrostriatal neurons.
The normal population of nigrostriatal pigmented neurons is relatively low, showing a mean value of 163,238 ± 42,372 in normal human (Ma et al, 1997). The relatively low population number of the nigrostriatal neurons and the high workload placed on these specialized cells play a role in their metabolic durability. This relationship may help to explain the rapid decline in the ability to effectively execute rapid and skillful movement-related skills as a function of aging. This is evident in the short time that a competitive athlete can maintain his or her exceptional ability. A 100-meter runner, for example, is normally competitive for only one or two olympic game and skillful ballet dancers are young people. Even the ability to play the game of golf requires skills that deteriorate to non-competitiveness by the time the athlete reaches early middle age. So, even under normal living condition the nigrostriatal neurons are under moment-by-moment demands by the motor and other functions that they control, and their capability naturally deteriorates in time. The demands placed on these neurons by muscles, for example, are continuously occurring, even during sleep, since skeletal muscle activities are maintained for limb and eye movements. Demands on the nigrostriatal neurons are continuous during regular activities and increased during stress-related physical activities, so, these neurons never rest, unlike neurons that control functions such as hearing, vision and cognition that are at rest at least during sleep. Therefore, while other neuronal sets with less stressful functions and without experiencing an early assault will age at a regular rate, the functional stress imposed on already susceptible dopamine neurons, during the process of living, will cause them to deteriorate at a fast rate to below the threshold that maintains normal functions. This means, therefore, that the prenatal exposure hypothesis will explain cases of juvenile PD that occur at about the age of forty years, in patients that are functionally normal high into the thirties. So, early markers for juvenile PD that are known to be caused by genetic abnormalities, likely exist long before the occurrence of the PD symptoms. The early markers may exist as subtle but serious sub-threshold genetic nigrostriatal abnormality that is below the threshold at which PD symptoms are expressed. So, as compared to idiopathic PD, that has its onset about in the sixth decade, juvenile PD, because of it more serious early impairments, requires a shorter duration of time before the added stress induces threshold level nigrostriatal damage. The overall analogy, therefore, means that at least two stages or two sets of factors or groups of factors are involved in PD:
The first stage: the predisposing/sensitization/susceptible/vulnerable stage.
The second stage: the inducing/precipitating/superimposing stage.
Again, the first stage is defined by subtle or sub-threshold level of adverse changes that start early in life and form the weak link for the second stage, defined by stressful events occurring later in life and coupled with the first stage to cause the expression of the disease symptoms. It should be noted that normal functional and age-related existence may cause enough stress to produce the ‘added-on’ second stage damage to the nigrostriatal neurons in individuals with early stage predisposition.
4. The predisposing, sensitization, susceptible or vulnerable stage of the hypothesis
Normally, immature neurons or neuroblast are subject to chemical and mechanical influences that cause them to migrate to various locations in the nervous system, to extend axonal and dendritic processes toward other cells and then to make and break synaptic connections with these cells before a final pattern of branching and connections are established (Levitan and Kaczmarek, 2002). Moreover, factors released by other cells influence the type of neurotransmitter the neuron will synthesize and the specific type and mixture of receptor, ion channels and other proteins that determine the characteristics of the fully differentiated neurons (Levitan and Kaczmarek, 2002). Along with or besides the normal pattern of development that occur, the differentiating and young neurons may be subjected to toxic and interfering influences that shape them for life. There could be failure in the normal process of apoptosis, that acts via cytochrome c, caspase 9, caspase 3 and other cellular constituents, to cause cellular pruning and to allow the remaining neurons to survive and to be properly organized.
In general, brain neurons are known to be susceptible or vulnerable to insults during prenatal and the early postnatal stage of the life of the individual. This is the basic reasons for the practice of protecting the pregnant mother, new born and young children from chemical and other potentially harmful exposures. For the midbrain dopaminergic system, the most susceptible time is likely to be the period of neurogenesis, proliferation and migration of the cells to produce the nigrostriatal dopaminergic phenotype. These midbrain dopamine neurons are generated early during development, first in the midbrain-hindbrain junction (Voorn et al, 1988), and they migrated radially to their final position in the ventral midbrain to form the substantia nigra, the ventral tegmental area and the retrorubal nuclei (Perrone-Capano and di Porzio 1996). Tyrosine hydroxylase (TH) immunoreactivity is used to identify those dopamine tegmental neurons, and the first appearance of the TH marker is regarded as the birth of the tegmental cells, which occurs on embryonic day 9 for the mouse. The periods close to the birth of these neurons are likely to be a very critical window through which the environment causes long-term changes to the cells and to the motor performance of the organism. In fact, it is these types of manipulations that may be relevant in causing diseases and in enhancing special features related to the functions of the basal ganglia, and they will have effects similar to natural selection and imprinting.
The signal for the differentiation of the NS DA neurons is through a protein called the sonic hedgehog (SHH). The amino-terminal product is the inductive moiety. SHH is produced by the floor plate cells and induces the dopaminergic phenotype (Hayes, et al., 1995). The signal for the SHH protein can be antagonized by increasing the activity of cyclic AMP-dependent protein kinase A. High activity of cAMP blocked the induction of dopamine neurons (Hayes et al, 1995), therefore it could be reasoned that other molecules, e.g. environmental toxins, that modulate cyclic AMP-dependent protein kinase A will interfere with cellular differentiation and migration of these emerging DA neurons. Biomolecules may also affect the metabolic and structural components of the emerging DA neurons, resulting in different degrees of effects that may be enhancing or detrimental to the functions and longevity of the new born DA neurons. If the modulation enhances the metabolism and functions of the nigrostriatal neurons it is expected that the adult may possess motor features that are superior in functions, and will endure to advance ages. On the other hand if the modulations impair metabolism and functions of the nigrostriatal neurons, it is expected that the adult will possess motor features that fail early in life to produce PD symptoms. So, the severity of the prenatal impairment will dictate the age of onset of PD symptoms. Susceptible type of impairments that are most severe, and do not result in death of the fetus, will be closest to the threshold at which PD symptoms are seen, so patients with early onset or juvenile PD may be endowed with sub-threshold but severely impaired NS system that developed early in life.
In summary, the period for the reorganization of the cellular membranes, organization of the chromatid for cell division, the synthesis of structural proteins, production of sub-systems for neurotransmitter synthesis and storage and the synthesis of molecules for intracellular transport and cell movement make the emerging dopaminergic cells well exposed to interfering factors and incidents. During this transforming cellular period the lack of essential metabolites, exposure to inappropriate metabolites and to exogenous and/or endogenous toxins can interfere with the molecular processes to cause permanent changes to the differentiating and migrating cells, that will reduce the resilience of the cell population. The affected neuronal set will become sensitive, susceptible, predisposed or vulnerable to the “wear-and-tear” of living or to toxic type of interventions that are encountered later in life. So, harmful basal ganglia neuronal changes that occur early in life could set the stage and shape the destiny of the individuals to the development of PD.
The dopamine neurons that are degenerated in PD have as their distinguishing feature long axons that project from the substantia nigra in the midbrain to the neostriatum in the forebrain region. One of the key sub-structures of the axon is cytoskeleton. Since they are involved in major cytoarchitectural changes during the development of the nigrostriatal dopamine neurons, the cytoskeleton and other associated molecules, including the kinases, are prime targets for modifications that will determine the outcome of the nigrostriatal dopaminergic neurons.
4.1. The involvement of cytoskeleton and alpha-synuclein as axonal constituents
The cytoskeleton proteins are important structures in the developmental and maintenance of the basal ganglia dopaminergic neurons. They support cellular shape, axonal and dendritic extensions, trafficking and transportation of macromolecules. More importantly, they allow the neurons to extend their reaches and influences far distances from the soma in the midbrain to the striatum in the forebrain region. So, the cytoskeleton serves to distinguish the new nigrostriatal dopaminergic neurons from the parent parochial cells and is the key components that enable the neurons to be functional; noting that the cell bodies may be correctly in place in the substantia nigra, but they will be non-functional without their far-reaching axons. So, by virtue of their relative cyto-architectural and functional significance, cytoskeleton synthesis and assembling ought to be one of the most vulnerable features affected by agents that interfere with the differentiation and proliferation of the far-reaching nigrostriatal dopaminergic neurons. Accordingly the molecules of the cytoskeleton protein classes, (i) microtubules, (ii) neurofilaments and (iii) microfilaments are seen as prime targets. Their vulnerability may help to explain why key markers of neurodegenerative disorders are mostly insoluble remnants of cytoskeleton protein. Lewy bodies, the major pathological marker for PD are composed principally of neurofilament proteins, alpha synuclein, actin-like protein, microtubules associated protein 2 (MAT 2), microtubules associated protein 5 (MAT 5), syaptophysin, tubulin (Giasson et al, 2000). Lewy bodies are also reactive for cytoskeletal protein kinases, calcium/calmodulin-dependent protein kinase (Iwatsubo et al, 1991), cyclin-dependent kinase 5 (Nakamura et al, 1997) and stress activated protein kinases (Giasson et al, 2000).
The microtubules include the subunits, (i) alpha-tubulin and beta-tubulin and (ii) polymerization regulator proteins that include microtubule associated protein 2 and 5 (MAP2 and MAP5). Microtubules span the length of axon and dendrites, serving as the track for macromolecular transport. They are the major component of mitotic spindle, an organelle that participates in cell division and are of importance in the differentiation of cells to form the nigrostriatal dopaminergic neuronal phenotype. Microtubules also play an important role in cell movement. The subunit, tubulin, synthesized in the cell body is actively transported down the axon, so they are relatively easy target for interfering molecules, such as colchicines. Moreover, the turnover of microtubules requires the polymerization and depolymerization of the molecule. This is a cyclic process that is more stable in mature dendrites and axons but is active in dividing cells, which again is a potential target for molecules, such as colchicines and vinblastine. So, the process that involves polymerization and depolymerization of microtubules is a weak link in the life of a far-reaching neuron during which modifications of a permanent nature can be made.
The neurofilaments are the most abundant fibrillar components of axon (Schwartz, 1991). They include the light (L), medium (M) and heavy (H) molecular weight neurofilament subunit proteins. Neurofilaments are oriented along the length of the axons, are most abundant in axons and are critical for axonal extension, a feature that enables the DA cell bodies in the substantia nigra to extend their axons to the striatum. So, neurofilament proteins form the ‘backbones of the nigrostriatal DA neurons and interference with the protein will likely cause significant and permanent change.
Microfilaments are made up of globular subunits of (i) beta-actin and (ii) gamma-actin. Actin plays a major role in the function of growth cones and in dendritic spines. High concentrations occur in dendritic spines and they are located just underneath the plasmalemma, together with a large number of actin binding proteins, including spectrin-fodrin, ankyrin, talin and actinin. They play key role in motility of growth cone during development, the generation of specialized micro domains on the cell surface and in the formation of presynaptic and postsynaptic morphological specializations. They undergo cycles of polymerization and depolymerization (Kandel, Schwartz and Jessel, 2000).
Alpha-synuclein is also a likely prime target for prenatal toxins. It is a heat stable protein associated with synaptic vesicles and axonal terminals (Withers et al, 1997). It plays important roles in neurotransmission, synaptic organization and neuronal plasticity (George et al, 1995). Alpha-Synuclein is the major building block for the fibrillary component of Lewy’s bodies (Pollannen et al, 1993), the major antigenic component of Lewy’s bodies (Baba et al. 1997; Spillantini et al, 1997) and may be critical for the expression of PD symptoms (van Duinen et al, 1999). It is also a component of the thread-like structures seen in the perikarya of some neurons in the brainstem nuclei of the PD victims (Arima at al, 1998). It has been shown also that the association of alpha-synuclein with membrane promotes alpha synuclein aggregation (Lee et al. 2002) and that alpha-synuclein binds with dopamine transporters (Lee et al. 2001).
The interaction of the cytoskeleton proteins and other proteins of interest has been observed. For example, tubulin seeds the fibrillar form of alpha synuclein (Alim et al, 2002) and parkin has been shown to be a novel tubulin binding protein (Ren et al, 2003). It was also observed that 1-methyl-4-phenylpyridinium (MPP+), the toxic metabolite of MPTP, reduced the synthesis of tubulin in PC12 cell model (Capelletti et al, 1999, Capelletti et al, 2000) and that MPP+ inhibited tubulin polymerization (Capelletti et al, 2001), by specifically binding to tubulin in the microtubule lattice (Capelletti et al, 2005). Antibodies that recognize phosphorylated neurofilamant-M and neurofilaments-H also label Lewy’s bodies, therefore the phosphorylation state of neurofilaments may be important in the formation of Lewy’s bodies (Julien and Mushynski, 1998; Sternberger et al. 1983; Lee et al. 1987).
4.2. There may be a window of vulnerability for nigrostriatal dopamine neuronal sensitization
PD occurs in a relatively small number of the population, which may be so because a relatively short window of time exists during which the nigrostriatal DA neurons of the individual can be easily harmed. Such a window of vulnerability, we believe, is the period of differentiation, neurogenesis and migration of cells to form the nigrostriatal DA neurons, and this period occurs during gestational day 9-11 in mice. As mentioned above, the synthesis and laying down of cytoskeleton and neurotransmitter synthesis, storage, uptake and release capacities are likely the prime time during which the transforming cells are most vulnerable to toxic type of interference and inappropriate levels of metabolites and factors. So, idiopathic PD and some other degenerative disorders may have their origin in the fetus and the vulnerability may occur during pregnancy. This should not be seen as shifting the blame of having PD on pregnancy, but the fact is, pregnancy also produces the life and existence of the individual in the first place. So, the probability of having PD would be proportionate to the duration of the neurogenesis/neuronal development time, the number of pregnancy, the frequency by the individual encounter the toxic factor and the potency of the toxic encounter.
4.3. The susceptible stage may set the age of onset of PD and the severity of PD symptoms
If the rate of change is constant during the precipitating stage, it means that the more severe the sensitization, susceptible or vulnerable stage of affliction is, the earlier will the threshold reached for expressing the symptoms of PD. Thus, the age at which PD occurs may be directly related to the severity of the impairments that occur during the sensitization or the first stage affliction. So, juvenile PD may be marked by basal ganglia that were severely affected or were made less resilience by the changes that occur during the sensitization, susceptible or vulnerable stage of affliction. The individuas whose basal ganglia are less severely affected during the sensitization, susceptible or vulnerable stage may experience a delay in the expression of PD symptoms, since more harm will need to be made during the precipitating stage to reach the threshold at which PD symptoms will be seen. So individuals with the least affected nigrostriatal system during the susceptible stage are those that may live without the experiencing the symptoms of PD. In other words, the severity of the changes that occur during the sensitization, susceptible or vulnerable stage may very well predetermine the age at which PD symptoms will occur and the severity of the symptoms.
4.4. The number of NS DA neurons may also determine the susceptibility to PD
The proposed early exposures of the basal ganglia may reduce the number of NS neurons in a random pattern, among the population, so that the average individual possesses a normal population of, say 120,000 (120K) NS DA neurons and with various fractions of the population having values above and below the 120K. Thus, a bell-shaped frequency distribution pattern will exist, with some individuals represented at the far left of the curve, say with 30K or 25%. The individuals among the population who will most likely develop PD would be those endowed with a low (pre-threshold) population of 30K NS DA neuronal subset and PD will occur following a reduction of merely 6K neurons, to 20% of the mean. This low population number of neurons, similar to the marginally resilience neurons mentioned above, would constitute the 1st stage or the sensitization, susceptible or vulnerable stage, and contributes to the cause of PD. During the wear-and-tear of aging, that involves the reduction of NS DA neurons, individuals with the 30K number of NS DA neurons will be those most likely to develop PD symptoms and also at an early age (juvenile). This analogy could form the basis for the early-onset to late-onset PD cases. It may also explain the PD-like dispositions that are exhibited by the very old, due to the chronic reduction of NS DA neurons. The population at the right of the bell shape curve may be those that live to old ages without basal ganglia impairments.
4.5. The coincidental involvement of other neuronal sets with the NS neuronal changes
When the NS DA neurons are made susceptible during the early stage of life other neuronal groups may also be harmed by the modifying factor(s) and the coincidence will determine the occurrence of other symptoms with the symptoms of PD. The coincidental involvement may occur if the window of exposure or neurogenesis for the basal ganglia DA neurons overlap the period of neurogenesis for other neuronal sets, or the period of exposure to the interfering factor/factors is long enough to overlap the period of neurogenesis of all neuronal sets. If that is the case all the neuronal sets will be harmed by the interfering factor/factors. For example, if the nucleus basilis of Meynert acetylcholinergic neurons and the mesolimbic or mesocortical catecholaminergic neurons are affected, as proposed for the NS DA neurons, these other neuronal sets will be scared early in life and succumb to the wear-and-tear of aging later in life. Such co-incident may explain the comorbidity of Alzheimer-like dementia as well as depression with the occurrence of PD. It is of interest, therefore, that the Guam amyotrophic lateral sclerosis-parkinsonism-dementia that may be caused by toxins from the cycad plant (Spencer, 1987), may involve the early damage to upper motor and lower neurons, NS DA neurons and nucleus basalis of Meynert neurons and that the failure of the neuronal sets later in life precipitates the triage of symptoms. This may involve a longer time for the early exposure, which is reasonable because the toxin in cycad was taken in as food. So, the impairments of various neuronal sets during the stage of neurogenesis and neuronal development may help to explain the variations and complexity of the PD related syndrome.
4.6. Agents that may cause neuronal susceptibility
Parkinson’s disease was described by James Parkinson in 1817, almost two centuries ago. So, if external factors are involved in the cause of PD they were in the environment during those early times and the factors would be widely distributed since the occurrence of idiopathic PD is universal. Moreover, since aging is the key risk factor for having PD, PD can be seen as the outcome of the changes that occur during the wear-and-tear of aging. As mentioned above, the best scenario is that the changes in aging coupled with early events that render the nigrostriatal neurons susceptible. Several agents or conditions may be involved in causing the NS DA neurons to be susceptible because all that is required is for the factor to cause damage to dividing and developing neurons, and for the factors to be available during the critical stage of the birth of the NS DA neuronal phenotype. The deficiency and excesses of otherwise normal metabolites, such as momentary fetal hypoxia during the development of the NS DA neurons may be all that is required to trigger the sensitization, susceptible or vulnerable stage. There may also be excesses of normal metabolites, since high activity of cyclic AMP can block the induction of dopamine neurons (Hayes et al, 1995).
It is highly likely that the susceptible phase occurs over a short period, which may help to explain the relatively low incidence of PD. We have used the toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to model the sensitization stage in the mice (Muthian et al, 2010), so structurally similar agents to MPTP that occur in nature could affect the basal ganglia long before the synthetic MPTP became available as a toxicant. It is proposed, also, that agents such as colchicine and vincristine that have been in use as medicine for over 2000 years could have played a role as a sensitization factor for PD. Colchicine is an alkaloid from the Lily family, including Autumn lily or Colchicum autumnale and of the saffron family, that is still used today, as food coloring and cosmetics. Vincristine is an alkaloid obtained from the periwinkle plant. These two compounds are not known to target the nigrostriatal dopamine neurons, however, they bind to tubulin and prevent the polymerization of tubulin to form microtubules. By doing so, they interfere with cell division and are known to arrest cell division in the metaphase stage. It means that these agents will interfere with the division of the newly proliferating nigrostriatal dopamine neurons if they are administered during the period of neurogenesis. They will also interfere with cellular transport, cell polarization, cell growth and axonal extension that depend on the integrity of cytoskeleton proteins. These features are especially important for a group of cells, such as the basal ganglia DA neurons that require their long axonal reaches to the striatum for their actions and effectiveness. By interfering with the assembling of the microtubules of the cells, colchicines and vincristine and now MPTP, via MPP+, (Capelletti et al, 2005), will also impede and/or retard the new neurons from migrating to their place of destination in the substantia nigra, pars compacta. The phenomenon will also prevent the cells from extending their axons to their targets in the striatum. Since colchicines have been found to abolish retrograde transport in neurons resulting in the withdrawal of presynaptic terminals (Schwartz, 1991), these alkaloids will eventually result in cell death due to the lack of contact or contact inhibition. Today colchicines are used as a research tool and as a drug and the range of their toxicity is well known. Toxins, such as colchicines and vincristine are not disease specific, but they can cause a specific disease outcome based on the timing of their toxic effects to coincide with the vulnerable stage of a cellular substrate that underlie a specific disorder. For example, if a fetus is exposed to colchicines or vinblastine during the period of the neurogenesis and development of cells to produce the nigrostriatal dopaminergic phenotype, these neurons will be selectively harmed, and likely will result in PD later in life. If the effect of the toxin coincides with the birth of the nucleus basalis of Meynert neurons, Alzheimer’s type dementia will occur. However, if the exposure time is extended to overlap both the birth of the nigrostriatal and acetylcholine neuronal sets the final symptoms will show parkinsonism and Alzheimer’s like dementia.
4.7. Testing the prenatal sensitization, susceptibility or vulnerable concept
In studies designed to test the effects of toxin on the development of the midbrain neurons that are destined to become the nigrostriatal phenotype, we administered MPTP during the stage of neurogenesis, proliferation, migration and development of these DA cells. In the mouse, this period occurs during gestation day 9 - 11 and is marked by the appearance and maturation of TH-containing immunoreactive nigrostriatal neurons. The pregnant dams were treated with various dosages of MPTP or with phosphate buffered saline (PBS), as the control. We found that the dams treated with the 20 mg/kg and 30 mg/kg levels of MPTP, amounts that did not caused marked acute toxicity in the dams, caused very low to no full term pregnancy, suggesting that the higher dosage of MPTP may cause the pups to be aborted. For the 10 mg/kg of MPTP, however, the dams delivered normal looking pups, and this dosage was used to test the prenatal effects of MPTP.
4.7.1. Prenatal effects of MPTP on body weight, motor activity, TH and DA.
The outcome showed that the birth weights of pups born to dam that were exposed to prenatal 10 mg/kg of MPTP lagged behind the PBS control, but caught up within 4 weeks (Muthian et al, 2010). This recovery in birth weight and the appearance of the offspring indicated that they were in good physical health. The prenatal exposure to MPTP also reduced motor activity, measured as the total distance travelled, the movement time and the number of movements (Muthian et al, 2010) and Western blot detection showed that the exposure of the pregnant dams to MPTP at G9-11, that targeted the developing nigrostriatal dopamine neurons, reduced striatal tyrosine hydroxylase (TH) protein by 38%. DA and the metabolites of DA were also studied in the brain of the 12 week old C57BL/CJ mouse offspring following the prenatal exposure to10 mg/kg of MPTP or to PBS (Muthian et al, 2010). As shown in table 1, the prenatal exposure to MPTP reduced the concentrations of striatal dopamine (DA), homovanillic acid (HVA) and 3-methoxytyramine (3-MT) by 13.80%, 16.48% and 66.25%, respectively (Muthian et al, 2010). The level of dihydroxyphenylacetic acid (DOPAC) showed a slight increase (table 1).
Dopamine and metabolites (ng/mg protein)
Prenatal Treatments
DA[%]
DOPAC[%]
HVA[%]
3-MT[%]
PBS
157.3 ± 17.30[0.0]
5.2 ± 0.76 [0.0]
18.2 ± 0.80 [0.0]
1.60 ± 0.20 [0.0]
MPTP
135.6 ± 4.80[13.8]
5.9 ± .88 [+13.46]
15.2 ± 0.80[16.48]
0.54 ± 0.12 [66.25]
Table 1.
Effects of prenatal MPTP on striatial DA, DOPAC, HVA and 3-MT. C57BL/6J dams were treated with 10 mg/kg MPTP or with PBS during G8-G12 to target the developing nigrostriatal dopamine neurons in the fetus. The table shows the levels of DA, DOPAC, HVA and 3-MT in the striatum of the 12 weeks old offspring. MPTP reduced DA, HVA and 3-MT, as compared to the values for the PBS group.
Figure 1.
Substantia nigra, compacta of mice showing tyrosine hydroxylase immunoreactivity. The figure shows tyrosine hydroxylase (TH) immunoreactivity (I) in the substantia nigra compacta of a 12 weeks old mouse that was exposed to PBS (left) and one that was exposed to MPTP (right) in utero. The pregnant dam was treated during gestation days 8-12 and TH-I was determined in the 12 weeks old offspring.
Figure 2.
Nissl staining of the substantia nigra of mice exposed to prenatal PBS or MPTP. The Nissl staining highlights the cells (dots) of the substantia nigra, pars compacta. The overall morphology is closely similar, but the cellular composition of the PBS exposed mice are more concentrated within a defined zone in the compacta and with larger cells, as compared to the mice exposed to MPTP in which the smaller cells, especially within the rostro-medial (R-M) zone, are more abundant.
4.7.2. Prenatal MPTP on the in situ TH immunoreactivity in the substantia nigra
Figure 1 shows the effects of the prenatal exposure to MPTP on midbrain TH immunohistochemistry. Polyclonal antibodies against tyrosine hydroxylase (TH) were used to detect the changes that occurred in 12 weeks old mice offspring that were exposed to 10 mg/kg of MPTP, in utero, during G8-12 of the dam’s pregnancy, when the midbrain neurons are developing the tyrosine hydroxylase phenotype. The results show that TH-like immunoreactivity was reduced in the midbrain substantia nigra of a mouse exposed to MPTP. The rostroventral section of the substantia nigra compacta was taken from horizontal slice of the mouse brain. The left section shows the TH immunoreactivity from a mouse offspring that was preexposed to PBS during G8-12 of the pregnant dam. The right section shows the TH inmmunoreactivity of a mouse offspring that was exposed to 10 mg/kg of MPTP during G8-12. The study shows that marked reduction of TH-I occurred in the mouse that was exposed in utero to MPTP (right).
4.7.3. Prenatal effect of MPTP on the Nissl Stained substantia nigra
The effect of prenatal exposure to MPTP on cellular distribution pattern in the substantia nigra, compacta of C57BL/CJ mice is shown in figure 2 as low magnification Nissl stained section of the 12 weeks old mice offspring. The differences in the cellular patterns for the PBS and the MPTP exposed animals were not marked, but cellular pattern seems to occur in the compacta zone for the PBS control as compared to the mouse that was exposed to MPTP, in which more scattered smaller cells can be seen in the medial (M) to rostral (R) zone of the substantia nigra (figure 1). The proportion of neurons to glia cells are unknown and are yet to be determined.
5. The inducing, precipitating or superimposing stage of the hypothesis
PD shares some characteristics with aging and the incidence of PD is higher in the aged individuals, but only a relatively small number of elders (about 0.3%) developed full-blown PD, therefore, since PD is sporadic it would appear that a predisposition exists for the disorder. The individuals that developed PD may have been predisposed or susceptible throughout their lives, and they develop PD symptoms when metabolic changes associated with getting older caused further harms to the nigrostriatal DA neurons and reduced the number of neurons. The precipitating effects may be due to various factors, such as changes that allow molecules that serve normal functions early in life to become toxic via direct or indirect ways, such as the production of toxic byproducts, for example. The exposure to exogenous toxic insults may also occur. This is represented by the outbreak of the 1919 encephalitis lethargic epidemic (Ravenholt et al, 1992) that precipitated PD symptoms among some of those that were affected by the encephalitis virus. Whether the inducing, precipitating or superimposing stage is due to metabolic changes or exposure to toxins, it should be noted that the effects do not have to be specific to cause the expression of the specific symptoms of PD, since the incidence during the first stage marks or sensitizes the nigrostriatal system, accordingly, any toxin or any change that can cause further harm to neurons, even in a general way, will affects those neurons that were made fragile.
DA and Metabolites (ng/mg protein)
Prenatal Exposure.
Postnatal MPTP Challenges (mg/kg)
0 (PBS)
10
20
30 mg/kg
DA
PBS
MPTP 10mg/kg
157.3 ± 17.3 [0.0]
135.6 ± 4.80 [13.80]
141.0 ± 5.50 [10.35]
48.0 ± 7.10 [69.96]
34.5 ± 1.7 [78.06]
28.0 ± 2.0 [82.20]
16.40 ± 2.0 [89.57]
3.95 ± 1.0 [97.49]
DOPAC
PBS
MPTP 10mg/kg
5.2 ± 0.76 [0.0] 5.9 ± 0.88 [+13.46]
6.00 ± 1.00 [15.38] 1.04 ± 0.96 [80.0]
3.3 ± 0.4 [36.53] 0.46 ± 0.58 [91.15]
1.95 ± 0.41 [62.5]
0.41 ± 0.33 [92.11]
HVA
PBS
MPTP 10mg/kg
18.2 ± 0.80 [0.0] 15.2 ± 0.80 [16.48]
17.5 ± 1.00 [3.85] 9.4 ± 0.66 [48.35]
9.84 ± 0.6 [45.93] 8.3 ± 2.1 [54.39]
6.0 ± 0.47 [67.03] 4.7 ± 0.70 [74.17]
3-MT
PBS
MPTP 10mg/kg
1.6 ± 0.20 [0.0]
0.54 ± 0.12 [66.25]
1.2 ± 0.15 [25.0] 0.45 ± 0.11 [65.38)
0.75 ± 12 [53.22]
0.32 ± 0.05 [80.0]
0.54 ± 0.11 [66.25]
0.32 ± 0.06 [80.0]
Table 2.
Postnatal effects of MPTP in mice offspring exposed to in utero MPTP or PBS. Effects of postnatal MPTP (10, 20, 30 mg/kg) on striatal DA, DOPAC, HVA and 3-MT in 12 weeks old mice offspring exposed to prenatal MPTP or PBS. The percent changes based on the normal PBS population levels are enclosed by brackets below the respective concentrations. The results show that postnatal MPTP was more effective in reducing DA and its metabolites in the offspring that were exposed to prenatal MPTP. However, for the 20 and 30 mg/kg doses of MPTP the significance of the postnatal, precipitating concept was masked because those doses of MPTP also markedly reduced DA and its metabolites in the prenatal PBS offspring.
5.1. Testing the inducing, precipitating or superimposing stage
We have shown that MPTP can be used to model the inducing, precipitating or superimposing stage. This was demonstrated in our studies in which we found that the postnatal administration of MPTP to 12 weeks old offspring, that were exposed in utero to MPTP earlier, during the developmental stage of the NS DA neurons, showed dramatically reduced levels of DA and its metabolites, as compared to similar mice that were exposed to the PBS treatment. The magnitude of the changes matches the level seen in PD, when compared with the normal population, or the PBS controls (table 2). The 10 mg/kg dosage of MPTP given to the mice that were exposed to prenatal MPTP caused the most dramatic reduction of DA and its metabolites, as compared to the PBS control (Table 2, column 3 vs. 4 showing values for prenatal PBS vs. prenatal MPTP). The 20 and 30 mg/kg of postnatal MPTP markedly reduced DA in the prenatal exposed MPTP mice, but these dose levels of MPTP also caused dramatic reductions of DA and its metabolites in the prenatal PBS mice, as well, so the differences between the prenatal MPTP and the prenatal PBS were not as dramatic (Fig 2, column 3 vs. 5 and 6 showing values for prenatal PBS vs. pre natal MPTP).
6. Analogy that depicts the two stages of affliction hypothesis
The two stages of affliction hypothesis for PD may be best illustrated by an analogy of a motor vehicle tire that was manufactured with a specific defect due to poor quality steel cords imbedded in the carcass or the body of the tire, during a critical period in the manufacture of the tire. The tire shows all of the characteristics of normal tires, but on exposure to the roadway the frictions that cause normal wear in tires turn out to cause serious failure in the defective tire. An inspection of the failed tire will show specific failure of the steel cords. The subtle imperfection that occurs during the manufacture of the tire may be seen as the sensitization factor that tags the tire for the specific type of failure that occurs under normal usage. In this scenario, such a normal tire usage may constitute the period for the precipitating stage, the tire serves to depict the human brain, the cords depict the nigrostriatal dopamine neurons with their far-reaching axonal projections, and the roadway-frictions represent the wear-and-tear of living that increases as a function of age. The two stages of afflictions or the sensitization-precipitating hypothesis for PD may also explain the discordance for PD in monozygotic twins. The life-long personality difference between monozygotic twins discordant for Parkinson\'s disease suggests that the process responsible for the disorders of PD has its inception early in life (Ward et al, 1983). The developmental personality of the member of the monozygotic twins who developed PD was found to be more introvert but since being an introvert is not usually abnormal within the population, it may be deduced that at least a second factor should be involved in causing the PD in the affected twin. The primary factor could be the early changes that render the nigrostrital DA neurons susceptible and also reflected or coincide with personality difference. The second factor for the disorder expression may be related to the regression in dopamine cells that occurs during aging (see McGree et al 1977).
7. Special cases of PD may involve early-life and multiple neuronal groups
The Guam amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC) may represent an incident of PD in which wide-scale neuronal damage occurred during the sensitization stage, and the wear-and-tear of living or the aberrations associated with aging take their toll later in life. In other words, the nigrostriatal dopaminergic neurons that were impaired during the fetal development degenerate to the threshold level that causes PD symptoms. Above threshold neuronal death also occurred for the nucleus basalis of Meynert acetylcholinergic neurons and cortical neurons involve in memory and cognition and caused the dementia phase of ALS-PDC syndrome (Oyanagi, 2005). The lower and upper motor neurons systems that control skeletal muscle contraction also died to cause the amyotrophic lateral sclerosis phase of the disorder. The theory is based on the report that the ALS-PDC or otherwise PDC-ALS is essentially the convergence of three disorders. Patients with PDC showed the signs of rigidity, tremor and bradykinesia (Oyanagi, 2005), the classical signs of Parkinson’s disease as well as dementia (Oyanagi, 2005), the main sign of Alzheimer’s disease. The ALS phase of the Guam ALS-PDC disorder has been reported to be essentially similar to those of classic ALS. Moreover 5% of the patients with ALS subsequently developed the total clinical symptoms of the ALS-PDC and 38% of the patients with PDC eventually developed the PDC-ALS syndrome (Elizan, et al, 1966; Oyanagi, 2005). So the PDC syndrome may be based on the exposure of the fetus to the cycad toxin during the period of the neurogenesis of both nigrostriatal DA neurons and nucleus basalis neurons. The duration of the toxic exposure of the patients may have been long enough to coincide with the neurogenesis and migration of the nigrostriatal DA neurons as well as the nucleus basalis of Meynert acetylcholinergic neurons. For the ALS patients, it is proposed that the exposure to the prenatal toxin coincides with the birth of upper and lower motor neurons and causing deleterious effects early in life that sensitized them to stress that occurred later in life. The higher 38 percent of patients with ALS may be matching to the longer neurogenesis and proliferation period for the related motor neurons and therefore longer fetal exposure time.
7.1. Proposed fetal basis for the Guam ALS-PDC disorder
The proposition that beta-methylaminoalanine (BMAA), a toxin found in flour produced from the Cycad plant and eaten as food, caused ALS-PDC (Spencer et al, 1987), is of interest. It was also claimed that the basal ganglia symptoms were produced in monkeys fed BMAA (Spencer 1966), but this claim was disputed on the basis that the dosage used was far too high to represent the amounts that are eaten by human (Ince and Codd, 2005; McGree and Steele, 2011), and the disease produced in the monkeys was a classic acute toxicity model (Ince and Codd, 2005), rather than the progressing model of the ALS-PDC seen in the Guam patients. Moreover, the disease occurred in patients who had not used cycad products for many years (Sacks 1998), again suggesting the fetal basis for this ALS-PDC disorder. The risk of ALS-PDC was carried by migrants who had resided on Guam for the first 18 years of life (Ince and Codd, 2005), suggesting that early exposure is important for those who developed the ALS/PDC disorder, and the disorder takes over 35 years to develop, which is a very long time for a metabolic toxin to cause direct toxicity, and this also deviates from the short-term toxic models that have been presented.
It would be surprising that a major toxin consumed as a major source of food by several families would be so limiting in the number of individual within a family who were affected. In other words, if the ALS-PDC syndrome is due to a single-stage bout of toxic exposure, it would be expected that the toxin, which is ingested regularly as food, would affect a larger proportion of the group. So, it is apparently more reasonable to propose that the individuals that developed the ALS-PDC in Guam were exposed during the period of vulnerability of the nigrostriatal dopaminergic neurons, the nucleus basilis of Meynert acetylcholinergic neurons and the upper and lower motor neurons. They bourne the scar of the early exposure that pair with the changes that occur during aging to precipitate the ALS-PDC syndrome later in life. The sensitization-precipitation concept may be true also for the PD-like toxicity caused by MPTP in the later years of the 70s to the 80s. This may be so because not all individuals who were exposed to intravenous MPTP eventually developed full blown PD symptoms. Those that developed the symptoms of PD were probably predisposed with less resilient nigrostriatal neuronal set, and those that were spared had highly resilient nigrostriatal dopaminergic neurons. It means therefore, that most cases of PD may be caused by encounter made during the stage of neurogenesis and development of the nigrostriatal dopamine neurons, and that aging, the key risk factor for PD, precipitates idiopathic PD. The progressive nature of idiopathic PD may be based on the fact that aging is relenting and progressive in its own right.
8. S-adenosyl-L-methionine (SAM): A model precipitating factor for Parkinson’s disease
S-adenosyl-L-methionine (SAM) is presented as a likely precipitating factor for PD. SAM is a naturally occurring and ubiquitous molecule derived from methionine and ATP (Cantoni 1953). It is one of the most reactive and important biochemical (Kotb and Geller, 1993), but its activity seems to be harnessed by the limits and the control placed on its synthesis. SAM is apparently synthesized on demand and rapidly utilized by several enzymes, as the biological methyl donor (Cantoni 1953), for trans-sulfuration reactions and in the synthesis of polyamine (Andres and Cederbaum 2005). As the biological methyl donor, SAM is the co-factor for several methyl transferases, including catechol-O-methyl transferase (COMT) and indole amine methyl transferase. COMT transfers the methyl of SAM to dopamine (DA) to produce 3-methoxytyramine and to norepinephrine (NE) to produce normetaphrene and by doing so SAM terminates the synaptic activities of DA and NE, via irreversible reactions. SAM also serves to methylate N-acetyl-serotonin, via indoleamine methyltransferase to form melatonin and in the process may deplete serotonin (5-HT). These are major metabolic processes since DA, NE and 5-HT are important in synaptic transmission and in behavior (Agnoli et al, 1976) and are reported to be depleted in PD. So, SAM is a highly reactive endogenous molecule.
The injection of SAM into the cerebral ventricle of rodents produced symptoms that are similar or identical to those described for PD, including hypokinesia, rigidity, tremors (Charlton and Way 1978), the loss of DA, loss of striatal and substantia nigra tyrosine hydroxylase (Charlton, 1990; Charlton and Crowell, 1995; Crowell et al, 1993) and loss of neurons in the substantia nigra (Charlton and Mack, 1994).The PD-like changes that occurred following the cerebral ventricular administration of SAM are based on very logical and mechanistic grounds, since SAM reacts avidly with L-dopa and DA and reduced DA. More importantly, the loss of DA is the hallmark of PD disease, and the methylation of DA at the synapse (Axelrod, 1965) terminates the neurotransmitter activity of DA; a process that irreversibly destroys the dopamine molecule by covalently converting it to 3-methoxytyramine. SAM also drives the synthesis of phosphotidylcholine (PTC) (Hirata et al, 1981) that is accompanied with increases in lyso-PTC (Lee and Charlton 2001), a potent membrane damaging surfactant. It has been shown also, that SAM interacted with and methylated DA receptor protein and inhibited DA receptor binding (Lee and Charlton, 2004). In addition, the carboxylmethylation of protein, including DA receptor protein, by SAM, generates methanol (Axelrod and Daly, 1965), formaldehyde and formic acid (Lee et al 2008), reactive byproducts that can cause irreversible and accumulative damaging changes to cells and cellular constituents. Although the biological role of methanol, formaldehyde and formic acid are not viewed with much significance, these molecules are likely to be of primordial origin, helping to shape the destiny of life. They are produced in the body and are extremely reactive. The activity of SAM is also increased during aging (Mays and Borek 1973; Stramentinoli et al, 1977; Gharib et al, 1982; Sellinger et al, 1988), a critical period for cellular attrition and a stage of life during which the symptoms of idiopathic PD are seen. Today SAM is well studied as the major driver of the epigenetic modification of various genes. The biochemical control that SAM exhibited is remarkable on the basis that SAM is the limiting factor for dozens of methyltransferases, so any increase or decrease in the level of SAM serves as a key driving force for most methylation reactions.
8.1. Common markers exist for methylation and parkinsonism
A review of the results from various laboratories, include our own, shows that various biochemical, functional, anatomical and other markers are common to PD and to the methylation process (Table 3). Metabolites and byproducts of SAM, such as N-methyl dopamine, 3,4-dimethoxy-dopamine, N-methylsalsolinol (Maruyama, et al, 1996; Naoi et al, 2002; Matsubara et al, 2002) and harman and norharman (Kuhn, et al, 1996) are elevated in the CSF of PD patients and homocysteine (Lee et al, 2005) may cause PD like toxic changes. In addition, methyl-beta-carboline was reported to cause PD-like changes (Collins, et al. 1992; Gearhart et al, 1997). Furthermore, it has been shown that the tissues of PD patients methylate nicotinamide greatly higher than tissues of the control patients (Willams et al, 1993); and that nicotinamide methylation is proposed to be a key factor in the development of degenerative diseases (Williams and Ramsden, 2005). The enzyme, nicotinamide-N-methyltransferase, that transfers the methyl group from SAM to nicotinamide, was shown to be high in the CSF of PD patients (Aoyama et al, 2001) and N-methyl-nicotinamide was also higher in the brain of PD victims as compared to the control (Williams and Ramsden, 2005). So, as shown, many biological changes seen in PD correspond with the effects of SAM, its enzymes and its metabolites (table 3)
More prevalent Alleviates Aggravates Causes/in PD brain Causes Causes Found in Found in Found in Aggravates Aggravates PD-like effects High in CSF
Yes Yes Yes Yes Yes Yes Yes Yes
Yes Yes Yes Yes
Yes Yes
High activity of SAM Depletes SAM Increased SAM SAM metabolite SAM metabolite Enhances methylation SAM metabolite SAM metabolite SAM metabolite Increased SAM activity Increased SAM activity Increased by SAM SAM is the cofactor
Table 3.
Many biological changes seen in PD correspond with the effects of SAM. The table shows the parallel relationship between changes associated with Parkinson’s disease and with the effects and biochemical activities of S-adenosyl-L-methionine and its metabolites. A one-one relationship is shown in the activities listed.
8.2. Actions and effects that support the role of SAM as a precipitation factor in PD
If a secondary precipitating factor is associated with PD, it would more likely fits as a toxic metabolite that is associated with aging. Such a metabolite would be expected to be very reactive. It would show age-related increases in activity, would have a narrow index of safety so that even slight increases would cause toxic reactions. It should react with normal biochemicals that are critically needed on a moment-by-moment basis for the maintenance of essential functions. Moreover, the metabolite should react with biochemical that are found to be modified during the course of PD, for example, DA that is depleted in PD and which is an avid methyl acceptor. In addition, the mode of reactivity of the metabolite should explain others changes that are related to the degenerative disease process, such as the effective therapy for PD and the development of tolerance to the therapeutic agent. So, an evaluation of S-adenosyl-L-methionine (SAM), the biological methyl donor, based on the above criteria, indicates that it fits the role of a precipitating factor for PD. Again, it is an endogenous molecule, its activity is increased during aging, it is very reactive, it has a narrow index of safety, it controls the metabolism of specific chemicals that are modified in PD, the major drug for PD, which is L-dopa, reacts avidly with SAM and L-dopa, in turn, induced methionine adenosyl transferase, the enzyme that produces SAM (Benson et al, 1993; Zhoa et al, 2001). Moreover, as mentioned above, several SAM-induced changes seem to be associated with the neuronal degeneration and many of the biochemical changes that occur in PD.
8.2.1. Age-dependent increases in SAM-dependent methylation
The activities of SAM, denoted by increases in its synthesis and utilization, are increased during aging. This has been reported as, an age-related increase in methionine-adenosyl transferase, the enzyme that produces SAM, increases of various methyl transferases, and the accumulation in products of SAM-dependent methylation reactions, including homocysteine and adenosine (Mays et al 1973; Stramentinoli et al, 1977; Sellinger et al 1988; Gharib et al 1982). It should be noted that a decrease in the absolute concentration of SAM in rats was reported to be related to aging (Baldessarini and Kopin, 1966) but the reduction was apparently due to increases in the turnover of SAM that also occurred during aging (Stramentinoli et al, 1977).
8.2.2. SAM depletion of biogenicamines may occur in PD
In the presence of catechol-O-methyltransferase and other transferases SAM serves as a cofactor in the methylated metabolism of several biogenic amines, including DA and norepinephrine, by donating its reactive methyl group mainly to receptive hydroxyl of the molecular ring and the nitrogen of the ethylamine side chain (Axelrod, 1965). SAM dependent methylation is the most important mechanism in mammals for the inactivation of catecholamine (Lambrosse et al 1958, Axelrod et al, 1965), consequently SAM is an important factor in controlling the neuronal levels of the biogenic amines. The decreased levels of DA (Hornykiewicz, 1966), norepinephrine (Erhinger and Hornykiewicz, 1960) and serotonin (Bernheimer et al, 1961) observed in PD could be explained by an increase in the methylation of DA, norepinephrine and of N-acetyl-serotonin. The methylation of DA may also explain the increase ratio of homovanillic acid (HVA) to DA (HVA/DA) in PD and the increased level of 3,4-dimethoxyphenylethylamine, the dimethoxy metabolite of DA, that was reported to be contained in the urine of PD patients. More importantly, the DA derived alkaloid, N-methyl-(R)-salsolinol, was shown to occur in the human brain, accumulates in the nigrostriatal system and may play a role in PD (Naoi et al, 2002). An increase SAM-dependent methylation may also help to explain the pharmacology of L-dopa, in treating the symptoms of PD, because L-dopa is not only converted to DA, but it also reacts avidly with SAM, and depletes SAM. SAM dependent regulation of biogenicamines is achieved by methylated catabolism as well as by increasing synthesis, because it has been shown that preincubation with SAM caused activation of tyrosine hydroxylase in the corpus striatum of rats (Mann and Hill, 1983). These and other outcomes suggest that SAM is functioning both intra- and extra-neuronal, therefore its bio-availability at specific sites should be critical in determining the up or down regulation of the activity of biogenicamines. SAM activation of tyrosine hydroxylase (Mann and Hill, 1983) may help to explain the increase in DA turnover that occurs in PD. An increase in the methylation of L-dopa and DA will shunt tyrosine toward the production of L-dopa and L-dopa toward the production of DA, thus, tyrosine will be shunted away from the synthesis of melanin, a process that may help to explain the reduction of melanin in the substantia nigra of PD patients: noting that melanin is a product of tyrosine. Likewise, SAM also methylates phosphotidylethanolamine to produce phosphotidylcholine and phosphotidylcholine, in turn, is metabolized to generates choline molecules for the synthesis of acetylcholine. So, an increase in methylation could conceivable increase the level of acetylcholine and acetylcholinergic activity that occurred in PD, and which may form the basis for the utility of anticholinergic agents in the treatment of PD symptoms.
8.3.3. Mechanisms and selectivity of SAM for the basal ganglia
Conditions that increase the rate of methylation, for example aging (Sellinger et al 1988), may precipitate PD in individuals with susceptible DA neuronal population. In individuals with the normal complement of substantia nigral DA neurons the same level of methylation may represent an age-dependent normal regression of cell population, because the critical cell level that will result in PD would not be reached. Thus, the final effects of an increase in methylation in persons with normal populations of DA neurons would be different degrees of aging. Besides aging, other factors that facilitate an increase in methylation ought to be emplaced. It turns out that (i) the chemistry of the basal ganglia, (ii) the anatomical and physical state of the basal ganglia and (iii) the functions that are controlled by the basal ganglia coexist in a cooperative way to facilitate the uniqueness of SAM as the methyl donor and as a putative precipitating factor for PD.
For the chemistry of the basal ganglia, the methylation of DA and the methylation of phosphotidylethanolamine may be of major importance. First, the methylation of DA by SAM depletes DA at the synaptic cleft. This is an irreversible reaction that also generates 3-methoxytyramine, a metabolite that has been shown to competes with DA for its receptor binding (Charlton and Crowell, 2000). So, the reaction of SAM with DA and the generation of an competing metabolite will not only depletes DA, but also will interfere with the binding of DA to its receptors, which is consistent with a SAM-induced dopaminolytic state. SAM also methylates phosphotidylethanolamine to produce phosphotidylcholine, and, as mentioned above, to produce choline for the synthesis of acetylcholine. In addition, phosphotidylcholine is readily hydrolyzed to form the toxic surfactant, lyso-phosphotidylcholine (Lee et al, 2001; 2005). The reaction is also relevant on the basis that lyso-phosphotidylcholine is a potent surface-active agent that will damage cellular vesicles and nerve ending, and can contribute to the progression of the degeneration that occurs in PD. The biochemical peculiarity of the basal ganglia, therefore, includes the fact that the neostriatum contains large quantities of L-dopa, DA and norepinephine that are avid methyl acceptors, so they utilize high levels of SAM. SAM is also required for the methylation of phospholipid and the synthesis of acetylcholine, so the neostriatum is a high utility site of SAM, or a chemical ’sink’ for, SAM.
The precise functions of the basal ganglia marked it for visible impairments. The basal ganglia dopaminergic system controls precise articulation of the hands, finger, lips and whole body to support emotional expression, gesture and feelings. Therefore in the awaking human the neostriatum is constantly under stress to maintain the delicately balanced and fine-tuned processes that it controls, so slight impairments of the nigrostriatal system will upset the postural balances and precise muscle regulations and will cause visible impairments, that are seen as PD, even when such a degree of impairment or degeneration would not be physically obvious if occurred in other systems. SAM-related age-related changes may also affect vision and hearing, but the changes in the quality of life are not of the same magnitude as seen when the basal ganglia is impacted.
The anatomical or physically states of the basal ganglia also make this structure very accommodative to the effects of an increase in SAM, because SAM, which is very water soluble, will accumulate in the cerebral spinal fluid (CSF). In the CSF SAM is in close proximity to the neostriatum, which courses along and protruded into the lateral ventricle and contains the sensitive dopamine nerve terminals. Studies have shown that the administration of SAM into the lateral ventricle damaged the delicate ependymal cell barrier that separates the CSF from the caudate nucleus neuronal environment. By doing so, SAM gained access to the neostriatum, where it can deplete DA (Crowell et al, 1993), can methylate phospholipids (Lee and Charlton 2001) and DA receptor protein (Lee et al, 2004) and generate methanol, formaldehyde and formic acid (Lee et al, 2008) that are damaging to nigrostriatal dopamine nerve endings. These metabolites, especially formaldehyde will result in permanent changes to the dopaminergic neurons. Interestingly, in a more recent study, we found that the co-administration of a retrograde neuronal tracer with SAM into the lateral ventricle caused the labeling of cells in the substantia nigra, indicating that molecules placed in the lateral ventricle can gain access to the caudate nucleus DA nerve endings.
The increase in methylation can caused other significant changes, for example, the utilization of SAM imposes a great demand on ATP, because for every mole of DA methylated at the 3-OH and 4-OH positions 2 moles of ATP are utilized to replenish the utilized SAM and for every mole of phosphotidylethanolamine that is methylated to form phosphotidylcholine 3 mole of ATP are required to replenish SAM. Furthermore, the carboxyl methylation of protein by SAM will increase the isoprenylation of the proteins and each farnesyl molecule that is utilized requires 3 moles of ATP for its synthesis and each geranyl-geranyl requires 4 moles of ATP for its synthesis. So, an increased methylation will require increased production of ATP, which increases oxygen utilization and the probability of generating reactive oxygen species. In addition, 1 mole of potentially toxic homocysteine and 1 mole of adenosine may be produced for every mole of SAM utilized, and huge amounts of adenosine will be produced as a result of the metabolism of ATP to replenish SAM. The depletion of ATP may be relevant in this connection, because inhibition of mitochondrial oxidation and ATP reduction are proposed to be involved in the actions of MPTP or MPP+. It is well understood that SAM-dependent methylation is a normal physiological process, so for one to imagine how SAM may be involved in PD it should be understood that the symptoms of PD are due directly to dopamine biochemical deficiency and indirectly to the neuronal degeneration. This is so because drugs, such as L-dopa and DA receptor agonists relieve the tremors and other symptoms of PD, in spite of the fact that the permanent neuronal degeneration remains. Furthermore, the syndrome of PD wax-and-wane, which, cannot be explained by the existence of a permanent degenerated neuronal set. These examples show that the symptoms of PD, such as tremor and freezing, are striatal biochemical deficiency symptoms, due to the loss of dopamine as a result of the neuronal degeneration.
In spite of the doubts about the methylation concept, it is of interest that most of the other hypotheses concerning the genesis of PD cannot explain many of the changes that are seen in PD. One-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxyl-dopamine (6-OHDA) serve as the most important chemical models for PD. Their efficacies are mostly related to the targeted nigrostriatal cell death, but these agents do not cause changes that reflect the whole spectrum of PD symptoms. For example, MPTP does not cause PD-like symptoms in the rat, which also has a nigrostriatal dopamine system, but SAM does (Crowell et al, 1992; Charlton and Mack, 1994).
9. Conclusion
The abberrations that cause the nigrostriatal degeneration that result in Parkinson’s disease are unknown. Since about 90-95% of all cases of PD are not due to genetic changes, it means that the environment plays a major role in the cause of PD. The environment is not restricted to the toxins that might be involved, but includes the biochemical melieu that the nigrostriatal cells encounter from their origin to the outcome that causes them for die. So, the encounter with inappropriate biochemicals and inappropriate levels of the appropriate biochemicals may occur, and the outcome will vary and will be restricted to the nigrostriatal neurons or will involve other neuronal sets. This type of encounter will produce the syndrome that are eventually expressed and may include symptoms related to nigrostriatal damage only, but may be accompanied with other syndrome. So the expression of symptoms in addition to the classical PD other symptoms, suggests that nigrostriatal neuronal impairment may be accompanied with the impairments of other neuronal groups. These may include the basal nucleus of Meynert acetylcholinergic neurons that are degenerated in Alzheimer’s disease (AD) and the upper and lower motor neurons that are involved in the cause of amyotrophic lateral sclerosis (ALS). So, the existence of the Guam amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC, suggests that the factors that cause PD are not specific for the nigrostriatal neurons, but will affect other neuronal groups, as well.
For PD, it is suggested that the nigrostriatal dopaminergic neurons were exposed by chance encounter during a vulnerable stage of development of the neuronal set. Since aging is the key risk factor for PD, it also means that at least two stages of afflictions are involved in the cause of PD. Evidence and circumstance suggest that the first stage occurs in utero during the neurogenesis and development of cells to form the substantia nigra dopaminergic phenotype. The neuronal set is harmed in a subtle way that does not cause visual symptoms, but the sub-threshold effects weakened the resilience of the neurons so that the stress encounter during the course of living causes further harm to the already affected neurons and precipitates the symptoms of PD. So, the first impairment may occur during the neurogenesis and development of the nigrostriatal dopamine neurons by inappropriate levels of regulatory molecules or by toxins. An increased activity of cyclic-AMP-dependent protein kinase A, for example, may antagonize the signal for sonic hedgehog protein and blocked the induction of dopamine neurons (Hayes et al, 1995). The exposure to alkaloids, such as colchicine or vinblastine may also occur, and these alkaloids may interfere with the development of the cytoskeleton, with long-term and sub-threshold levels of effects. The stress of aging that causes globally deteriorating change will then take a toll on these low resilient neuronal sets to precipitate the symptoms of PD. The prenatal and postnatal effects can also explain the occurrence of juvenile PD, which would involve the substantia nigral dopamine neurons that were affected in ways that make them less resilient and more sensitive to age-related stress, so a short course of living would be enough to precipitate the symptoms of PD in the young individual. The Guam ALS-PDC cases are proposed to be caused by the exposure to the Cycad toxin during the neurogenesis and development of the nigrostriatal dopamine neurons, the basal neucleus of Meynert acetylcholinergic neurons and upper and lower motor neurons. The exposure caused subthreshold harms to those neuronal sets and they failed before other major groups of neurons during the course of aging.
The hypothesis that neurodegenerative disorders, such as PD and others have their origin in the womb is in line with normal physiology, since the lives of all mammals have their origin in the womb. If the hypothesis is tested to be true further investigation will identify the specific agents and/or the mechanisms that may be involved in the sensitization stage and measures could be adapted to protect the vulnerable neuronal groups during critical stages of fetal development.
Acknowledgement
The author wishes to thank Gladson Muthian, Ph.D., Lemuel Dent, MD., MS; Veronica Mackay, B.S., Marquitta Smith, B.S. and Brenya Griffin, B.S. for their support of science in our laboratory. Supported by NIH NINDS R21NS049623, RO1xlink8432 and R01NS31177 and Bernard Crowell, Jr. MD, Ph.D., Little Rock AR.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/41743.pdf",chapterXML:"https://mts.intechopen.com/source/xml/41743.xml",downloadPdfUrl:"/chapter/pdf-download/41743",previewPdfUrl:"/chapter/pdf-preview/41743",totalDownloads:2239,totalViews:156,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"December 1st 2011",dateReviewed:"October 3rd 2012",datePrePublished:null,datePublished:"January 2nd 2013",dateFinished:"December 27th 2012",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/41743",risUrl:"/chapter/ris/41743",book:{slug:"basal-ganglia-an-integrative-view"},signatures:"Clivel G. Charlton",authors:[{id:"145066",title:"Dr.",name:"Clivel",middleName:null,surname:"Charlton",fullName:"Clivel Charlton",slug:"clivel-charlton",email:"ccharlton@mmc.edu",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Major symptoms and the proposed causes for Parkinson’s disease",level:"1"},{id:"sec_2_2",title:"2.1. Aberrations in non-basal ganglia systems.",level:"2"},{id:"sec_4",title:"3. The fetal basis hypothesis for Parkinson’s disease. ",level:"1"},{id:"sec_4_2",title:"3.1. Chance encounter of the nigrostriatal neurons with harmful factors. ",level:"2"},{id:"sec_5_2",title:"3.2. High workload may explain the vulnerability of the nigrostriatal neurons.",level:"2"},{id:"sec_7",title:"4. The predisposing, sensitization, susceptible or vulnerable stage of the hypothesis ",level:"1"},{id:"sec_7_2",title:"4.1. The involvement of cytoskeleton and alpha-synuclein as axonal constituents",level:"2"},{id:"sec_8_2",title:"4.2. There may be a window of vulnerability for nigrostriatal dopamine neuronal sensitization",level:"2"},{id:"sec_9_2",title:"4.3. The susceptible stage may set the age of onset of PD and the severity of PD symptoms",level:"2"},{id:"sec_10_2",title:"4.4. The number of NS DA neurons may also determine the susceptibility to PD",level:"2"},{id:"sec_11_2",title:"4.5. The coincidental involvement of other neuronal sets with the NS neuronal changes",level:"2"},{id:"sec_12_2",title:"4.6. Agents that may cause neuronal susceptibility",level:"2"},{id:"sec_13_2",title:"4.7. Testing the prenatal sensitization, susceptibility or vulnerable concept",level:"2"},{id:"sec_13_3",title:"Table 1.",level:"3"},{id:"sec_14_3",title:"4.7.2. Prenatal MPTP on the in situ TH immunoreactivity in the substantia nigra",level:"3"},{id:"sec_15_3",title:"4.7.3. Prenatal effect of MPTP on the Nissl Stained substantia nigra",level:"3"},{id:"sec_18",title:"5. The inducing, precipitating or superimposing stage of the hypothesis",level:"1"},{id:"sec_18_2",title:"5.1. Testing the inducing, precipitating or superimposing stage",level:"2"},{id:"sec_20",title:"6. Analogy that depicts the two stages of affliction hypothesis",level:"1"},{id:"sec_21",title:"7. Special cases of PD may involve early-life and multiple neuronal groups",level:"1"},{id:"sec_21_2",title:"7.1. Proposed fetal basis for the Guam ALS-PDC disorder",level:"2"},{id:"sec_23",title:"8. S-adenosyl-L-methionine (SAM): A model precipitating factor for Parkinson’s disease",level:"1"},{id:"sec_23_2",title:"8.1. Common markers exist for methylation and parkinsonism",level:"2"},{id:"sec_24_2",title:"8.2. Actions and effects that support the role of SAM as a precipitation factor in PD",level:"2"},{id:"sec_24_3",title:"8.2.1. Age-dependent increases in SAM-dependent methylation",level:"3"},{id:"sec_25_3",title:"8.2.2. SAM depletion of biogenicamines may occur in PD",level:"3"},{id:"sec_26_3",title:"8.3.3. Mechanisms and selectivity of SAM for the basal ganglia",level:"3"},{id:"sec_29",title:"9. Conclusion",level:"1"},{id:"sec_29_2",title:"Acknowledgement",level:"2"}],chapterReferences:[{id:"B1",body:'AgnoliAAndreoliVCasacchiaMand CerboREffect of S-adenosyl-L- methionione (SAM-e) upon depressive symptoms. J. Psychiar. Res. 1319764354'},{id:"B2",body:'AlimM. AHossainM. SArimaKTakedaKIzumiyamaYNakamuraMKajiHShinodaTHisanagaSUedaKTubulin seeds alpha-synuclein fibril formation.J. Biol. Chem. 2772002321122117'},{id:"B3",body:'Alvord JrEC., Forno, LS., Kusske, JA., Jaufman, RJ., Rhodes, JS., Goetowski, CR. The pathology of parkinsonism: Comparison of degeneration in cerebral cortex and brainstem. Adv. Neurol. 51974175193'},{id:"B4",body:'AndresAand CederbaumA. IAntioxidant properties of S-adenosyl-L-methionine in Fe2+-initiated oxidants. Free Radical Biology & Med. 3620041013031316'},{id:"B5",body:'AoyamaKMatsubaraKKondaMMurakawaYSunoMYamashitaSYamaguchiSand KobayashiSNicotinamide-N-methyl transferase is higher in the lumbar cerebrospinal fluid of patients with Parkinson’s disease. Neurosci. Lett. 29820017880'},{id:"B6",body:'ArimaKUedaKSunoharaNet alImmunoelectron-microscope demonstration of NACP/alpha-synuclein-epitopes on the filamentous component of Lewy bodies in Parkinson’s disease and in dementia with Lewy’s bodies. Brain Res. 808199893100'},{id:"B7",body:'AxelrodJand DalyJPituitary gland: Enzyme formation of methanol from S-adenosyl- methionine. Science 1501965892893'},{id:"B8",body:'AxelrodJThe metabolism, storage and release of catecholamine. Recent Prog. In Hormone Res. 211965597619'},{id:"B9",body:'BabaMNakajoSTuPet alAggregation of alpha-synuclein in Lewy’s bodies of sporadic Parkinson’s disease and dementia with Lewy’s bodies. Am. J. Pathol. 1521997879884'},{id:"B10",body:'BaldessariniR. Jand Kopin, IJ. S-adenosylmethionine in brain and other tissues.J. Neurochem. 131966769777'},{id:"B11",body:'BensonRCrowellBHillBDoonquahKand CharltonCThe effects of L-dopa on he activity of methionine adenosyltransferase: Relevance to L-dopa therapy and olerance. Neurochem. Res. 1819933325330'},{id:"B12",body:'BernheimerHBirkmayerWand HornykiewiczOVerteilung des 5-hydroxytamin serotonin) im gehirn des menschen und sein verhaltan bei patienten mit Parkinson syndrom. Klin. Ther. Wschr. 39105610591961'},{id:"B13",body:'BonM. AJansenE. NDevosR. Aand VermesICorrelates of Parkinson disease: Apolipoprotein-E and cytochrome 450D6 genetic polymorphism. Neurosci. Lett. 266(2):149-151, 1999'},{id:"B14",body:'CantoniG. L. S-a. d. e. n. o. s. y. l. m. e. t. h. i. o. n. i. n. ea new intermediate formed enzymatically from L- methionine and adenosine-triphosphate. J. Biol. Chem. 2041953403416'},{id:"B15",body:'CapellettiGMaggioniM. Gand MaciRInfluence of MPP+ on the state of tubulin polymerization in NGF-differentiated PC12 cells. J. Neurosci. Res. 5619992835'},{id:"B16",body:'CapellettiGMaggioniM. Gand MaciRRole of microtubules in the genesis of MPTP neurotoxicity. In: Neurotoxic Factors in Parkinson’s Disease and Related Disorders. Eds: Storch, A. and Collins, MA., 4548Kluwer Academic/Plenum Publishers, New York.'},{id:"B17",body:'CapellettiGPedrottiBMaggioniM. Gand MaciRTubilin polymerization is directly affected by MPP+ in vitro. Cell Biol. Int. 252001981984'},{id:"B18",body:'CapellettiGSurreyTand MaciRThe parkinsonism producing MPP+ affects microtubule dynamics by acting as a destabilizing factor. FEBS Letters 579200547814786'},{id:"B19",body:'CasanovaMDeyoD. Fand HeckH. ACovalent binding of inhaled formaldehyde to DNA in the nasal mucosa of Fisher 344 rats: analysis of formaldehyde and DNA by high performance liquid chromatography and provisional pharmacokinetic nterpretation. Fund. Appl. Toxicol. 121989397417'},{id:"B20",body:'CharltonCand CrowellBStriatal dopamine depletion, tremors, and hypokinesia ollowing the intracranial injection of S-adenosylmethionine. Mol. and Chem. Neuropath. 261995269281'},{id:"B21",body:'CharltonC. GMackJSubstantia nigra degeneration and tyrosine hydroxylase depletion caused by excess S-adenosylmethionine in the rat brain: Support for an excess methylation hypothesis for parkinsonism.Mol. Neurobio. 9199414961'},{id:"B22",body:'CharltonC. Gand CrowellBThe effects of metabolites of DA on locomotor activities and dopamine receptor binding in rats: Relevance to the side effects of L-dopa. Life Sci. 6620002221592171Hormone Res. 21: 597-619, 1965.\n\t\t\t'},{id:"B23",body:'CharltonC. G1990A parallel relationship between Parkinson’s Disease and excess of S-adenosylmethionine-dependent biological methylation in the brain. Basic, Clinical and Therapeutic Aspects of Alzheimer’s and Parkinson’s Disease. 1Cpt. 65. Plenum Press. N.Y.'},{id:"B24",body:'CharltonC. Gand WayE. LTremor induced by S-adenosy1-L- methionine: possible relation to L-dopa effects. J. Pharm. Pharmacol. 301978819820'},{id:"B25",body:'CharltonC. Gand CrowellBStriatal dopamine depletion, tremors and hypokinesia following the intracranial injection of S-adenosylmethionine: A possible role for hypermethylation on Parkinsonism.Mol. and Chem. Neuropath. 261995269284'},{id:"B26",body:'CharltonC. G1-Methyl-4-phenylpyridinium (MPP+) but not 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) serves as methyl donor for dopamine: A possible mechanism of action.J. Geriat. Psychia. Neurol. 519922114118'},{id:"B27",body:'ChristensenDIdanpann-heikkilaJ. JGuilgaudGand KayserVThe antinociceptive effects of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)-HA966, in a rat model of peripheral neuropathy. Br. J. Pharmacol. 1251998816411650'},{id:"B28",body:'ChuNHochbergFCalneDand OlanowCNeurotoxicology of manganese. In: Handbook of Neurotoxicolog, Eds: Chang L. and Dyer, R. Mercel Dekker, New York, 911031995'},{id:"B29",body:'CrowellBBensonRShockleyDand Charlton, CG. S-adenosyl-methionine decreases motor activity in the rat: Similarity to Parkinson’s disease-like symptoms. Behav. and Neural Biology 591993186193'},{id:"B30",body:'DauerWKholodilovNVilaMTrillatA. CGoodchildRLarsenK. EStaalRTieuKSchmitzYYuanC. ARochaMJackson-lewisVHerschSSulzerDPrzedborskiSBurkeRand HenRResistance of alpha-synuclein null mice to the parkinsonian neurotoxin MPTP.Proc. Natl. Acad. Sci., USA, 9920021452414529'},{id:"B31",body:'DavisG. CWilliamsA. CMarkeyS. PElbertM. HCaineE. DReichertC. Mand KopinI. JChronic Parkinsonism secondary to intravenous injection of meperidine analogues.Psychiatry Res. 11979249254'},{id:"B32",body:'EadieM. JThe pathology of certain medullary muclei in parkinsonism. Brain. Res. 861963781790'},{id:"B33",body:'EgenspergerRKoselSSchnoppN. Met alAssociation of the mitochondria tRNA (A4336G) mutations with Alzheimer and Parkinson’s disease. Neuropathol. Appl. Neurobiol. 231997315321'},{id:"B34",body:'EhringerHand HornykeiwiczOVerteilung von noradrenalin unddopamin (3- hydroxytyramin) im gehirn des menscen und ihr verhalten bei erkrankungen des extra- phyramidalen systems. Klin-ther. Wschr. 3812361239cited in Scultz, 1960'},{id:"B35",body:'ElbleR. JHughesLand HiginsCThe syndrome of senile gait.J. Neurol. 23919927175'},{id:"B36",body:'ElbleR. JHughesLHiginsCand ColliverJStride-dependent changes in the gait of older people. J. Neurol. 238199115'},{id:"B37",body:'ElbleR. JThe role of aging in the clinical expression of essential tremors. Exp. Gerontol. 301995337347'},{id:"B38",body:'ElizanT. SHiranoAAbramsB. MNeedR. LVannuisCand KurlandL. TAmylotrophic lateral sclerosis and parkinsonism-dementia complex of Guam. Arch. Neurol. 141966256368'},{id:"B39",body:'FoixCand NicolescoJOverview of morphological changes in Parkinson’s disease. Mason, Paris 1925. (Cited in Hillinger K. Adv. Neurology 451181986'},{id:"B40",body:'FornoL. SAnd Norvill, RL. Ultrastructure of Lewy bodies in the stellate ganglion.Acta Neuropathol. 341976183197'},{id:"B41",body:'GasserTWszolekZ. KOehlmannRet alA susceptibility locus for Parkinson’s disease on chromosome 213Nat.Genet. 18: 262-265, 1998'},{id:"B42",body:'GeorgeJ. MJinHHoodsW. Sand ClaytonD. FCharacterization of a novel protein regulated during the critical period for song learning in the zebra finch.Neuron151995361372'},{id:"B43",body:'Gharib, A., Sarda, N., Chabannes, B., Cronenberger, L. and Pacheco, H. The regional concentrations of S-adenosyl-L-homocysteine and adenosine in rat brain. J. Neurochem. 38\n\t\t\t\t1982\n\t\t\t\t810815 .'},{id:"B44",body:'GiassonB. Iand MushynskiW. EAberrant stress-induced phosphorylation of perikaryal neurofilaments.J. Biol. Chem. 27119903040430409'},{id:"B45",body:'GiassonB. IGalvinJ. ELeeV. Mand TrojanowskiJ. QThe cellular and molecular pathology of Parkinson disease. In: Neurodegenerative Dementias, Eds: Clark, CM. and Trojanowski, JQ, McGraw-Hill, New York, Cpt 162000219228'},{id:"B46",body:'GreenfieldJ. Gand BosanquetF. DThe brainstem lesions in Parkinsonism. J. Neurol Neurosurg Psychiat 161953213126'},{id:"B47",body:'GuggenheimM. ACouchJ. Rand WeinbergWMotor dysfunction as a permanent complication of methanol ingestion. Presentation of a case with a beneficial response to levodopa treatment.Arch. Neurol. 241971550554'},{id:"B48",body:'HayesMPorterJ. AChiangCChangDTessier-lavigneMBeachyP. Aand RosenthalAInduction of midbrain dopaminergic neurons by Sonic hedgehog. Neuron 1519953544'},{id:"B49",body:'HirataFand AxelrodJPhospholipid methylation and biological signal transmission.Science 209198010821089'},{id:"B50",body:'HochbergFMillerGValenzuelaRet alLate motor defecits of Chilean manganese miners: a blinded control study. Neurology 471996788795'},{id:"B51",body:'HornykiewiczODopamine (3-hydroxytryamine) and function. Pharmacol Rev 181966925964'},{id:"B52",body:'InceP. Gand CoddG. AReturn of the cycad hypothesis-does the amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health? Neuropathol. Appl. Neurobiol. 312005345353'},{id:"B53",body:'IwatsuboTNakanoIFugunagaKand MiyamotoECa2+/calmodulin-dependent protein kinase II immunoreactivity in Lewy’s bodies. Acta Neuropathol. 821991159163'},{id:"B54",body:'JagerD. Hand BethlemJ. JThe distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitansNeurol. Neurosurg. Psychiat. 231960283290'},{id:"B55",body:'JagerW. ADen Sphingomyelin in Lewy includes bodies in Parkinson’s disease. Arch. Neurol. (Chicago) 211969615619'},{id:"B56",body:'JulienJ. Pand MuskynakiW. EMultiple phosphorylation sites in mammalian neuro- filamant polypeptides. J. Biol. Chem. 25719981046710470'},{id:"B57",body:'KitadaTAsakawaSHattoriNMatsumineHYamamuraYMinoshimaSYokochiMMizonoYand ShimizuNMutations in the parkin gene cause autosomal recessive juvenile parkinsonism.Nature39219986676605608'},{id:"B58",body:'KollerW. CAnd Huber, SJ. Tremor disorders of aging: Diagnosis and management.Geriatrics4419893336'},{id:"B59",body:'KoselSLuckingC. BEgenspergerRMehraeinPand GraeberM. BMitochondrial NADH dehydrogenase and CYP2D genotypes in Lewy-body parkinsonism. J. Neurosci. Res. 4419962174183'},{id:"B60",body:'KotbMand GellerA. MMethionine adenosyltransferase: Structure and function. Pharm. Therap. 59(2(: 125-143, 1993'},{id:"B61",body:'KrugerRVieir-saeckerA. MKhunWet alIncreased susceptibility in sparadic Parkinson’s disease by certain combined alpha-synuclein/apolipoprotein E genotype. Ann. Neurol 451999611617'},{id:"B62",body:'KrugerSKuhnW. TWoitallaDet alAla30Pro mutation in the gene encoding alpha-synuclein in Parkinson disease. Nat. Genet 181998106108'},{id:"B63",body:'KuhnWMullerTGrosseHand RommelspacherHElevated levels of Harman and norharman in cerebrospinal fluid of Parkinson’s disease patients. J. Neural Transm. 103199614351440'},{id:"B64",body:'LangstonJ. WAnd Forno, LS. The hypothalamus in Parkinson’s disease. Ann. Neurol. 31978129133'},{id:"B65",body:'LansburyP. Tand BriceAGenetics of Parkinson’s disease and biochemical studies of implicated gene productsCurr. Opin. Cell Biol. 142002653660'},{id:"B66",body:'LeeVCardenM. LSchlaepferW. WTrojanowskiJ. QMonoclonal antibodies distinguish several differently phosphorylated states of the two largest rat neurofilament subunits (NF-H and NF-M) and demonstrate their existence in the normal nervous system of adult rats. J. Neurosci. 7198734743488'},{id:"B67",body:'Lee, E. and Charlton, C. One-methyl-4-phenylpyridinium (MPP+) increases S-adenosyl- methionine dependent phospholipid methylation. Pharm. Biochem. and Beh. 70: 105- 114, 2001.'},{id:"B68",body:'LeeE. YChenHShepherdK. RLamangoN. SSolimanK. Fand CharltonC. GThe inhibitory role of methylation on the binding characteristics of dopamine receptors and transporter.Neurosci. Res. 482004335344'},{id:"B69",body:'LeeE. SChenHHardmanHSimmAand CharltonCExcessive S-adenosyl.L- methionine-dependent methylation increases levels of methanol, formaldehyde and formic acid in rat brain striatal homogenate: Possible role in S-adenosyl-L-methionie- induced Parkinson’s disease-like disordersLife Sci. 32008821827'},{id:"B70",body:'LeeE. SChenHSolimanK. Fand CharltonC. GEffects of homocysteine on the dopaminergic system and behavior in rodents.NeuroToxicology2620053361371'},{id:"B71",body:'LeeE. SChenHShepherdKLamangoN. SSolimanK. Fand CharltonC. GThe inhibitory role of methylation on the binding characteristics of dopamine receptors and transporter.Neurosci. Res. 482004335244'},{id:"B72",body:'LeeE. SSolimanK. Fand CharltonC. GLyso-phosphatidylcholine decreases locomotor activities and dopamine turnover rate in rats. NeuroToxicol 2620052738'},{id:"B73",body:'LeeF. JChoiCand LeeS. JMembrane bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. J. Biol. Chem. 2772002671678'},{id:"B74",body:'LeeF. JLiuFPristupaZ. Band NiznikH. BDirect binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis.FASEB J. 152001916926'},{id:"B75",body:'LeeE. Sand CharltonCOne-methyl-4-phenylpyridinium (MPP+) increases S- adenosylmethionine-dependent phospholipid methylation. Pharmacol. Biochem. Beh. 702001105114'},{id:"B76",body:'LeroyEAnastosooulosDKonitsiotisSLarkenCand PolymeropoulosM. NDeletions in the Parkin gene and genetic heterogencity in a Greek family with earcy onset Parkinson disease. Hum. Genet. 10344244271998'},{id:"B77",body:'Levitan, IB. and Kaczmarek, LK. The birth and death of a neuron. In: The Neuron: Cell and Molecular Biology. 3rd ed, pp. 375-393. 2002.'},{id:"B78",body:'MaS. YRoyttaMRinneJ. OCollanYand RinneU. KCorrelation between neuromorphometry in the substantia nigra and clinical features in Parkinson’s disease using dissector counts. J. Neurol. Scs. 15119978387'},{id:"B79",body:'MannS. Pand HillM. WActivation and inactivation of striatal tyrosine hydroxylase: the effects of pH, ATP and cyclic AMP, S-adenosylmethionine and S-adenosylhomocysteineBiochem. Pharmacology 32198333693374'},{id:"B80",body:'MatsubaraKAoyamaKSumaMand Awaya, T. N-methylation underlying Parkinson’s disease.Neurotoxicology and Teratology242002593598'},{id:"B81",body:'MaysL. IBorekEand FinchC. EGlycine N-methyltransferase is a regulatory enzyme which increases in aging animals. Nature 2431973411413'},{id:"B82",body:'McgeerP. Land SteeleJ. CThe ALS/PDC syndrome of Guam: Potential biomarkers for an enigmatic disorderProg. Neurobio. 952011663669'},{id:"B83",body:'MurrayM. PKoryR. Cand ClarksonB. HWalking patterns in healthy old menJ. Gerontol. 241969169178'},{id:"B84",body:'MuruyamaWAbeTTohgiHDostertPand NaoiMA dopaminergic neurotoxin, (R)-N-methylsalsolinol increases in parkinsonism cerebrospinal fluid. Ann. Neurol. 401996119112'},{id:"B85",body:'MuthianGMackeyVKingJand CharltonCModeling a Sensitization stage and a Precipitation stage for Parkinson’s disease using Prenatal and Postnatal 1-Methyl-4- phenyl-1,2,3,4-tetrahydropyridine (MPTP) administration. Neurosci. J. 169201010851093'},{id:"B86",body:'Nagatsu, T. and Yoshida, M. An endogenous substance of the brain, terrahydroisoquinoline, produces parkinsonism in primates with decreased dopamine, tyrosine hydroxylase and biopterin in the nigrostriatal regions. Neurosci. Lett. 87\n\t\t\t\t1988\n\t\t\t\t178182 .'},{id:"B87",body:'NakamuraSKawamotoYNakanoSet al35nck5aand cyclin-dependent kinase 5 colocalize in Lewy bodies of brains with Parkinson’s disease.Acta Neuropathol. 94: 153- 157, 1997'},{id:"B88",body:'NaoiMMaruyamaWYukihiroAand YiHDopamine-derived endogenous N- methyl-(R)-salsolinol. Its role in Parkinson’s disease. Neurotoxi. and Teratol. 242002579591'},{id:"B89",body:'OchiNNaoiMMogiMOhyaYMizutaniNWatanabeKHaradaMand HagatsuTEffects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in prenatal stage on the dopamine system in the postnatal mouse brain.Life Sci. 4819913217223'},{id:"B90",body:'OhamaEand IkutaFParkinson disease distribution of Lewy bodies and monoamine neuron system. Acta Neuropathol. (Berl) 341976311319'},{id:"B91",body:'OppenheimR. WCell death during development of the nervous system.Annu. Rev. Neurosci. 141991453501'},{id:"B92",body:'OrtelW. HBandmannOEichhornTand GlasserTPeripheral markers of PD. An overview. In: Neurology, 69Ed: Battistin, L., Scarlato, G., Caraceni, T. and Ruggieri, S. Lippincott-Raven Publishers, Philadelphia, 2832911996'},{id:"B93",body:'OyanagiKThe nature of the parkinsonian-dementia complex and amyotrophic lateral sclerosis of Guam and magnesium deficiency. Parkinsonism and Related Disorders 11: S17S23, 2005'},{id:"B94",body:'PapadimitriorAVeletaVHadjigerogiouG. Met alMutated alpha-synuclein gene in two Greek kindreds with familial PD: incomplete penetrance. Neurology 521999651564'},{id:"B95",body:'Perrone-capanoCand di Porzio, U. Epigenetic factors and midbrain dopaminergic neurone development. BioEssays 18199610817824'},{id:"B96",body:'PollanenM. SDickenD. WBergeronCPathology and biology of Lewy’s body. J. Neuropathol. Exp. Neurol. 521993183191'},{id:"B97",body:'PolymeropoulosM. NLavedanCLeroyEet alMutations in alpha-synuclein gene identified in families with Parkinson disease. Science 276199720452047'},{id:"B98",body:'RajputA. Hand RozdilskyBDysautonomia in parkinsonism: a clinicopathological study. J. Jeurol. Neurosurg. Psychiatr. 39197010921100'},{id:"B99",body:'RavenholtR. TInflueza, Encephalitis Lethargica, Parkinsonism. Lancet 32619828303860864'},{id:"B100",body:'RenYZhaoJand FengJParkin binds to alpha and beta tubulin and increases their ubiquitination and degradation. J. Neurosci. 232003833163324'},{id:"B101",body:'SabbaghNBruceAMarezDDurrALegrandMLoguidiceJ. MDestceAAgridYand BrolyFCypDpolymorphism and Parkinson disease susceptibility. Mov. Disord. 141999230236'},{id:"B102",body:'SacksOCycad island. In: The Island of the Colorblind. New York: Vintage,971771998'},{id:"B103",body:'Schneider, JS., Yuwiler, A. and Markham, CH. Production of Parkinson-like syndrome in the cat with N- methyl-4- phenyl-1,2,3,6- trtrahydropyridine. Proc. Natl. Acad. Sci. USA. 80\n\t\t\t\t1983\n\t\t\t\t293307 .'},{id:"B104",body:'SelbyGCerebral atrophy in parkinsonism.J. Neurol. Sci. 61968517559'},{id:"B105",body:'SellingerO. ZKramerC. MCongerAand DuboffG. SThe carboxylmethylation of cerebral membrane-bound proteins increases with age.Mechanisms of Aging and Develop 431988161173'},{id:"B106",body:'Schwartz, JH. Synthesis and trafficking of neural proteins. In: Principles of Neural Science. 3rd ed. Eds: Kandal, ER., Schwartz, JH. And Jessel, TM. Appleton and Lange, Norwalk, pp 49-65, 1991.'},{id:"B107",body:'SolomonM. JLarsenPand VarshavskyAMapping protein-DNA interactions in vivo with formaldehyde: evidence that histone H4 is retained on a highly transcribed gene.Cell531988937947'},{id:"B108",body:'SpencerP. SNunnPHugonJLudolphAand RoyD. NMotorneurone disease on Guam: Possible role of food neurotoxin.Lancet965 EOF1986'},{id:"B109",body:'SpenserPGuam ALS/parkinsonism-dementia: a long-latency neurotoxic disorder caused by a “slow” toxin(s) in food. Can J. Neurol. Sci 141987347357'},{id:"B110",body:'SpillantiniM. GSchmidtM. LLee, VMY., et alAlpha-synuclein in Lewy’s bodies. Nature 3881997839840'},{id:"B111",body:'SternbergerL. Aand SternbergerN. HMonoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ.Proc. Natl. Acad. Sci. USA. 80198361266130'},{id:"B112",body:'StramentinoliGGualanoMCattoEand AlgeriSTissue levels of S-adenosyl- methionine in aging rats. J. Gerontol. 3219774392394'},{id:"B113",body:'TarlaciSVincristine-induced fetal neuropathy in non-Hodkin’s lymphoma. Neurotoxicol. 2920084748749'},{id:"B114",body:'TretiakoffCContribution a l’etude de l’anatomic pathologique du locus niger de Soemmering avec quelique deductions relatives a la pathogenia des troubles du tonus musculaire de la maladie de Parkinson. Thesis. Paris. (1919). Cited in Schultz, Prog. Neurol. 18121661982'},{id:"B115",body:'Van DuinenS. GLammersG. LMatt-Schieman, MLC. And Roos, RAC. Numerous and widespread alpha synuclein-negative Lewy’s bodies in an asymptomatic patient. Acta Neuropathol. 971999533539'},{id:"B116",body:'VanderhaegenJ. JPoiriorOand SterononJ. EPathological findings in idiopathic orthostatic hypotension. Arch. Neurol. 111970207214'},{id:"B117",body:'VoornPKalsbeekAJorritsma-byhamBand Groenewa-jenH. JThe pre- and post- natal development of the dopaminergic cell groups in the ventral mesencephalon and the dopaminergic innervation of the striat irn of the rat. Neuroscience 251988857887'},{id:"B118",body:'WaiteL. MBroeG. ACreaseyHet alNeurological signs, aging and neurodegenerative syndromes. ArchNeurol. 531996498502'},{id:"B119",body:'WardC. DDuvosinR. CInceS. ENuttJ. Dand CalneD. BParkinson’s disease in 65 pairs of twins and in a set of quadruplets. Neurology 331983815824'},{id:"B120",body:'WeissA. DThe locus of reaction time change with set, motivation and age. J. Gerontol. 2019656064'},{id:"B121",body:'WelfordA. TMotor performance. In: Handbook of the Psychology of Aging. Eds: Birren, JE. And Schaine, KW, New York, Van Nostrand Reinhold, 4504961977'},{id:"B122",body:'WesemannWGroteCClementH. WBlockFand SontagK. HFunctional studies on monoaminergic transmitter release in parkinosonism. Prog. Neuropsychopharmacol. Biol. Psychiatry 171993487499'},{id:"B123",body:'WilliamsA. Cand RamsdenD. BNicotinamide homeostasis: A xenobiotic pathway that is key to development and degenerative diseases. Medical Hypothesis 652005353362'},{id:"B124",body:'WilliamsA. CPallH. SSteventonG. BGreenSButtrumSMollyHand Waring, RR. N-methylation of pyridines and Parkinson’s disease. Adv. Neurol. 601993194196'},{id:"B125",body:'WithersG. SGeorgeJ. MBankerG. Aand ClaytonD. FDelayed localization of synelfin (synuclein, NACP) to presynaptic terminals in cultured rat hippocampal neurons Dev. Brain Res. 9919978794'},{id:"B126",body:'YahrM. Dand BeringE. AIn: Parkinson disease. Present status and research trends. Eds. Yahr MD and Dering, EA. US-DHEW 471968'},{id:"B127",body:'ZhoaWLatinwoLLiuX. XLeeELamangoNand Charlton, C. L-dopa upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase. Exprl. Neurology. 1712001127138'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Clivel G. Charlton",address:null,affiliation:'
'}],corrections:null},book:{id:"2604",title:"Basal Ganglia",subtitle:"An Integrative View",fullTitle:"Basal Ganglia - An Integrative View",slug:"basal-ganglia-an-integrative-view",publishedDate:"January 2nd 2013",bookSignature:"Fernando A. Barrios and Clemens Bauer",coverURL:"https://cdn.intechopen.com/books/images_new/2604.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"147924",title:"Dr.",name:"Fernando A.",middleName:null,surname:"Barrios",slug:"fernando-a.-barrios",fullName:"Fernando A. Barrios"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"41746",title:"Clinical Motor and Cognitive Neurobehavioral Relationships in the Basal Ganglia",slug:"clinical-motor-and-cognitive-neurobehavioral-relationships-in-the-basal-ganglia",totalDownloads:6259,totalCrossrefCites:3,signatures:"Gerry Leisman, Robert Melillo and Frederick R. Carrick",authors:[{id:"145059",title:"Prof.",name:"Gerry",middleName:null,surname:"Leisman",fullName:"Gerry Leisman",slug:"gerry-leisman"},{id:"145246",title:"Dr.",name:"Robert",middleName:null,surname:"Melillo",fullName:"Robert Melillo",slug:"robert-melillo"},{id:"167807",title:"Prof.",name:"Frederick R.",middleName:null,surname:"Carrick",fullName:"Frederick R. Carrick",slug:"frederick-r.-carrick"}]},{id:"41743",title:"Fetal and Environmental Basis for the Cause of Parkinson’s Disease",slug:"fetal-and-environmental-basis-for-the-cause-of-parkinson-s-disease",totalDownloads:2239,totalCrossrefCites:0,signatures:"Clivel G. Charlton",authors:[{id:"145066",title:"Dr.",name:"Clivel",middleName:null,surname:"Charlton",fullName:"Clivel Charlton",slug:"clivel-charlton"}]},{id:"41744",title:"Basal Ganglia and the Error Monitoring and Processing System: How Alcohol Modulates the Error Monitoring and Processing Capacity of the Basal Ganglia",slug:"basal-ganglia-and-the-error-monitoring-and-processing-system-how-alcohol-modulates-the-error-monitor",totalDownloads:1853,totalCrossrefCites:2,signatures:"M.O. Welcome and V.A. Pereverzev",authors:[{id:"145006",title:"Dr.",name:"Menizibeya",middleName:null,surname:"Welcome O.",fullName:"Menizibeya Welcome O.",slug:"menizibeya-welcome-o."},{id:"149228",title:"Prof.",name:"Vladimir",middleName:null,surname:"Pereverzev A.",fullName:"Vladimir Pereverzev A.",slug:"vladimir-pereverzev-a."}]},{id:"41742",title:"The Integrative Role of the Basal Ganglia",slug:"the-integrative-role-of-the-basal-ganglia",totalDownloads:2399,totalCrossrefCites:0,signatures:"Clemens C.C. Bauer, Erick H. Pasaye, Juan I. Romero-Romo and Fernando A. Barrios",authors:[{id:"147924",title:"Dr.",name:"Fernando A.",middleName:null,surname:"Barrios",fullName:"Fernando A. Barrios",slug:"fernando-a.-barrios"},{id:"146493",title:"Dr.",name:"Clemens",middleName:"Christian Chimalpopoca",surname:"Bauer",fullName:"Clemens Bauer",slug:"clemens-bauer"},{id:"147923",title:"Dr.",name:"Erick Humberto",middleName:null,surname:"Pasáye",fullName:"Erick Humberto Pasáye",slug:"erick-humberto-pasaye"},{id:"153678",title:"Dr.",name:"Juan I.",middleName:null,surname:"Romero-Romo",fullName:"Juan I. Romero-Romo",slug:"juan-i.-romero-romo"}]},{id:"41745",title:"Organization of Two Cortico–Basal Ganglia Loop Circuits That Arise from Distinct Sectors of the Monkey Dorsal Premotor Cortex",slug:"organization-of-two-cortico-basal-ganglia-loop-circuits-that-arise-from-distinct-sectors-of-the-monk",totalDownloads:2810,totalCrossrefCites:6,signatures:"Masahiko Takada, Eiji Hoshi, Yosuke Saga,\nKen-ichi Inoue, Shigehiro Miyachi, Nobuhiko Hatanaka, Masahiko Inase and Atsushi Nambu",authors:[{id:"45780",title:"Prof.",name:"Masahiko",middleName:null,surname:"Takada",fullName:"Masahiko Takada",slug:"masahiko-takada"}]}]},relatedBooks:[{type:"book",id:"5313",title:"Update on Dementia",subtitle:null,isOpenForSubmission:!1,hash:"6b264ef130a59fe71274c3811750e6c3",slug:"update-on-dementia",bookSignature:"Davide Vito Moretti",coverURL:"https://cdn.intechopen.com/books/images_new/5313.jpg",editedByType:"Edited by",editors:[{id:"147154",title:"Dr.",name:"Davide",surname:"Moretti",slug:"davide-moretti",fullName:"Davide Moretti"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"52167",title:"Alternative Splicing and Alzheimer’s Disease",slug:"alternative-splicing-and-alzheimer-s-disease",signatures:"Gonzalo Emiliano Aranda Abreu, Sonia Lilia Mestizo Gutiérrez,\nMaría Elena Hernández Aguilar and Fausto Rojas Durán",authors:[{id:"72314",title:"Dr.",name:"Gonzalo Emiliano",middleName:null,surname:"Aranda Abreu",fullName:"Gonzalo Emiliano Aranda Abreu",slug:"gonzalo-emiliano-aranda-abreu"},{id:"186065",title:"Dr.",name:"Sonia Lilia",middleName:null,surname:"Mestizo Gutiérrez",fullName:"Sonia Lilia Mestizo Gutiérrez",slug:"sonia-lilia-mestizo-gutierrez"},{id:"186066",title:"Dr.",name:"María Elena",middleName:null,surname:"Hernández Aguilar",fullName:"María Elena Hernández Aguilar",slug:"maria-elena-hernandez-aguilar"},{id:"186067",title:"Dr.",name:"Fausto",middleName:null,surname:"Rojas Durán",fullName:"Fausto Rojas Durán",slug:"fausto-rojas-duran"}]},{id:"51676",title:"Neuroinflammation and Neurodegeneration",slug:"neuroinflammation-and-neurodegeneration",signatures:"Inelia Morales, Gonzalo A. Farías, Nicole Cortes and Ricardo B.\nMaccioni",authors:[{id:"137002",title:"Dr.",name:"Gonzalo",middleName:null,surname:"Farias",fullName:"Gonzalo Farias",slug:"gonzalo-farias"},{id:"183194",title:"Dr.",name:"Ricardo",middleName:"Benjamín",surname:"Maccioni",fullName:"Ricardo Maccioni",slug:"ricardo-maccioni"},{id:"183196",title:"MSc.",name:"Inelia",middleName:null,surname:"Morales",fullName:"Inelia Morales",slug:"inelia-morales"},{id:"183197",title:"MSc.",name:"Nicole",middleName:null,surname:"Cortes",fullName:"Nicole Cortes",slug:"nicole-cortes"}]},{id:"51651",title:"High-Fat and Cholesterol Intake Affects Brain Homeostasis and Could Accelerate the Development of Dementia: A Systemic View",slug:"high-fat-and-cholesterol-intake-affects-brain-homeostasis-and-could-accelerate-the-development-of-de",signatures:"Marco Antonio Meraz-Ríos and Perla Leal-Galicia",authors:[{id:"114746",title:"Dr.",name:"Marco",middleName:null,surname:"Meraz-Ríos",fullName:"Marco Meraz-Ríos",slug:"marco-meraz-rios"},{id:"187600",title:"Dr.",name:"Perla",middleName:null,surname:"Leal-Galicia",fullName:"Perla Leal-Galicia",slug:"perla-leal-galicia"}]},{id:"51637",title:"Plasma Biomarkers in Alzheimer’s Disease",slug:"plasma-biomarkers-in-alzheimer-s-disease",signatures:"Hitoshi Sohma and Yasuo Kokai",authors:[{id:"179340",title:"Prof.",name:"Hitoshi",middleName:null,surname:"Sohma",fullName:"Hitoshi Sohma",slug:"hitoshi-sohma"},{id:"180263",title:"Prof.",name:"Yasuo",middleName:null,surname:"Kokai",fullName:"Yasuo Kokai",slug:"yasuo-kokai"}]},{id:"51964",title:"Alzheimer’s-Related Amyloid Beta Peptide Aggregates in the Ageing Retina: Implications for Sight Loss and Dementia",slug:"alzheimer-s-related-amyloid-beta-peptide-aggregates-in-the-ageing-retina-implications-for-sight-loss",signatures:"J. Arjuna Ratnayaka and Savannah Lynn",authors:[{id:"183572",title:"Dr.",name:"J Arjuna",middleName:null,surname:"Ratnayaka",fullName:"J Arjuna Ratnayaka",slug:"j-arjuna-ratnayaka"},{id:"183847",title:"Ms.",name:"Savannah A.",middleName:null,surname:"Lynn",fullName:"Savannah A. Lynn",slug:"savannah-a.-lynn"}]},{id:"51804",title:"Proteomic Study of Degenerative Protein Modifications in the Molecular Pathology of Neurodegeneration and Dementia",slug:"proteomic-study-of-degenerative-protein-modifications-in-the-molecular-pathology-of-neurodegeneratio",signatures:"Sunil S. Adav and Siu Kwan Sze",authors:[{id:"184065",title:"Dr.",name:"Siu Kwan",middleName:null,surname:"Sze",fullName:"Siu Kwan Sze",slug:"siu-kwan-sze"},{id:"187076",title:"Dr.",name:"Sunil S",middleName:null,surname:"Adav",fullName:"Sunil S Adav",slug:"sunil-s-adav"}]},{id:"52003",title:"Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease",slug:"brain-lipids-in-the-pathophysiology-and-treatment-of-alzheimer-s-disease",signatures:"Manuel Torres, Xavier Busquets and Pablo V. Escribá",authors:[{id:"184164",title:"Prof.",name:"Pablo",middleName:null,surname:"Escribá",fullName:"Pablo Escribá",slug:"pablo-escriba"},{id:"191108",title:"Prof.",name:"Xavier",middleName:null,surname:"Busquets",fullName:"Xavier Busquets",slug:"xavier-busquets"},{id:"191260",title:"Dr.",name:"Manuel",middleName:null,surname:"Torres",fullName:"Manuel Torres",slug:"manuel-torres"}]},{id:"52048",title:"Beta Amyloid Peptides: Extracellular and Intracellular Mechanisms of Clearance in Alzheimer’s Disease",slug:"beta-amyloid-peptides-extracellular-and-intracellular-mechanisms-of-clearance-in-alzheimer-s-disease",signatures:"Luis F. Hernández-Zimbrón, Elisa Gorostieta-Salas, Mei-Li Díaz-\nHung, Roxanna Pérez-Garmendia, Gohar Gevorkian and Hugo\nQuiroz-Mercado",authors:[{id:"75951",title:"BSc.",name:"Hugo",middleName:null,surname:"Quiroz-Mercado",fullName:"Hugo Quiroz-Mercado",slug:"hugo-quiroz-mercado"},{id:"181180",title:"Dr.",name:"Luis Fernando",middleName:null,surname:"Hernandez-Zimbron",fullName:"Luis Fernando Hernandez-Zimbron",slug:"luis-fernando-hernandez-zimbron"},{id:"181277",title:"Dr.",name:"Roxanna",middleName:null,surname:"Pérez-Garmendia",fullName:"Roxanna Pérez-Garmendia",slug:"roxanna-perez-garmendia"},{id:"181278",title:"BSc.",name:"Elisa",middleName:null,surname:"Gorostieta-Salas",fullName:"Elisa Gorostieta-Salas",slug:"elisa-gorostieta-salas"},{id:"181279",title:"MSc.",name:"Mei-Li",middleName:null,surname:"Díaz-Hung",fullName:"Mei-Li Díaz-Hung",slug:"mei-li-diaz-hung"},{id:"190226",title:"Dr.",name:"Gohar",middleName:null,surname:"Gevorkian-Markosian",fullName:"Gohar Gevorkian-Markosian",slug:"gohar-gevorkian-markosian"}]},{id:"52062",title:"Alzheimer's Disease: From Animal Models to the Human Syndrome",slug:"alzheimer-s-disease-from-animal-models-to-the-human-syndrome",signatures:"Erika Orta‐Salazar, Isaac Vargas‐Rodríguez, Susana A Castro‐\nChavira, Alfredo I. Feria‐Velasco and Sofía Díaz‐Cintra",authors:[{id:"184728",title:"Dr.",name:"Erika Maria",middleName:null,surname:"Orta Salazar",fullName:"Erika Maria Orta Salazar",slug:"erika-maria-orta-salazar"},{id:"185118",title:"Ph.D. Student",name:"Isaac",middleName:null,surname:"Vargas-Rodríguez",fullName:"Isaac Vargas-Rodríguez",slug:"isaac-vargas-rodriguez"},{id:"185119",title:"Ph.D. Student",name:"Susana Angelica",middleName:null,surname:"Castro-Chavira",fullName:"Susana Angelica Castro-Chavira",slug:"susana-angelica-castro-chavira"},{id:"185120",title:"Ph.D.",name:"Alfredo I",middleName:null,surname:"Feria-Velasco",fullName:"Alfredo I Feria-Velasco",slug:"alfredo-i-feria-velasco"},{id:"185121",title:"Ph.D.",name:"Sofia",middleName:null,surname:"Diaz-Cintra",fullName:"Sofia Diaz-Cintra",slug:"sofia-diaz-cintra"}]},{id:"51441",title:"Risk Factors for Alzheimer’s Disease",slug:"risk-factors-for-alzheimer-s-disease",signatures:"Dongming Cai and Farida El Gaamouch",authors:[{id:"183531",title:"Prof.",name:"Dongming",middleName:null,surname:"Cai",fullName:"Dongming Cai",slug:"dongming-cai"},{id:"183867",title:"Dr.",name:"Farida",middleName:null,surname:"El Gaamouch",fullName:"Farida El Gaamouch",slug:"farida-el-gaamouch"}]},{id:"51355",title:"Normal Aging and Dementia",slug:"normal-aging-and-dementia",signatures:"Michał Prendecki, Jolanta Florczak-Wyspianska, Marta Kowalska,\nMargarita Lianeri, Wojciech Kozubski and Jolanta Dorszewska",authors:[{id:"31962",title:"Dr.",name:"Jolanta",middleName:null,surname:"Dorszewska",fullName:"Jolanta Dorszewska",slug:"jolanta-dorszewska"},{id:"83372",title:"Prof.",name:"Wojciech",middleName:null,surname:"Kozubski",fullName:"Wojciech Kozubski",slug:"wojciech-kozubski"},{id:"183236",title:"Dr.",name:"Jolanta",middleName:null,surname:"Florczak-Wyspianska",fullName:"Jolanta Florczak-Wyspianska",slug:"jolanta-florczak-wyspianska"},{id:"186409",title:"MSc.",name:"Michal",middleName:null,surname:"Prendecki",fullName:"Michal Prendecki",slug:"michal-prendecki"},{id:"186528",title:"MSc.",name:"Marta",middleName:null,surname:"Kowalska",fullName:"Marta Kowalska",slug:"marta-kowalska"},{id:"186529",title:"Dr.",name:"Margarita",middleName:null,surname:"Lianeri",fullName:"Margarita Lianeri",slug:"margarita-lianeri"}]},{id:"52137",title:"Changes in Visual Cortex in Healthy Aging and Dementia",slug:"changes-in-visual-cortex-in-healthy-aging-and-dementia",signatures:"Alyssa A. Brewer and Brian Barton",authors:[{id:"115304",title:"Dr.",name:"Alyssa",middleName:"A",surname:"Brewer",fullName:"Alyssa Brewer",slug:"alyssa-brewer"},{id:"149246",title:"Dr.",name:"Brian",middleName:null,surname:"Barton",fullName:"Brian Barton",slug:"brian-barton"}]},{id:"52368",title:"Clusterin (APOJ) in Alzheimer’s Disease: An Old Molecule with a New Role",slug:"clusterin-apoj-in-alzheimer-s-disease-an-old-molecule-with-a-new-role",signatures:"Sarah K. Woody and Liqin Zhao",authors:[{id:"182716",title:"Prof.",name:"Liqin",middleName:null,surname:"Zhao",fullName:"Liqin Zhao",slug:"liqin-zhao"},{id:"187597",title:"Ms.",name:"Sarah",middleName:null,surname:"Woody",fullName:"Sarah Woody",slug:"sarah-woody"}]},{id:"51440",title:"New Targets for Diagnosis and Treatment Against Alzheimer’s Disease: The Mitochondrial Approach",slug:"new-targets-for-diagnosis-and-treatment-against-alzheimer-s-disease-the-mitochondrial-approach",signatures:"María José Pérez, Claudia Jara, Ernesto Muñoz‐Urrutia and Rodrigo\nA. Quintanilla",authors:[{id:"182849",title:"Dr.",name:"Rodrigo",middleName:null,surname:"Quintanilla",fullName:"Rodrigo Quintanilla",slug:"rodrigo-quintanilla"},{id:"183872",title:"MSc.",name:"María José",middleName:null,surname:"Pérez",fullName:"María José Pérez",slug:"maria-jose-perez"},{id:"183873",title:"Dr.",name:"Claudia",middleName:null,surname:"Jara",fullName:"Claudia Jara",slug:"claudia-jara"},{id:"183874",title:"MSc.",name:"Ernesto",middleName:null,surname:"Muñoz",fullName:"Ernesto Muñoz",slug:"ernesto-munoz"}]},{id:"51819",title:"The Impact of the Eye in Dementia: The Eye and its Role in Diagnosis and Follow‐up",slug:"the-impact-of-the-eye-in-dementia-the-eye-and-its-role-in-diagnosis-and-follow-up",signatures:"Elena Salobrar‐García, Ana I. Ramírez, Rosa de Hoz, Pilar Rojas, Juan\nJ. Salazar, Blanca Rojas, Raquel Yubero, Pedro Gil, Alberto Triviño\nand José M. Ramírez",authors:[{id:"142707",title:"Prof.",name:"José M.",middleName:null,surname:"Ramírez",fullName:"José M. Ramírez",slug:"jose-m.-ramirez"},{id:"142864",title:"Prof.",name:"Alberto",middleName:null,surname:"Triviño",fullName:"Alberto Triviño",slug:"alberto-trivino"},{id:"145761",title:"Prof.",name:"Juan J",middleName:null,surname:"Salazar",fullName:"Juan J Salazar",slug:"juan-j-salazar"},{id:"145765",title:"Prof.",name:"Rosa",middleName:null,surname:"De Hoz",fullName:"Rosa De Hoz",slug:"rosa-de-hoz"},{id:"145766",title:"Prof.",name:"Blanca",middleName:null,surname:"Rojas",fullName:"Blanca Rojas",slug:"blanca-rojas"},{id:"145767",title:"Prof.",name:"Ana I.",middleName:null,surname:"Ramírez",fullName:"Ana I. Ramírez",slug:"ana-i.-ramirez"},{id:"183853",title:"MSc.",name:"Elena",middleName:null,surname:"Salobrar-García",fullName:"Elena Salobrar-García",slug:"elena-salobrar-garcia"},{id:"183854",title:"MSc.",name:"Pilar",middleName:null,surname:"Rojas",fullName:"Pilar Rojas",slug:"pilar-rojas"},{id:"183858",title:"Dr.",name:"Pedro",middleName:null,surname:"Gil",fullName:"Pedro Gil",slug:"pedro-gil"},{id:"183859",title:"Dr.",name:"Raquel",middleName:null,surname:"Yubero",fullName:"Raquel Yubero",slug:"raquel-yubero"}]},{id:"52006",title:"Caring for Individuals with Dementia on a Continuum: An Interdisciplinary Approach Between Music Therapy and Nursing",slug:"caring-for-individuals-with-dementia-on-a-continuum-an-interdisciplinary-approach-between-music-ther",signatures:"Kendra Ray, Ayelet Dassa, Jan Maier, Renita Davis and Olayinka\nOgunlade",authors:[{id:"183246",title:"Dr.",name:"Kendra",middleName:null,surname:"Ray",fullName:"Kendra Ray",slug:"kendra-ray"},{id:"183915",title:"Prof.",name:"Renita",middleName:null,surname:"Davis",fullName:"Renita Davis",slug:"renita-davis"},{id:"183916",title:"Ms.",name:"Jan",middleName:null,surname:"Maier",fullName:"Jan Maier",slug:"jan-maier"},{id:"184382",title:"Dr.",name:"Ayelet",middleName:null,surname:"Dassa",fullName:"Ayelet Dassa",slug:"ayelet-dassa"},{id:"184383",title:"Mr.",name:"Olayinka",middleName:null,surname:"Ogunlade",fullName:"Olayinka Ogunlade",slug:"olayinka-ogunlade"}]},{id:"52128",title:"Behavior and Emotion in Dementia",slug:"behavior-and-emotion-in-dementia",signatures:"Teresa Mayordomo Rodríguez, Alicia Sales Galán, Rita Redondo\nFlores, Marta Torres Jordán and Javier Bendicho Montes",authors:[{id:"184060",title:"Dr.",name:"Teresa",middleName:null,surname:"Mayordomo Rodríguez",fullName:"Teresa Mayordomo Rodríguez",slug:"teresa-mayordomo-rodriguez"}]},{id:"51705",title:"Non-Pharmacological Approaches in the Treatment of Dementia",slug:"non-pharmacological-approaches-in-the-treatment-of-dementia",signatures:"Grazia D’Onofrio, Daniele Sancarlo, Davide Seripa, Francesco\nRicciardi, Francesco Giuliani, Francesco Panza and Antonio Greco",authors:[{id:"184079",title:"Dr.",name:"Daniele",middleName:null,surname:"Sancarlo",fullName:"Daniele Sancarlo",slug:"daniele-sancarlo"},{id:"184080",title:"Dr.",name:"Grazia",middleName:null,surname:"D’Onofrio",fullName:"Grazia D’Onofrio",slug:"grazia-d'onofrio"},{id:"184081",title:"Dr.",name:"Antonio",middleName:null,surname:"Greco",fullName:"Antonio Greco",slug:"antonio-greco"}]},{id:"52095",title:"Medication Management for People Living with Dementia: Development and Evaluation of a Multilingual Information Resource for Family Caregivers of People Living with Dementia",slug:"medication-management-for-people-living-with-dementia-development-and-evaluation-of-a-multilingual-i",signatures:"Robyn Gillespie, Pippa Burns, Lindsey Harrison, Amanda Baker, Khin\nWin, Victoria Traynor and Judy Mullan",authors:[{id:"183243",title:"Mrs.",name:"Robyn",middleName:null,surname:"Gillespie",fullName:"Robyn Gillespie",slug:"robyn-gillespie"},{id:"190390",title:"Dr.",name:"Pippa",middleName:null,surname:"Burns",fullName:"Pippa Burns",slug:"pippa-burns"},{id:"190391",title:"Dr.",name:"Judy",middleName:null,surname:"Mullan",fullName:"Judy Mullan",slug:"judy-mullan"},{id:"190392",title:"Dr.",name:"Lindsey",middleName:null,surname:"Harrison",fullName:"Lindsey Harrison",slug:"lindsey-harrison"},{id:"190393",title:"Dr.",name:"Amanda",middleName:null,surname:"Baker",fullName:"Amanda Baker",slug:"amanda-baker"},{id:"190394",title:"Dr.",name:"Khin",middleName:null,surname:"Win",fullName:"Khin Win",slug:"khin-win"},{id:"190395",title:"Dr.",name:"Victoria",middleName:null,surname:"Traynor",fullName:"Victoria Traynor",slug:"victoria-traynor"}]},{id:"52044",title:"Diabetes Mellitus and Depression as Risk Factors for Dementia: SADEM Study",slug:"diabetes-mellitus-and-depression-as-risk-factors-for-dementia-sadem-study",signatures:"Juárez‐Cedillo Teresa, Hsiung Ging‐Yuek, Sepehry A. Amir, Beattie\nB. Lynn, Jacova Claudia and Escobedo de la Peña Jorge",authors:[{id:"183147",title:"Dr.",name:"Teresa",middleName:null,surname:"Juarez-Cedillo",fullName:"Teresa Juarez-Cedillo",slug:"teresa-juarez-cedillo"},{id:"187568",title:"Dr.",name:"Ging-Yuek",middleName:null,surname:"Hsiung",fullName:"Ging-Yuek Hsiung",slug:"ging-yuek-hsiung"},{id:"187569",title:"Dr.",name:"Amir",middleName:"Ali",surname:"Sepehry",fullName:"Amir Sepehry",slug:"amir-sepehry"},{id:"187570",title:"MSc.",name:"B. Lynn",middleName:null,surname:"Beattie",fullName:"B. Lynn Beattie",slug:"b.-lynn-beattie"},{id:"187571",title:"Dr.",name:"Claudia",middleName:null,surname:"Jacova",fullName:"Claudia Jacova",slug:"claudia-jacova"},{id:"187572",title:"Dr.",name:"Jorge",middleName:null,surname:"Escobedo De La Peña",fullName:"Jorge Escobedo De La Peña",slug:"jorge-escobedo-de-la-pena"}]},{id:"51311",title:"Idiopathic Normal Pressure Hydrocephalus: An Overview of Pathophysiology, Clinical Features, Diagnosis and Treatment",slug:"idiopathic-normal-pressure-hydrocephalus-an-overview-of-pathophysiology-clinical-features-diagnosis-",signatures:"Rubesh Gooriah and Ashok Raman",authors:[{id:"183615",title:"Dr.",name:"Rubesh",middleName:null,surname:"Gooriah",fullName:"Rubesh Gooriah",slug:"rubesh-gooriah"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"75025",title:"Nociceptive TRP Channels and Sex Steroids",doi:"10.5772/intechopen.95552",slug:"nociceptive-trp-channels-and-sex-steroids",body:'\n
\n
1. Introduction
\n
The somatosensory system is a complex network of neurons and peripheral receptors that encodes specific information about the state of organisms and their environment, providing them with the ability to detect harmful stimuli [1, 2, 3].
\n
According to the International Association for the Study of Pain (IASP), the neuronal process encoding noxious stimuli is known as nociception. A subpopulation of high-threshold sensory neurons known as nociceptors mediates this process by detecting harmful signals from chemical and physical nature \nFigure 1\n [1, 4]. Nociceptors are neurons with a peripheral axonal branch that innervates cutaneous, articular and visceral afferents, and a central axonal branch that innervates the dorsal horn of the spinal cord. The cell bodies of mammalian nociceptors are located in the dorsal root ganglia (DRG) and in the trigeminal ganglia (TG) and they are classified as medium and small diameter neurons. The axons of these nociceptors are classified as Aδ- and C-fibers depending on their diameter, degree of myelinization, conduction speed and the type of sensory stimuli that they transmit [1, 4, 5].
\n
Figure 1.
Nociception. Harmful stimuli are transduced along the terminal axon of specialized pseudounipolar neurons (nociceptors), which are classified as unmyelinated C fibers (red) and thinly myelinated Aδ fibers (orange); myelinated Aβ fibers (blue) transduce innocuous stimuli. The cell bodies of these peripheral sensory neurons are located in the dorsal root ganglia and trigeminal ganglia. Nociceptors innervate the epidermis and viscera, transducing noxious stimuli through the activation of several ion channels such as members of the TRP family. Finally, the information is transmitted to second order neurons located in the dorsal horn: C fibers and Aδ fibers mainly establish contact with neurons from layers I and II, while tactile Aβ fibers end mainly in layers III and V.
\n
The Aδ-fibers are characterized by 2–6 μm diameters, are myelinated and present a relatively fast conduction speed between 5 and 30 m/s. The central branch of these fibers reaches the superficial laminae of the dorsal horn. These nociceptor fibers allow the conduction of cold, pressure and heat signals [5].
\n
Remarkably, C-fibers are the ones to mainly establish nociceptive innervation. These are unmyelinated axons with a diameter of 0.4 to 1.2 μm and a conduction speed between 0.5 and 2 m/s. C-fibers innervate laminae I and II of the dorsal horn of the spinal cord and are activated in a polymodal fashion by mechanical, thermal (noxious cold or heat) and chemical stimuli [4, 5].
\n
Diverse injurious stimuli detected by nociceptors are transformed into electrical activity, a process known as transduction where thermal, mechanical, or chemical signals are converted into ion flux through the activation of specialized ion channels [1]. In this way, noxious signals trigger fluctuations in the electrochemical gradient of nociceptors leading to membrane depolarization and subsequent action potentials, as a direct consequence of changes in the activation of ion channels expressed in the nociceptors [6]. Action potentials reach second-order neurons housed in the superficial laminae of the dorsal horn that project towards the spinothalamic and/or spinoparabrachial tracts contributing to the perception of noxious stimuli [2, 3, 7].
\n
The study of the impact of sex steroids on the processing of noxious stimuli has been relevant to our understanding of the underlying differences between females and males. In the last decades, growing evidence related to sexual dimorphism in the perception of harmful signals and the development of pain conditions has been highlighted [8]. Several studies in humans using mechanical, chemical, electrical, or thermal stimuli have suggested that women have more sensitivity to some noxious stimuli than men [8, 9, 10, 11]. However, other contrasting reports have concluded that there is no difference in nociception between genders [12, 13]. Even though these differences are still not clear, the most reasonable explanation pinpoints sex steroids as the most relevant effectors. For example, some conditions such as headache, back and temporomandibular pain increase with pubertal development in girls, where the gonadal steroids produce crucial changes in women physiology [14]. Remarkably, differences in the perception of thermal stimuli between different sexes have also been reported, suggesting that women have greater sensitivity to heat than men [15]. In relation to this, an epidemiological study indicated that low testosterone concentrations in women are associated with an increase in the sensation of cold [16], clearly suggesting that steroids influence nociception.
\n
\n
\n
2. Nociceptive TRP channels
\n
The functional properties of nociceptors are critically regulated by the activity of ion channels expressed in their plasma membrane. Some of these channels belong to the Transient Receptor Potential (TRP) family that play vital roles as detectors of a wide range of biological signals. Some TRP channels are crucial receptors within nociceptors since they function as molecular machinery to transduce several noxious sensory stimuli [17].
\n
In mammals, the TRP family consists of 27 members grouped into 6 subfamilies based on their sequence homology as follows: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin) and TRPA (ankyrin) subfamilies. A seventh group is the TRPN (no mechanoreceptor) subfamily which is not found in mammals, although it is found in the fruit fly, in C. elegans and zebrafish [18]. These receptors are nonselective cation channels that show an overall tetrameric structure, with each monomer being a six-pass transmembrane (S1-S6) protein with a hydrophilic re-entrant loop between the last two transmembrane segments that give rise to the ion conduction pore in the tetrameric arrangement, \nFigure 2\n. These channels have cytosolic N- and C- termini which are highly variable between the different members of the TRP subfamilies [19].\n
\n
Figure 2.
Overall 3D-structure of a TRP channel. Tetrameric assemble for TRP channels. The colored domains represent conserved domains in these channels: Transmembrane domain (S1-S6); the re-entrant loop forms the ion conduction pore; the pre-S1 helix joins the N-terminal to the S1; TRP box localized in the C-terminus. TM and Cyt: transmembrane and cytosolic regions. (TRPV1 3D- structure, PDB: 3J5P).
\n
Some TRP channels are expressed in nociceptors where they display essential roles in the transduction of several noxious stimuli. Among these nociceptive TRP channels are TRPA1, TRPV1–4, TRPM2–3 and TRPM8 [17] which are activated by noxious thermal, chemical and mechanical signals and hence they are important pain-mediators, \nTable 1\n.
Nociceptive TRP channels and their main activators.
\n
The TRPA1 channel, originally described as a cold sensor [20], is activated by several external compounds such as isothiocyanates contained in natural products such as wasabi, horseradish and mustard oil. Other natural TRPA1 activators are allicin and cinnamaldehyde, compounds found in garlic and cinnamon, respectively, and acrolein is also an exogenously-found compound that activates this ion channel [21, 22, 23, 24]. TRPA1’s activation by temperature in humans is still controversial, since some reports have described that TRPA1 is an insensitive cold-channel [23, 24], while several experiments have strengthened its role as a cold sensor [21, 25, 26, 27]. Furthermore, it has also been reported that TRPA1 channel has a redundant role as a noxious heat sensor in the mouse [28]. Indeed, this channel is also indirectly activated by inflammatory mediators like bradykinins and directly by lysophosphatidic acid (LPA, a compound released during injury tissue) and some reactive species produced as the 4-hydroxynonenal [24, 29, 30]. Thus, TRPA1 activation by these endogenous mediators produces inflammatory pain.
\n
Among nociceptive TRP channels some members of the vanilloid receptors (i.e., TRPV1–4 channels) are also included. They are activated by warm (TRPV3-V4) to noxious heat (TRPV1-V2) and by several chemical compounds and osmotic changes.
\n
The most studied channel of the vanilloid subfamily is the TRPV1 channel, originally described as the capsaicin receptor, since it is specifically activated by this pungent compound found in chili peppers [31]. This channel is also activated by compounds such as allicin, resiniferatoxin (a toxin found in the cactus-like plant Euphorbia resinifera) and by animal toxins such as the double-knot (a peptide toxin from the Earth Tiger tarantula), among others [31, 32, 33]. Additionally, several reports have demonstrated that TRPV1 activation is achieved by extracellular acid and intracellular basic pHs and heat (≥42°C) [31]. Furthermore, TRPV1 activation is produced by diverse compounds released during inflammation and tissue injury, for example, some arachidonic acid- and lipoxygenase-derived products, LPA and anandamide [34, 35, 36]. The high expression of the TRPV1 channel in small and medium-diameter neurons and its polymodal activation through several endogenous noxious stimuli, highlight it as a portal to pain; thus, the understanding of its regulation is a promising field to develop new strategies in the research field of pain and analgesia.
\n
The vanilloid subfamily contains two less studied than TRPV1 members: TRPV2 and TRPV3 channels. The former is expressed in medium- and large DRG neurons, activated by temperatures with a threshold of 52°C [37] and by mechanical stretch and osmotic swelling [38]; exogenous compounds like some cannabinoids and endogenous lipids as lysophosphatidyl choline are also TRPV2 activators [39, 40]. Interestingly, the key role of TRPV2 as a noxious sensor is related to mechanical nociception in the somatosensory system, where it is required for the detection of noxious mechanical stimuli [41].
\n
The TRPV3 channel is expressed in keratinocytes and co-expressed with TRPV1 channels in small-diameter sensory neurons. This channel is activated by temperatures between 30 and 39°C [42, 43] and camphor and cannabidiol are exogenous compounds that are also TRPV3 activators [44, 45]. Interestingly, it has been reported that polymorphisms found in the human TRPV2 and TRPV3 genes are associated to the susceptibility and severity to fibromyalgia, suggesting the role of these channels in chronic pain disorders [46].
\n
The other vanilloid receptor playing a nociceptive role is the TRPV4 channel. This channel is activated by warm temperatures (~30–43°C) and hypotonicity [47, 48, 49]. Among the endogenous compounds that are TRPV4 activators are some derivates of arachidonic acid [50, 51]. Interestingly, this ion channel transduces osmotic stimuli inducing nociception and it is also an important mediator of the pruritogens effects of some compounds like serotonin [52, 53].
\n
Finally, another TRP channels important to nociception are some members of the TRPM subfamily: TRPM2-M3 and TRPM8 channels. Although the TRPM2 channel is mainly expressed in immune cells, some expression has also been detected in neurons from DRG and TG [54, 55]. The TRPM2 channel is a warm thermo-sensor, since it is activated at 35°C [56]; other activators for this channel are adenosine 5′-diphosphoribose (ADPR) and H2O2 [57, 58]. The activation of this channel through the generation of reactive species (ROS) implicates it as an important mediator of pain perception during stress oxidative conditions, that prevail in some conditions as fibromyalgia and neuropathy diabetic [59, 60].
\n
The TRPM3 channel, initially identified in β-pancreatic cells [61] has an important role as a sensor of noxious heat, since it is activated by temperatures ≥40°C [62]. The activation of this channel can modulate glucose-induced insulin secretion and also nociception [61, 62]. Its role in the latter is due to high expression in small-diameter sensory neurons from DRG and TG [62] where it also serves as a sensor of noxious chemical stimuli to produce painful responses [62, 63]. Remarkably, TRPM3 together with TRPA1 and TRPV1 channels, form a redundant trio of sensors that mediates noxious heat transduction and provide protection against burn damage [28].
\n
The group of nociceptive TRP channels also comprises the TRPM8 channel, a cold-transducer receptor (10–28°C) which is activated by natural compounds as menthol [64, 65]. This ion channel is predominantly expressed in a subpopulation of small-diameter sensory neurons lacking TRPV1 expression [64, 65]. TRPM8 overactivation is related to cold allodynia and hypersensitivity, pain caused by an innocuous cold stimulus and pain produce by enhanced sensitivity to cold stimulus, respectively [66, 67]. Similarly, to other TRP channels, some endogenous compounds such as artemin induces pain through TRPM8 activation [66]. Curiously, a steroid such as testosterone directly binds to this channel and induces its activation [68].
\n
Clearly, the activation of these nociceptive channels is closely related to acute or chronic pain development and interestingly, some of these channels are targets for sex steroids actions, as we will describe here.
\n
\n
2.1 Estrogens and nociceptive TRP channels
\n
Estrogens influence sexual differentiation in women and they have other essential functions in different biological processes as regulators of the cardiovascular system, metabolism, bone resorption and neuronal physiology [69]. These sex steroids comprise estrone (E1) and 17β estradiol (E2) and estriol (E3) [70]. Similarly, to other steroids, these estrogen’s actions are exerted by their interaction with specific nuclear receptors, the estrogen receptors alpha and beta (ERα and ERβ) that act as transcription factors to trigger gene regulation through a classical genomic pathway [71]. Furthermore, their actions also are through the activation of a membrane localized receptor, the G Protein-Coupled Estrogen Receptor 1 or GPER1 (previously named GPR30), establishing a non-classical pathway to regulate molecular targets [72, 73]. Several reports have suggested that estrogens influence some painful conditions like fibromyalgia, migraine, irritable bowel syndrome and temporomandibular disorder, all of which are conditions with major prevalence in women than in men [74, 75, 76, 77, 78].
\n
Indeed, several experiments made in pain animal models have demonstrated the existence of sexual dimorphism in response to pain. For example, rats from a diabetic neuropathy model exhibited lower mechanical pain thresholds than males. This difference was abolished in gonadectomized animals, highlighting the sex-related differences in diabetic hypersensitivity [79].
\n
These differences could be attributed to estrogen actions on different targets implicated in the transduction of noxious stimuli such as TRP channels, as will be described below.
\n
A close relationship between estrogens and the TRPV1 channel has been demonstrated by several reports. Initially, it was stablished through behavioral assays that female rats exhibited increased capsaicin pain-related responses as compared to males. Furthermore, ovariectomized rats increased their pain threshold to capsaicin, which was reverted by replacement with E2 in these ovariectomized rats [80]. E2 effects on the TRPV1 nociception have also been evaluated during the rat estrous cycle, where the rats in the proestrus phase showed higher capsaicin-pain responses than the rats in estrus. This observation suggested that high E2 levels exhibited in the proestrus, positively regulate pain associated to TRPV1 activation [80]. These results have also been obtained evaluating the mechanical and thermal pain threshold during the mice estrous cycle, showing that mice in the proestrus displayed lower pain thresholds than the mice in estrus [81]. Remarkably, female TRPV1 knockout mice exhibited comparable mechanical and thermal pain thresholds during the proestrus and estrus [81], strongly suggesting that this channel has a pivotal role in the transduction of these noxious stimuli and that its activation is regulated by estrogen levels. A partial molecular mechanism through which estrogens regulate the capsaicin-evoked pain has been described. Initially, it was suggested that TRPV1 protein levels are downregulated in the DRG from the ERα and ERβ knockout mice-model [82], indicating that this ion channel is a molecular target for the effects of estrogen receptors, \nFigure 3\n. Furthermore, several reports have evidenced that TRPV1 mRNA levels are upregulated by E2. For example, primary cell cultures of rat TG or mice DRG neurons treated with E2 displayed increases in TRPV1 mRNA levels [81, 83]. This TRPV1 mRNA upregulation has also been observed in the hippocampus from ovariectomized rats treated with E2, heightening the allodynia displayed in a rat inflammatory temporomandibular model [84].
\n
Figure 3.
Schematic representation of the estrogen classical genomic effect in the regulation of TRPV1 gene expression. The inactive estrogen receptors (ER) localized in the cytoplasm form a protein complex with the heat shock protein (HSP). Internalized 17β estradiol (E2) interacts with the ER, activating and targeting them to the nucleus where they recognize the estrogen response element (ERE), a specific sequence located in the target genes (i.e., TRPV1 gene), resulting in positive regulation of TRPV1 expression.
\n
The upregulation on TRPV1 gene expression has been also evidenced in synoviocytes, osteoclast precursors and endometrium [85, 86, 87]. Furthermore, experiments performed in cultures of human sensory neurons treated with E2 have shown increases in TRPV1 mRNA levels and similar results were obtained when the sensory neurons were incubated with a specific agonist of the ERβ [81, 88]. The E2-dependent effects in the aforementioned cell systems were observed after 24 h of treatment, suggesting that E2 achieves its actions through the classical genomic pathway. This possibility is strengthened by the identification of a putative estrogen response element (ERE) located in the promoter region of the mouse Trpv1 gene, implying that ERα could interact with this gene regulatory sequence to control TRPV1 gene transcription [89], \nFigure 3\n. These ERα bindings sites were also identified in the promoter sequences of the Trpv3–6 genes pointing out that estrogens are regulators of the transcription of these genes [89]. Additionally, it has been determined that different areas of the brains of mice in the proestrus (where the estrogens levels are high) display augmented mRNA levels for the Trpv2, v4 and v6 genes [89]. In contrast, this report also showed that TRPV1 and TRPV5 mRNA levels are downregulated in the brain from mice in the proestrus [89].
\n
Additionally, negative E2 effects on TRPV1 activation have been evidenced in ovariectomized rats, which displayed reduced production of gonadal estrogens and augmented neuronal mitochondrial oxidative stress [90]. This was demonstrated using primary cultures of hippocampal and DRG neurons from these rats, determining that the current densities produced through TRPV1 activation are augmented. A similar effect was observed for the TRPA1 and TRPM2 currents [90]; consequently, overactivation of these channels caused rises in cytosolic Ca2+ and triggered apoptotic dead of these neurons. These effects were prevented in cultures of neurons derived from ovariectomized rats treated with E2 suggesting that this steroid could have neuroprotective actions, avoiding Ca2+ overload caused by the activation of some nociceptive TRP channels and preventing neuronal death [90].
\n
Negative E2 actions on TRPV1 regulation have also been shown in primary cultures of rat DRG neurons treated with E2 or with an ERβ agonist, displaying decreases in capsaicin-evoked currents while TRPV1 protein levels remained unchanged [91]. This effect was lost using a non-permeable E2 (E2 conjugated to bovine serum albumin) and a slight increase in capsaicin-evoked currents was observed [91]. This result suggests that the role of E2 on TRPV1 activation requires steroid internalization in order to establish an interaction with ERβ and to negatively regulate this ion channel [91]. The discrete increase in TRPV1 activation using the non-permeable E2 is in agreement with a previous report which showed that E2 potentiated capsaicin-induced currents in rat DRG primary cultures [92]. Moreover, it was recently described that E2 potentiates TRPV1 activity in an estrogen receptor independent fashion, suggesting that TRPV1 could be an ionotropic receptor for E2 [93]. An interesting outcome from these experimental evidences is that the changes observed in TRPV1 expression are achieved using low E2 concentrations (10–100 nM) [81, 83, 88]; however, the effects on TRPV1 activation need supraphysiological concentrations of the steroid (1–100 μM) [93, 94]. This suggests that low E2 concentrations could modify TRPV1 expression through a classical genomic pathway, whereas a non-classical E2 effect on TRPV1 activation requires high E2 concentrations.
\n
Non-classical E2 actions are produced faster than the genomic effects and are mediated by the interaction of this steroid with the GPER1 [72, 73]. The interaction of E2 with this receptor triggers different signaling pathways, such as those of protein kinase A (PKA) and C (PKC) [72, 95], which could produce TRPV1 phosphorylation. The phosphorylated state of the channel decreases its activation threshold to several stimuli, a process known as sensitization [96]. For instance, a phosphorylated TRPV1 channel can be activated at innocuous heat (i.e., 37°C) [96, 97]. TRPV1 phosphorylation also regulates the channel’s interaction with proteins like tubulin [98, 99], a protein association that is important to mediate mechanical gating of TRPV1 [100]. Interruption of the tubulin-TRPV1 complex through the TRPV1 phosphorylation on serine 800 (S800), decreases TRPV1 activation through osmotic stimuli [99, 100]. Interestingly, E2 through its association with GPER1, triggers the activation of PKCε signaling resulting in phosphorylation of TRPV1 in S800 and blocking the interaction of the channel with tubulin [99]; thus, E2 modifies microtubule-dependent TRPV1 mechanical pain sensitization.
\n
The above data exemplify how TRPV1 is a target of classical and non-classical effects of estrogens, highlighting the estrogenic influence on nociception and pain mediated through the TRPV1 channel.
\n
\n
2.1.1 Estrogens upregulate TRPA1 and TRPV1 expression in endometriosis
\n
Endometriosis is a debilitating chronic pelvic pain where the lining layer of the endometrium grows out of the uterus. This condition is highly estrogen-dependent and the lesion displays innervation of nociceptors co-expressing the TRPV1 and TRPA1 channels [101, 102]. Interestingly, mRNA levels for TRPA1 and TRPV1 are upregulated in the biopsies from women with endometriosis [88], thus it is feasible to consider that the overexpression of these channels could mediate the pain produced in this condition. The overexpression of these channels is likely to be through actions of estrogens, since they play a crucial role in the development of this anomalous pelvic condition. Particularly, it has been demonstrated that female rats treated with diethylstilbestrol, a non-selective estrogen receptor agonist, exhibited upregulation in the TRPV1 and TRPA1 mRNA levels [86] and this expression was found in endometrial cells. Moreover, cultured primary endometrial cells treated with this non-selective agonist also displayed increased TRPA1 and TRPV1 mRNA levels, whereas the treatment with E2 (which is a highly selective agonist of the ERα) only induced the upregulation of the TRPV1 mRNA levels [86]. The data suggests that these nociceptive TRP channels are regulated by the classical effects of estrogen receptors; additionally, these results showed the expression of these channels in non-neuronal cells from the rat endometria. TRPA1 and TRPV1 gene expression also has been demonstrated in human endometria from healthy women; furthermore, endometria samples from women suffering deep infiltrating endometriosis (one of the most severe forms of this condition) exhibit higher TRPV1 and TRPA1 expression, as compared to healthy women [103].
\n
Additionally, it has been reported that hydroxylated estrogens (catechol estrogens) directly activate the TRPA1 channel [104]. This was evidenced using TRPA1-expressing HEK293 cells and whole-cell patch-clamp recordings that showed that 2-hydroxy-estrone (a catechol-estrogen) evoked currents through activation of TRPA1, similarly to another agonist for this channel, cinnamaldehyde. Thus, this hydroxylated estrogen acts as an endogenous agonist for this nociceptive channel [104]. Although, the physiological role of this activation has been demonstrated for insulin secretion in β-pancreatic cells, it would be interesting to explore if the excessive production of catechol-estrogens in endometriosis (as it has been previously reported [105]) affects the function of the TRPA1 channel expressed in endometrial cells and in the free nerve terminals surrounding this area. The expression of these channels in endometrial cells could represent a therapeutic alternative to relieve the main symptoms related to this painful condition; thus, it would be relevant to deepen the studies about the functional roles of TRP channels in these non-neuronal cells.
\n
In addition to the above described evidence, the roles of TRPA1 and TRPV1 in endometriosis have been recently strengthened through the establishment of a mouse endometriosis model [106]. The endometriosis-like lesions induced in these animals displayed the presence of nerve fibers and inflammatory cells around the lesions. Remarkably, theses nerve fibers showed expression of TRPA1 and TRPV1 channels [106]. Furthermore, DRG neurons isolated from mice with induced endometriosis exhibited higher Ca2+ influx levels than neurons from sham animals, and this effect was through the activation of TRPA1 or TRPV1 channels [106]. The upregulation of these nociceptive channels could be directly associated with spontaneous abdominal pain observed in mice with endometriosis. Interestingly, the treatment of these mice with a synthetic androgen (danazol) or an aromatase inhibitor (letrozole), which are estrogen reducing agents, substantially relieved the spontaneously induced endometriosis pain [106]. These data reinforce the crucial role of estrogens in the development of endometriosis and highlight the importance of the TRPA1 and TRPV1 channels as molecular pain mediators in this debilitating form of abdominal pain.
\n
\n
\n
\n
2.2 Nociceptive TRP channels that are targeted by androgen actions
\n
Androgens are steroids that influence the development of male characteristics and they are produced in the gonads (testicles and ovaries) and adrenal glands [107]. The main endogenously produced androgens are testosterone, androstenedione, dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT) [108]. Similarly, to other steroids, testosterone and DHT act as ligands for a specific protein, such as the androgen receptor (AR), while other androgens are weak ligands of the AR. This receptor regulates the expression of several target genes through a classical genomic pathway; furthermore, AR modifies cell physiology through non-classical and non-genomic effects [109].
\n
Indeed, some androgens produce fast- non-genomic effects by interacting with other proteins like some TRP channels and modulating their function. For example, through whole-cell recording electrophysiological experiments, DHEA was shown to decrease capsaicin-dependent currents in dissociated DRG neurons [110]. DHEA effects seem to be direct and specific on TRPV1 channel activation, since with the use of a DHEA stereoisomer the inhibition of channel activation was no longer observed. Additionally, testosterone reduced the activation of TRPV1 to a lesser extent than DHEA [110]. This suggested the presence of a DHEA-binding site in the TRPV1 channel, which should be extracellularly localized, since the steroid was applied to the surface of the neurons during the electrophysiological recordings [110]. However, this remains undetermined and it is possible that DHEA has an antinociceptive role by inhibiting this channel.
\n
The above data exemplified the rapid non-genomic effects of DHEA on TRPV1 activation. Additionally, testosterone seems to negatively regulate the expression of this channel, suggesting that TRPV1 is also a target for the classical actions of androgens. Supporting evidence for this was obtained in dissected TG from castrated male rats with orofacial myositis (induced by the Complete Freund’s adjuvant) [111]. The trigeminal TRPV1 mRNA and protein levels from this rat model were upregulated. Interestingly, TRPV1 expression is unaffected in the TG from castrated rats subjected to testosterone replacement [111], suggesting that testosterone prevents the increase in TRPV1 expression, although the molecular mechanism for this regulation is still unknown.
\n
The TRPA1 channel is another molecular target for the non-classical effects of androgens. As a first approach, it was demonstrated that synthetic aromatase inhibitors evoked currents through TRPA1 channels in isolated DRG neurons; however, these compounds were unable to produce currents in DRG neurons from TRPA1 knockout mice, suggesting specific actions of the aromatase inhibitors on the activation of this channel [112]. Indeed, it was demonstrated that the aromatase inhibitors produced pain-like behavior in mice, a conduct not displayed in the TRPA1 knockout mice [112]. Since these compounds increase the levels of androstenedione in plasma, the effects of this androgen on TRPA1 activation have also been studied [113]. The results showed that androstenedione produces currents in mouse DRG neurons that are partially dependent on TRPA1 activation [113]. Furthermore, remanent androstenedione currents were abolished in the presence of the TRPV1 antagonist capsazepine, suggesting that this androgen could activate nociceptive TRPA1 and TRPV1 channels. Although, androstenedione is unable to cause acute pain-like behavior in mice, the animals exhibited mechanical allodynia 30 to 120 min after its intradermal injection into their paws, an effect that was abolished with a TRPA1 antagonist [113]. These data indicate that androstenedione could act as a pain sensitizing molecule leading to the activation of TRPA1.
\n
Finally, the TRPM8 channel is also regulated by androgens. Interestingly, this channel is a target for the classical and nonclassical actions of testosterone. Initial evidence showed that TRPM8 is an androgen-responsive gene since testosterone treatment in some prostate cancer cell lines produced upregulation in the TRPM8 mRNA levels [114, 115]. TRPM8 expression also increases in the urogenital tract from orchiectomized rats supplemented with testosterone, suggesting that this steroid positively regulates TRPM8 gene expression [116]. Bioinformatic gene analysis showed that the TRPM8 gene contains putative sites for the androgen receptor interaction (androgen response elements, ARE) in its promoter sequence. Through chromatin-immunoprecipitation assays, it was confirmed that androgens receptors bind to these AREs located near the start transcription site of the TRPM8 gene [117]. These data indicated that androgens regulate TRPM8 gene expression in a classical genomic fashion.
\n
The TRPM8 channel also acts as an ionotropic testosterone receptor due to direct interaction with this ion channel, resulting in its activation [68, 118]. Experiments have shown that the TRPM8 channel and the androgen receptor compete for testosterone and dihydrotestosterone because activation of TRPM8 by these androgens is lost when both receptors are co-expressed [68]. An extracellularly-located testosterone binding site in the TRPM8 channel has been suggested [68], and by using molecular docking simulation we have identified an additional intracellular testosterone pocket located between the firts intracellular loop (pre-S1) and the transmembrane segments 1 and 2 (S1-S2) of the TRPM8 protein [119]. This analysis has also shown that an H-bond is formed between testosterone and an arginine located in the TRP box, similar to the H-bond established between testosterone and an arginine in the aromatase enzyme [119]. The similarity in the testosterone pockets of the aromatase and the TRPM8 proteins could suggest that this is a functional binding site for TRPM8 through which activation by this steroid could be achieved in a non-classical and fast fashion. Interestingly, it has been demonstrated that topic testosterone application on humans produced cold- and pain-sensation; the women resulted more sensitized to the testosterone effects than men [68], suggesting a sexual dimorphism in testosterone-produced nociception through TRPM8 activation.
\n
A third non-classical mechanism for TRPM8 regulation by testosterone has been demonstrated in DRG neurons where the androgen receptor and TRPM8 channels form a protein complex in the plasma membrane [120]. High testosterone concentrations (100 nM) inhibit TRPM8 channel activation and the androgen receptor is translocated to the nucleus [120], \nFigure 4\n. The evaluation of the TRPM8-mediated cold perception performed in castrated mice or rats revealed a decrease in their threshold for mild-cold perception; interestingly, testosterone supplementation in these animals inhibited cold perception (temperatures between 16 and 18°C) [120]. This result would suggest that testosterone confers endurance to TRPM8-mediated mild cold perception, which could explain the underlying molecular mechanism for the cold sensation experienced by women presenting lower levels of testosterone [16].
\n
Figure 4.
Testosterone regulates the TRPM8-mediated mild-cold sensitivity. The mild-cold stimulus is transduced through the TRPM8 channel located in the cell surface of DRG neurons where it forms a protein complex with the androgen receptor (AR) (upper panel). A high concentration of testosterone (100 nM) decreases activation of the TRPM8 channel and produces translocation of the AR to the nucleus. The physiological consequence of this is the loss of the mild cold sensation (lower panel).
\n
\n
\n
2.3 Progesterone downregulates TRPV1 and TRPV4 channels expression
\n
Progesterone is a steroid indispensable to the maintenance of pregnancy and it also plays important roles in the cardiovascular, immune, nervous systems and in the bones [121]. Progesterone is produced by the granulosa cells and the corpus luteum in the ovaries and, during pregnancy, the placenta is the major source of this steroid. Additionally, progesterone is produced in the nervous system, adrenal glands and testes [122]. The effects of progesterone are produced through nuclear receptors A and B (PRA/B), activating the classical genomic pathway to regulate gene expression. Furthermore, this steroid exerts a non-classical pathway through the activation of several membrane receptors (mPR) and other receptors as the progesterone receptor membrane components 1 and 2 (PGRMC1/2) and by the Sigma-1 Receptor (Sig-1R) [123, 124].
\n
It has been demonstrated that progesterone regulates the expression of some TRP channels; for example, TRPV4 gene expression is negatively regulated by classical genomic progesterone effects [125]. Initial evidence for this was observed in epithelial and vascular cell lines and a recent report showed a correlation between TRPV4 expression and progesterone levels during the menstrual cycle, demonstrating that during the luteal phase when progesterone reaches its highest levels, TRPV4 expression is downregulated in human endometrial biopsies [126]. Furthermore, it has also been reported that TRPV4 expression is downregulated by a synthetic progestin (levonorgestrel) in a human Fallopian tubal epithelial cell line and mouse oviducts which could affect the transport of fertilized oocytes causing ectopic pregnancy [127].
\n
Our group has determined that progesterone impacts on nociception by regulating the expression of TRPV1 channels [128]. Interestingly, this regulation is through a non-classical mechanism that requires an intermediate protein, the Sig-1R, which is a dynamic chaperone mainly localized in the endoplasmic reticulum and that can also be mobilized to the plasma membrane and nuclear envelope [129]. Progesterone decreases the levels of channels localized in the cell surface in HEK293 cells transfected with TRPV1 cDNA [128]. But how does progesterone produce this effect? Our results have shown that this is achieved by disrupting a protein complex formed between TRPV1 channels and the Sig-1R and by affecting the proper folding of TRPV1. Consequently, the channels are degraded by the proteasomal pathway and capsaicin-evoked currents are reduced [128]. The TRPV1 downregulation through progesterone actions was also observed in primary cultures of DRG neurons and we also demonstrated that during mice pregnancy when there are high progesterone levels, the threshold to capsaicin-dependent pain-like behaviors are augmented in comparison to non-pregnant mice, suggesting that progesterone confers protection to pain produced through activation of TRPV1 [128]. This work exemplified the antinociceptive actions that progesterone exerts through the decrease in the levels of TRPV1 channels localized in the plasma membrane of nociceptors and by the reduction of the transduction of harmful signals through this ion channel. Moreover, it has also been reported that progesterone disrupts the protein complex formed between Sig-1R and the TRPA1 and TRPM8 channels [130], suggesting that this steroid could impact the nociception through these nociceptive TRP channels.
\n
\n
\n
\n
3. Conclusion
\n
Nociception is a neuronal process that protects against injurious stimuli that can be endogenously produced during inflammation or tissue injury processes. The transduction of these signals requires the activation of ion channels such as some members of the TRP family. In this chapter we have described how sex steroids influence nociception by regulating some of the TRP channels important for this neuronal process. Here we have described the data showing that estrogens and their nuclear receptors (ERα/β) positively regulate the expression of the TRPV1 and TRPA1 genes through a classical genomic pathway. The reports above discussed also show that progesterone and its nuclear receptors (PRA/B) negatively regulate TRPV4 gene expression.
\n
We have also compiled and discussed the evidence about androstenedione’s and testosterone’s non-classical effects in the regulation of the activation of TRPA1 and TRPM8 ion channels directly. We have suggested a testosterone binding-pocket in the TRPM8 channel and we have also pinpointed an androstenedione binding-pocket in the C-terminal and pre-S1 regions of TRPV1 and TRPA1 channels [119].
\n
These observations strengthen the notion that androgens act as direct molecular regulators of some nociceptive ion channels function, playing dual roles as nociceptive and antinociceptive molecules. For example, androstenedione has nociceptive actions on TRPA1 and TRPV1 activation and testosterone at low concentrations (picomolar range) can produce cold sensation through the TRPM8 channel, while high testosterone levels could improve resilience to cold sensation inhibiting the currents through TRPM8. Finally, the literature here reviewed shows that the nonclassical sex steroid effects are mediated by membrane receptors or even chaperones such as the Sig-1R, affecting signaling pathways and/or protein stability. This last finding exemplifies the antinociceptive effects of progesterone by which this hormone reduces the transduction of noxious stimuli mediated by TRPV1 channel activation. These data open a research field in which we will deepen our knowledge in the role of molecular sexual dimorphism and the interplay between nociceptive TRP channels and sex steroids.
\n
\n
Acknowledgments
\n
\nFunding: Este trabajo fue apoyado por el FORDECYT-PRONACES (FORDECYT-PRONACES/64392/2020) del Consejo Nacional de Ciencia y Tecnología. También recibió apoyo de la Dirección General de Asuntos del Personal Académico (DGAPA)-Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT) IN206819 y de los Estímulos a Investigaciones Médicas Miguel Alemán Valdés.
\n
\n
Conflict of interest
\n
The authors declare no conflict of interest.
\n
\n
Notes/thanks/other declarations
\n
Ó.E.P and K.A.M.R contributed equally to this work. This work comprises the MSc thesis work of Ó.E.P. from the Programa de Maestría y Doctorado en Ciencias Bioquímicas at the Universidad Nacional Autónoma de México and the PhD thesis work of K.A.M.R. student from the Programa de Doctorado en Ciencias Biomédicas at the Universidad Nacional Autónoma de México. We thank Alejandra Llorente for her administrative support.
\n
\n',keywords:"TRP channels, nociception, steroids, pain, sensory neurons",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75025.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75025.xml",downloadPdfUrl:"/chapter/pdf-download/75025",previewPdfUrl:"/chapter/pdf-preview/75025",totalDownloads:29,totalViews:0,totalCrossrefCites:0,dateSubmitted:"October 2nd 2020",dateReviewed:"December 18th 2020",datePrePublished:"March 24th 2021",datePublished:null,dateFinished:"February 1st 2021",readingETA:"0",abstract:"Proteins belonging to Transient Receptor Potential (TRP) family are nonselective cation channels that play an essential role in mammalian physiology, functioning as transducers of several environmental signals including those of chemical, thermal and mechanical natures. A subgroup of these receptors is expressed in sensory neurons where they are activated by noxious stimuli and are key players of pain responses in the organism. Some TRP channels are molecular targets for the classical and non-classical effects of sex steroids. This chapter will describe the close relationship between nociceptive TRP channels and sex steroids as well as their impact on nociception and pain-related responses.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75025",risUrl:"/chapter/ris/75025",signatures:"Óscar Enciso-Pablo, Karina Angélica Méndez-Reséndiz, Tamara Rosenbaum and Sara Luz Morales-Lázaro",book:{id:"10313",title:"Sex Hormones",subtitle:null,fullTitle:"Sex Hormones",slug:null,publishedDate:null,bookSignature:"Dr. Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/10313.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Nociceptive TRP channels",level:"1"},{id:"sec_2_2",title:"2.1 Estrogens and nociceptive TRP channels",level:"2"},{id:"sec_2_3",title:"2.1.1 Estrogens upregulate TRPA1 and TRPV1 expression in endometriosis",level:"3"},{id:"sec_4_2",title:"2.2 Nociceptive TRP channels that are targeted by androgen actions",level:"2"},{id:"sec_5_2",title:"2.3 Progesterone downregulates TRPV1 and TRPV4 channels expression",level:"2"},{id:"sec_7",title:"3. Conclusion",level:"1"},{id:"sec_8",title:"Acknowledgments",level:"1"},{id:"sec_8",title:"Conflict of interest",level:"1"},{id:"sec_9",title:"Notes/thanks/other declarations",level:"1"}],chapterReferences:[{id:"B1",body:'\nTracey, W.D., Jr. Nociception\n. Curr Biol. 2017. 27(4): p. R129-R133. 10.1016/j.cub.2017.01.037\n'},{id:"B2",body:'\nBasbaum, A.I., et al. Cellular and molecular mechanisms of pain. Cell. 2009. 139(2): p. 267-84. 10.1016/j.cell.2009.09.028\n'},{id:"B3",body:'\nWoolf, C.J. and Q. Ma. Nociceptors--noxious stimulus detectors. Neuron. 2007. 55(3): p. 353-64. 10.1016/j.neuron.2007.07.016\n'},{id:"B4",body:'\nArmstrong, S.A. and M.J. Herr, Physiology, Nociception, in StatPearls. 2020: Treasure Island (FL).\n'},{id:"B5",body:'\nDubin, A.E. and A. Patapoutian. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010. 120(11): p. 3760-72. 10.1172/JCI42843\n'},{id:"B6",body:'\nWaxman, S.G. and G.W. Zamponi. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci. 2014. 17(2): p. 153-63. 10.1038/nn.3602\n'},{id:"B7",body:'\nTodd, A.J. Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci. 2010. 11(12): p. 823-36. 10.1038/nrn2947\n'},{id:"B8",body:'\nFillingim, R.B., et al. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009. 10(5): p. 447-85. 10.1016/j.jpain.2008.12.001\n'},{id:"B9",body:'\nBartley, E.J. and R.B. Fillingim. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth. 2013. 111(1): p. 52-8. 10.1093/bja/aet127\n'},{id:"B10",body:'\nCairns, B.E. The influence of gender and sex steroids on craniofacial nociception. Headache. 2007. 47(2): p. 319-24. 10.1111/j.1526-4610.2006.00708.x\n'},{id:"B11",body:'\nHashmi, J.A. and K.D. Davis. Deconstructing sex differences in pain sensitivity. Pain. 2014. 155(1): p. 10-3. 10.1016/j.pain.2013.07.039\n'},{id:"B12",body:'\nRacine, M., et al. A systematic literature review of 10 years of research on sex/gender and experimental pain perception - part 1: are there really differences between women and men? Pain. 2012. 153(3): p. 602-18. 10.1016/j.pain.2011.11.025\n'},{id:"B13",body:'\nRacine, M., et al. A systematic literature review of 10 years of research on sex/gender and pain perception - part 2: do biopsychosocial factors alter pain sensitivity differently in women and men? Pain. 2012. 153(3): p. 619-35. 10.1016/j.pain.2011.11.026\n'},{id:"B14",body:'\nLeResche, L., et al. Relationship of pain and symptoms to pubertal development in adolescents. Pain. 2005. 118(1-2): p. 201-9. 10.1016/j.pain.2005.08.011\n'},{id:"B15",body:'\nLue, Y.J., et al. Thermal pain tolerance and pain rating in normal subjects: Gender and age effects. Eur J Pain. 2018. 22(6): p. 1035-1042. 10.1002/ejp.1188\n'},{id:"B16",body:'\nGotmar, A., et al. Symptoms in peri- and postmenopausal women in relation to testosterone concentrations: data from The Women\'s Health in the Lund Area (WHILA) study. Climacteric. 2008. 11(4): p. 304-14. 10.1080/13697130802249769\n'},{id:"B17",body:'\nMickle, A.D., A.J. Shepherd, and D.P. Mohapatra. Sensory TRP channels: the key transducers of nociception and pain. Prog Mol Biol Transl Sci. 2015. 131: p. 73-118. 10.1016/bs.pmbts.2015.01.002\n'},{id:"B18",body:'\nClapham, D.E., L.W. Runnels, and C. Strubing. The TRP ion channel family. Nat Rev Neurosci. 2001. 2(6): p. 387-96. 10.1038/35077544\n'},{id:"B19",body:'\nRosasco, M.G. and S.E. Gordon, TRP Channels: What Do They Look Like?, in Neurobiology of TRP Channels, T.L.R. Emir, Editor. 2017: Boca Raton (FL). p. 1-9.\n'},{id:"B20",body:'\nStory, G.M., et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003. 112(6): p. 819-29. 10.1016/s0092-8674(03)00158-2\n'},{id:"B21",body:'\nBandell, M., et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004. 41(6): p. 849-57. 10.1016/s0896-6273(04)00150-3\n'},{id:"B22",body:'\nBautista, D.M., et al. Pungent products from garlic activate the sensory ion channel TRPA1. Proc Natl Acad Sci U S A. 2005. 102(34): p. 12248-52. 10.1073/pnas.0505356102\n'},{id:"B23",body:'\nJordt, S.E., et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature. 2004. 427(6971): p. 260-5. 10.1038/nature02282\n'},{id:"B24",body:'\nBautista, D.M., et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell. 2006. 124(6): p. 1269-82. 10.1016/j.cell.2006.02.023\n'},{id:"B25",body:'\nFajardo, O., et al. TRPA1 channels mediate cold temperature sensing in mammalian vagal sensory neurons: pharmacological and genetic evidence. J Neurosci. 2008. 28(31): p. 7863-75. 10.1523/JNEUROSCI.1696-08.2008\n'},{id:"B26",body:'\nKarashima, Y., et al. TRPA1 acts as a cold sensor in vitro and in vivo. Proc Natl Acad Sci U S A. 2009. 106(4): p. 1273-8. 10.1073/pnas.0808487106\n'},{id:"B27",body:'\nMoparthi, L., et al. Human TRPA1 is intrinsically cold- and chemosensitive with and without its N-terminal ankyrin repeat domain. Proc Natl Acad Sci U S A. 2014. 111(47): p. 16901-6. 10.1073/pnas.1412689111\n'},{id:"B28",body:'\nVandewauw, I., et al. A TRP channel trio mediates acute noxious heat sensing. Nature. 2018. 555(7698): p. 662-666. 10.1038/nature26137\n'},{id:"B29",body:'\nTrevisani, M., et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2007. 104(33): p. 13519-24. 10.1073/pnas.0705923104\n'},{id:"B30",body:'\nKittaka, H., et al. Lysophosphatidic acid-induced itch is mediated by signalling of LPA5 receptor, phospholipase D and TRPA1/TRPV1. J Physiol. 2017. 595(8): p. 2681-2698. 10.1113/JP273961\n'},{id:"B31",body:'\nCaterina, M.J., et al. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997. 389(6653): p. 816-24. 10.1038/39807\n'},{id:"B32",body:'\nBohlen, C.J., et al. A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell. 2010. 141(5): p. 834-45. 10.1016/j.cell.2010.03.052\n'},{id:"B33",body:'\nSalazar, H., et al. A single N-terminal cysteine in TRPV1 determines activation by pungent compounds from onion and garlic. Nat Neurosci. 2008. 11(3): p. 255-61. 10.1038/nn2056\n'},{id:"B34",body:'\nHwang, S.W., et al. Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc Natl Acad Sci U S A. 2000. 97(11): p. 6155-60. 10.1073/pnas.97.11.6155\n'},{id:"B35",body:'\nNieto-Posadas, A., et al. Lysophosphatidic acid directly activates TRPV1 through a C-terminal binding site. Nat Chem Biol. 2011. 8(1): p. 78-85. 10.1038/nchembio.712\n'},{id:"B36",body:'\nZygmunt, P.M., et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999. 400(6743): p. 452-7. 10.1038/22761\n'},{id:"B37",body:'\nCaterina, M.J., et al. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature. 1999. 398(6726): p. 436-41. 10.1038/18906\n'},{id:"B38",body:'\nMuraki, K., et al. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ Res. 2003. 93(9): p. 829-38. 10.1161/01.RES.0000097263.10220.0C\n'},{id:"B39",body:'\nDe Petrocellis, L., et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol. 2011. 163(7): p. 1479-94. 10.1111/j.1476-5381.2010.01166.x\n'},{id:"B40",body:'\nMonet, M., et al. Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation. Biochim Biophys Acta. 2009. 1793(3): p. 528-39. 10.1016/j.bbamcr.2009.01.003\n'},{id:"B41",body:'\nKatanosaka, K., et al. TRPV2 is required for mechanical nociception and the stretch-evoked response of primary sensory neurons. Sci Rep. 2018. 8(1): p. 16782. 10.1038/s41598-018-35049-4\n'},{id:"B42",body:'\nSmith, G.D., et al. TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature. 2002. 418(6894): p. 186-90. 10.1038/nature00894\n'},{id:"B43",body:'\nXu, H., et al. TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature. 2002. 418(6894): p. 181-6. 10.1038/nature00882\n'},{id:"B44",body:'\nDe Petrocellis, L., et al. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf). 2012. 204(2): p. 255-66. 10.1111/j.1748-1716.2011.02338.x\n'},{id:"B45",body:'\nMoqrich, A., et al. Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science. 2005. 307(5714): p. 1468-72. 10.1126/science.1108609\n'},{id:"B46",body:'\nPark, D.J., et al. Polymorphisms of the TRPV2 and TRPV3 genes associated with fibromyalgia in a Korean population. Rheumatology (Oxford). 2016. 55(8): p. 1518-27. 10.1093/rheumatology/kew180\n'},{id:"B47",body:'\nGuler, A.D., et al. Heat-evoked activation of the ion channel, TRPV4. J Neurosci. 2002. 22(15): p. 6408-14. 20026679\n'},{id:"B48",body:'\nLiedtke, W., et al. Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell. 2000. 103(3): p. 525-35. 10.1016/s0092-8674(00)00143-4\n'},{id:"B49",body:'\nWatanabe, H., et al. Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J Biol Chem. 2002. 277(49): p. 47044-51. 10.1074/jbc.M208277200\n'},{id:"B50",body:'\nBerna-Erro, A., et al. Structural determinants of 5′,6′-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel. Sci Rep. 2017. 7(1): p. 10522. 10.1038/s41598-017-11274-1\n'},{id:"B51",body:'\nWatanabe, H., et al. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature. 2003. 424(6947): p. 434-8. 10.1038/nature01807\n'},{id:"B52",body:'\nAkiyama, T., et al. Involvement of TRPV4 in Serotonin-Evoked Scratching. J Invest Dermatol. 2016. 136(1): p. 154-160. 10.1038/JID.2015.388\n'},{id:"B53",body:'\nAlessandri-Haber, N., et al. Hypotonicity induces TRPV4-mediated nociception in rat. Neuron. 2003. 39(3): p. 497-511. 10.1016/s0896-6273(03)00462-8\n'},{id:"B54",body:'\nMatsumoto, K., et al. Role of transient receptor potential melastatin 2 (TRPM2) channels in visceral nociception and hypersensitivity. Exp Neurol. 2016. 285(Pt A): p. 41-50. 10.1016/j.expneurol.2016.09.001\n'},{id:"B55",body:'\nVandewauw, I., G. Owsianik, and T. Voets. Systematic and quantitative mRNA expression analysis of TRP channel genes at the single trigeminal and dorsal root ganglion level in mouse. BMC Neurosci. 2013. 14: p. 21. 10.1186/1471-2202-14-21\n'},{id:"B56",body:'\nTogashi, K., et al. TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. EMBO J. 2006. 25(9): p. 1804-15. 10.1038/sj.emboj.7601083\n'},{id:"B57",body:'\nPerraud, A.L., et al. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature. 2001. 411(6837): p. 595-9. 10.1038/35079100\n'},{id:"B58",body:'\nWehage, E., et al. Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem. 2002. 277(26): p. 23150-6. 10.1074/jbc.M112096200\n'},{id:"B59",body:'\nSozbir, E. and M. Naziroglu. Diabetes enhances oxidative stress-induced TRPM2 channel activity and its control by N-acetylcysteine in rat dorsal root ganglion and brain. Metab Brain Dis. 2016. 31(2): p. 385-93. 10.1007/s11011-015-9769-7\n'},{id:"B60",body:'\nYuksel, E., et al. Involvement of TRPM2 and TRPV1 channels on hyperalgesia, apoptosis and oxidative stress in rat fibromyalgia model: Protective role of selenium. Sci Rep. 2017. 7(1): p. 17543. 10.1038/s41598-017-17715-1\n'},{id:"B61",body:'\nWagner, T.F., et al. Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells. Nat Cell Biol. 2008. 10(12): p. 1421-30. 10.1038/ncb1801\n'},{id:"B62",body:'\nVriens, J., et al. TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron. 2011. 70(3): p. 482-94. 10.1016/j.neuron.2011.02.051\n'},{id:"B63",body:'\nHeld, K., et al. Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release. Proc Natl Acad Sci U S A. 2015. 112(11): p. E1363-72. 10.1073/pnas.1419845112\n'},{id:"B64",body:'\nPeier, A.M., et al. A TRP channel that senses cold stimuli and menthol. Cell. 2002. 108(5): p. 705-15. 10.1016/s0092-8674(02)00652-9\n'},{id:"B65",body:'\nBautista, D.M., et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007. 448(7150): p. 204-8. 10.1038/nature05910\n'},{id:"B66",body:'\nLippoldt, E.K., et al. Artemin, a glial cell line-derived neurotrophic factor family member, induces TRPM8-dependent cold pain. J Neurosci. 2013. 33(30): p. 12543-52. 10.1523/JNEUROSCI.5765-12.2013\n'},{id:"B67",body:'\nXing, H., et al. TRPM8 mechanism of cold allodynia after chronic nerve injury. J Neurosci. 2007. 27(50): p. 13680-90. 10.1523/JNEUROSCI.2203-07.2007\n'},{id:"B68",body:'\nAsuthkar, S., et al. The TRPM8 protein is a testosterone receptor: II. Functional evidence for an ionotropic effect of testosterone on TRPM8. J Biol Chem. 2015. 290(5): p. 2670-88. 10.1074/jbc.M114.610873\n'},{id:"B69",body:'\nBarkhem, T., S. Nilsson, and J.A. Gustafsson. Molecular mechanisms, physiological consequences and pharmacological implications of estrogen receptor action. Am J Pharmacogenomics. 2004. 4(1): p. 19-28. 10.2165/00129785-200404010-00003\n'},{id:"B70",body:'\nGruber, C.J., et al. Production and actions of estrogens. N Engl J Med. 2002. 346(5): p. 340-52. 10.1056/NEJMra000471\n'},{id:"B71",body:'\nYasar, P., et al. Molecular mechanism of estrogen-estrogen receptor signaling.Reprod Med Biol. 2017. 16(1): p. 4-20. 10.1002/rmb2.12006\n'},{id:"B72",body:'\nHammes, S.R. and E.R. Levin. Extranuclear steroid receptors: nature and actions. Endocr Rev. 2007. 28(7): p. 726-41. 10.1210/er.2007-0022\n'},{id:"B73",body:'\nRevankar, C.M., et al. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005. 307(5715): p. 1625-30. 10.1126/science.1106943\n'},{id:"B74",body:'\nBuse, D.C., et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013. 53(8): p. 1278-99. 10.1111/head.12150\n'},{id:"B75",body:'\nvan Oosterhout, W.P.J., et al. Female sex hormones in men with migraine. Neurology. 2018. 91(4): p. e374-e381. 10.1212/WNL.0000000000005855\n'},{id:"B76",body:'\nLovell, R.M. and A.C. Ford. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012. 10(7): p. 712-721 e4. 10.1016/j.cgh.2012.02.029\n'},{id:"B77",body:'\nWan, B., et al. Gender-Stratified Prevalence of Psychiatric and Pain Diagnoses in a Primary Care Patient Sample with Fibromyalgia. Pain Med. 2019. 20(11): p. 2129-2133. 10.1093/pm/pnz084\n'},{id:"B78",body:'\nBagis, B., et al. Gender difference in prevalence of signs and symptoms of temporomandibular joint disorders: a retrospective study on 243 consecutive patients. Int J Med Sci. 2012. 9(7): p. 539-44. 10.7150/ijms.4474\n'},{id:"B79",body:'\nJoseph, E.K. and J.D. Levine. Sexual dimorphism in the contribution of protein kinase C isoforms to nociception in the streptozotocin diabetic rat. Neuroscience. 2003. 120(4): p. 907-13. 10.1016/s0306-4522(03)00400-7\n'},{id:"B80",body:'\nLu, Y.C., et al. 17Beta-estradiol mediates the sex difference in capsaicin-induced nociception in rats. J Pharmacol Exp Ther. 2009. 331(3): p. 1104-10. 10.1124/jpet.109.158402\n'},{id:"B81",body:'\nPayrits, M., et al. Estradiol Sensitizes the Transient Receptor Potential Vanilloid 1 Receptor in Pain Responses. Endocrinology. 2017. 158(10): p. 3249-3258. 10.1210/en.2017-00101\n'},{id:"B82",body:'\nCho, T. and V.V. Chaban. Expression of P2X3 and TRPV1 receptors in primary sensory neurons from estrogen receptors-alpha and estrogen receptor-beta knockout mice. Neuroreport. 2012. 23(9): p. 530-4. 10.1097/WNR.0b013e328353fabc\n'},{id:"B83",body:'\nYamagata, K., et al. Estrogens Exacerbate Nociceptive Pain via Up-Regulation of TRPV1 and ANO1 in Trigeminal Primary Neurons of Female Rats. Endocrinology. 2016. 157(11): p. 4309-4317. 10.1210/en.2016-1218\n'},{id:"B84",body:'\nWu, Y.W., et al. 17-Beta-estradiol enhanced allodynia of inflammatory temporomandibular joint through upregulation of hippocampal TRPV1 in ovariectomized rats. J Neurosci. 2010. 30(26): p. 8710-9. 10.1523/JNEUROSCI.6323-09.2010\n'},{id:"B85",body:'\nChen, F., et al. Estrogen inhibits RANKL-induced osteoclastic differentiation by increasing the expression of TRPV5 channel. J Cell Biochem. 2014. 115(4): p. 651-8. 10.1002/jcb.24700\n'},{id:"B86",body:'\nPohoczky, K., et al. Estrogen-dependent up-regulation of TRPA1 and TRPV1 receptor proteins in the rat endometrium. J Mol Endocrinol. 2016. 56(2): p. 135-49. 10.1530/JME-15-0184\n'},{id:"B87",body:'\nWu, Y.W., et al. Synovial TRPV1 is upregulated by 17-beta-estradiol and involved in allodynia of inflamed temporomandibular joints in female rats. Arch Oral Biol. 2015. 60(9): p. 1310-8. 10.1016/j.archoralbio.2015.05.011\n'},{id:"B88",body:'\nGreaves, E., et al. Elevated peritoneal expression and estrogen regulation of nociceptive ion channels in endometriosis. J Clin Endocrinol Metab. 2014. 99(9): p. E1738-43. 10.1210/jc.2014-2282\n'},{id:"B89",body:'\nKumar, S., et al. Transient receptor potential vanilloid 1-6 (Trpv1-6) gene expression in the mouse brain during estrous cycle. Brain Res. 2018. 1701: p. 161-170. 10.1016/j.brainres.2018.09.005\n'},{id:"B90",body:'\nYazgan, Y. and M. Naziroglu. Ovariectomy-Induced Mitochondrial Oxidative Stress, Apoptosis, and Calcium Ion Influx Through TRPA1, TRPM2, and TRPV1 Are Prevented by 17beta-Estradiol, Tamoxifen, and Raloxifene in the Hippocampus and Dorsal Root Ganglion of Rats. Mol Neurobiol. 2017. 54(10): p. 7620-7638. 10.1007/s12035-016-0232-5\n'},{id:"B91",body:'\nXu, S., et al. 17beta-estradiol activates estrogen receptor beta-signalling and inhibits transient receptor potential vanilloid receptor 1 activation by capsaicin in adult rat nociceptor neurons. Endocrinology. 2008. 149(11): p. 5540-8. 10.1210/en.2008-0278\n'},{id:"B92",body:'\nChen, S.C., T.J. Chang, and F.S. Wu. Competitive inhibition of the capsaicin receptor-mediated current by dehydroepiandrosterone in rat dorsal root ganglion neurons. J Pharmacol Exp Ther. 2004. 311(2): p. 529-36. 10.1124/jpet.104.069096\n'},{id:"B93",body:'\nRamirez-Barrantes, R., et al. TRPV1-Estradiol Stereospecific Relationship Underlies Cell Survival in Oxidative Cell Death. Front Physiol. 2020. 11: p. 444. 10.3389/fphys.2020.00444\n'},{id:"B94",body:'\nChen, S.C. and F.S. Wu. Mechanism underlying inhibition of the capsaicin receptor-mediated current by pregnenolone sulfate in rat dorsal root ganglion neurons. Brain Res. 2004. 1027(1-2): p. 196-200. 10.1016/j.brainres.2004.08.053\n'},{id:"B95",body:'\nDeLeon, C., D.Q.-H. Wang, and C.K. Arnatt. G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases. 2020. 11(843). 10.3389/fendo.2020.578536\n'},{id:"B96",body:'\nLopshire, J.C. and G.D. Nicol. The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies. J Neurosci. 1998. 18(16): p. 6081-92.\n'},{id:"B97",body:'\nJoseph, J., et al. Phosphorylation of TRPV1 S801 Contributes to Modality-Specific Hyperalgesia in Mice. J Neurosci. 2019. 39(50): p. 9954-9966. 10.1523/JNEUROSCI.1064-19.2019\n'},{id:"B98",body:'\nGoswami, C., T.B. Hucho, and F. Hucho. Identification and characterisation of novel tubulin-binding motifs located within the C-terminus of TRPV1. J Neurochem. 2007. 101(1): p. 250-62. 10.1111/j.1471-4159.2006.04338.x\n'},{id:"B99",body:'\nGoswami, C., et al. Estrogen destabilizes microtubules through an ion-conductivity-independent TRPV1 pathway. J Neurochem. 2011. 117(6): p. 995-1008. 10.1111/j.1471-4159.2011.07270.x\n'},{id:"B100",body:'\nPrager-Khoutorsky, M., A. Khoutorsky, and C.W. Bourque. Unique interweaved microtubule scaffold mediates osmosensory transduction via physical interaction with TRPV1. Neuron. 2014. 83(4): p. 866-78. 10.1016/j.neuron.2014.07.023\n'},{id:"B101",body:'\nLiu, J., et al. The expression and functionality of transient receptor potential vanilloid 1 in ovarian endometriomas. Reprod Sci. 2012. 19(10): p. 1110-24. 10.1177/1933719112443876\n'},{id:"B102",body:'\nMcKinnon, B.D., et al. Inflammation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab. 2015. 26(1): p. 1-10. 10.1016/j.tem.2014.10.003\n'},{id:"B103",body:'\nBohonyi, N., et al. Local upregulation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 ion channels in rectosigmoid deep infiltrating endometriosis. Mol Pain. 2017. 13: p. 1744806917705564. 10.1177/1744806917705564\n'},{id:"B104",body:'\nMa, W., et al. Catechol estrogens stimulate insulin secretion in pancreatic beta-cells via activation of the transient receptor potential A1 (TRPA1) channel. J Biol Chem. 2019. 294(8): p. 2935-2946. 10.1074/jbc.RA118.005504\n'},{id:"B105",body:'\nHevir, N., M. Ribic-Pucelj, and T. Lanisnik Rizner. Disturbed balance between phase I and II metabolizing enzymes in ovarian endometriosis: a source of excessive hydroxy-estrogens and ROS? Mol Cell Endocrinol. 2013. 367(1-2): p. 74-84. 10.1016/j.mce.2012.12.019\n'},{id:"B106",body:'\nFattori, V., et al. Nonsurgical mouse model of endometriosis-associated pain that responds to clinically active drugs. Pain. 2020. 161(6): p. 1321-1331. 10.1097/j.pain.0000000000001832\n'},{id:"B107",body:'\nMooradian, A.D., J.E. Morley, and S.G. Korenman. Biological actions of androgens. Endocr Rev. 1987. 8(1): p. 1-28. 10.1210/edrv-8-1-1\n'},{id:"B108",body:'\nSchiffer, L., W. Arlt, and K.H. Storbeck. Intracrine androgen biosynthesis, metabolism and action revisited. Mol Cell Endocrinol. 2018. 465: p. 4-26. 10.1016/j.mce.2017.08.016\n'},{id:"B109",body:'\nBennett, N.C., et al. Molecular cell biology of androgen receptor signalling. Int J Biochem Cell Biol. 2010. 42(6): p. 813-27. 10.1016/j.biocel.2009.11.013\n'},{id:"B110",body:'\nChen, F., et al. Partial agonist/antagonist properties of androstenedione and 4-androsten-3beta,17beta-diol. J Steroid Biochem Mol Biol. 2004. 91(4-5): p. 247-57. 10.1016/j.jsbmb.2004.04.009\n'},{id:"B111",body:'\nBai, X., X. Zhang, and Q. Zhou. Effect of Testosterone on TRPV1 Expression in a Model of Orofacial Myositis Pain in the Rat. J Mol Neurosci. 2018. 64(1): p. 93-101. 10.1007/s12031-017-1009-7\n'},{id:"B112",body:'\nFusi, C., et al. Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1. Nat Commun. 2014. 5: p. 5736. 10.1038/ncomms6736\n'},{id:"B113",body:'\nDe Logu, F., et al. TRPA1 Mediates Aromatase Inhibitor-Evoked Pain by the Aromatase Substrate Androstenedione. Cancer Res. 2016. 76(23): p. 7024-7035. 10.1158/0008-5472.CAN-16-1492\n'},{id:"B114",body:'\nBidaux, G., et al. Evidence for specific TRPM8 expression in human prostate secretory epithelial cells: functional androgen receptor requirement. Endocr Relat Cancer. 2005. 12(2): p. 367-82. 10.1677/erc.1.00969\n'},{id:"B115",body:'\nZhang, L. and G.J. Barritt. Evidence that TRPM8 is an androgen-dependent Ca2+ channel required for the survival of prostate cancer cells. Cancer Res. 2004. 64(22): p. 8365-73. 10.1158/0008-5472.CAN-04-2146\n'},{id:"B116",body:'\nYang, Z., et al. Effect of surgical castration on expression of TRPM8 in urogenital tract of male rats. Mol Biol Rep. 2012. 39(4): p. 4797-802. 10.1007/s11033-011-1271-7\n'},{id:"B117",body:'\nAsuthkar, S., et al. TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells. Oncotarget. 2015. 6(19): p. 17221-36. 10.18632/oncotarget.3948\n'},{id:"B118",body:'\nAsuthkar, S., et al. The TRPM8 protein is a testosterone receptor: I. Biochemical evidence for direct TRPM8-testosterone interactions. J Biol Chem. 2015. 290(5): p. 2659-69. 10.1074/jbc.M114.610824\n'},{id:"B119",body:'\nMendez-Resendiz, K.A., et al. Steroids and TRP Channels: A Close Relationship. Int J Mol Sci. 2020. 21(11). 10.3390/ijms21113819\n'},{id:"B120",body:'\nGkika, D., et al. Testosterone-androgen receptor: The steroid link inhibiting TRPM8-mediated cold sensitivity. FASEB J. 2020. 10.1096/fj.201902270R\n'},{id:"B121",body:'\nTaraborrelli, S. Physiology, production and action of progesterone. Acta Obstet Gynecol Scand. 2015. 94 Suppl 161: p. 8-16. 10.1111/aogs.12771\n'},{id:"B122",body:'\nGoletiani, N.V., D.R. Keith, and S.J. Gorsky. Progesterone: review of safety for clinical studies. Exp Clin Psychopharmacol. 2007. 15(5): p. 427-44. 10.1037/1064-1297.15.5.427\n'},{id:"B123",body:'\nGarg, D., et al. Progesterone-Mediated Non-Classical Signaling. Trends Endocrinol Metab. 2017. 28(9): p. 656-668. 10.1016/j.tem.2017.05.006\n'},{id:"B124",body:'\nMaurice, T., C. Gregoire, and J. Espallergues. Neuro(active)steroids actions at the neuromodulatory sigma1 (sigma1) receptor: biochemical and physiological evidences, consequences in neuroprotection. Pharmacol Biochem Behav. 2006. 84(4): p. 581-97. 10.1016/j.pbb.2006.07.009\n'},{id:"B125",body:'\nJung, C., et al. The progesterone receptor regulates the expression of TRPV4 channel. Pflugers Arch. 2009. 459(1): p. 105-13. 10.1007/s00424-009-0706-7\n'},{id:"B126",body:'\nDe Clercq, K., et al. Functional expression of transient receptor potential channels in human endometrial stromal cells during the luteal phase of the menstrual cycle. Hum Reprod. 2015. 30(6): p. 1421-36. 10.1093/humrep/dev068\n'},{id:"B127",body:'\nLi, C., et al. TRPV4 is involved in levonorgestrel-induced reduction in oviduct ciliary beating. J Pathol. 2019. 248(1): p. 77-87. 10.1002/path.5233\n'},{id:"B128",body:'\nOrtiz-Renteria, M., et al. TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain. Proc Natl Acad Sci U S A. 2018. 115(7): p. E1657-E1666. 10.1073/pnas.1715972115\n'},{id:"B129",body:'\nHayashi, T. and T.P. Su. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 2007. 131(3): p. 596-610. 10.1016/j.cell.2007.08.036\n'},{id:"B130",body:'\nCortes-Montero, E., et al. Ligands Exert Biased Activity to Regulate Sigma 1 Receptor Interactions With Cationic TRPA1, TRPV1, and TRPM8 Channels. Front Pharmacol. 2019. 10: p. 634. 10.3389/fphar.2019.00634\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Óscar Enciso-Pablo",address:null,affiliation:'
Department of Cognitive Neuroscience, Institute of Cellular Physiology, UNAM, México City, México
Department of Cognitive Neuroscience, Institute of Cellular Physiology, UNAM, México City, México
'}],corrections:null},book:{id:"10313",title:"Sex Hormones",subtitle:null,fullTitle:"Sex Hormones",slug:null,publishedDate:null,bookSignature:"Dr. Courtney Marsh",coverURL:"https://cdn.intechopen.com/books/images_new/10313.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"255491",title:"Dr.",name:"Courtney",middleName:null,surname:"Marsh",slug:"courtney-marsh",fullName:"Courtney Marsh"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"15164",title:"Dr.",name:"Michele",middleName:null,surname:"Coletti",email:"coletti@soton.ac.uk",fullName:"Michele Coletti",slug:"michele-coletti",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"1",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[],chaptersAuthored:[{title:"Electric Propulsion Subsystem Architecture for an All-Electric Spacecraft",slug:"electric-propulsion-subsystem-architecture-for-an-all-electric-spacecraft",abstract:null,signatures:"Michele Coletti, Angelo Grubisic, Cheryl Collingwood and Stephen Gabriel",authors:[{id:"15164",title:"Dr.",name:"Michele",surname:"Coletti",fullName:"Michele Coletti",slug:"michele-coletti",email:"coletti@soton.ac.uk"},{id:"15169",title:"Dr.",name:"Angelo",surname:"Grubisic",fullName:"Angelo Grubisic",slug:"angelo-grubisic",email:"ang1j06@soton.ac.uk"},{id:"15170",title:"Prof.",name:"Cheryl",surname:"Collingwood",fullName:"Cheryl Collingwood",slug:"cheryl-collingwood",email:"cmc31@soton.ac.uk"},{id:"15171",title:"Prof.",name:"Stephen",surname:"Gabriel",fullName:"Stephen Gabriel",slug:"stephen-gabriel",email:"sbg2@soton.ac.uk"}],book:{title:"Advances in Spacecraft Technologies",slug:"advances-in-spacecraft-technologies",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"14508",title:"Dr.",name:"Sathyan",surname:"Krishnan",slug:"sathyan-krishnan",fullName:"Sathyan Krishnan",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"15120",title:"Dr.",name:"Tongli",surname:"Chang",slug:"tongli-chang",fullName:"Tongli Chang",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Tongli Chang is currently an Associate Professor in the College of Mechanical and Electrical Engineering at Northeast Forestry University, Harbin, China. He received his Doctor and Master degree from the School of Mechanical and Electrical Engineering at Harbin Institute of Technology, Harbin, China. He had 11-year-working experience as an mechantronic system designer and engineer in an state-own specific purpose vechile enterprise of China. He received his Bachelor degree from the School of Vechicle Engineering at Beijing Institute of Technology, Beijing, China, in 1991.",institutionString:null,institution:{name:"Northeast Forestry University",institutionURL:null,country:{name:"China"}}},{id:"15401",title:"Dr.",name:"Malcolm",surname:"Macdonald",slug:"malcolm-macdonald",fullName:"Malcolm Macdonald",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"15862",title:"Dr.",name:"Akihisa",surname:"Matsubara",slug:"akihisa-matsubara",fullName:"Akihisa Matsubara",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"17500",title:"Dr.",name:"Sang-Heon",surname:"Lee",slug:"sang-heon-lee",fullName:"Sang-Heon Lee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"17501",title:"Dr.",name:"Hung-Yao",surname:"Hsu",slug:"hung-yao-hsu",fullName:"Hung-Yao Hsu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"17502",title:"Dr.",name:"Gopinath",surname:"Konchady",slug:"gopinath-konchady",fullName:"Gopinath Konchady",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"17730",title:"Prof.",name:"Atsushi",surname:"Tomiki",slug:"atsushi-tomiki",fullName:"Atsushi Tomiki",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"17731",title:"Prof.",name:"Tomoaki",surname:"Toda",slug:"tomoaki-toda",fullName:"Tomoaki Toda",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Japan Aerospace Exploration Agency",institutionURL:null,country:{name:"Japan"}}},{id:"17732",title:"Prof.",name:"Takehiko",surname:"Kobayashi",slug:"takehiko-kobayashi",fullName:"Takehiko Kobayashi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"unsubscribe-successful",title:"Unsubscribe Successful",intro:"
You have been successfully unsubscribed.
",metaTitle:"Unsubscribe Successful",metaDescription:"You have been successfully unsubscribed.",metaKeywords:null,canonicalURL:"/page/unsubscribe-successful",contentRaw:'[{"type":"htmlEditorComponent","content":""}]'},components:[{type:"htmlEditorComponent",content:""}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5817},{group:"region",caption:"Middle and South America",value:2,count:5282},{group:"region",caption:"Africa",value:3,count:1755},{group:"region",caption:"Asia",value:4,count:10511},{group:"region",caption:"Australia and Oceania",value:5,count:906},{group:"region",caption:"Europe",value:6,count:15915}],offset:12,limit:12,total:119159},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{topicId:"9"},books:[{type:"book",id:"10519",title:"Middleware Architecture",subtitle:null,isOpenForSubmission:!0,hash:"c326d436ae0f4c508849d2336dbdfb48",slug:null,bookSignature:"Dr. Mehdia Ajana El Khaddar",coverURL:"https://cdn.intechopen.com/books/images_new/10519.jpg",editedByType:null,editors:[{id:"26677",title:"Dr.",name:"Mehdia",surname:"Ajana El Khaddar",slug:"mehdia-ajana-el-khaddar",fullName:"Mehdia Ajana El Khaddar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10651",title:"Machine Learning - Algorithms, Models and Applications",subtitle:null,isOpenForSubmission:!0,hash:"6208156401c496e0a4ca5ff4265324cc",slug:null,bookSignature:"Prof. Jaydip Sen",coverURL:"https://cdn.intechopen.com/books/images_new/10651.jpg",editedByType:null,editors:[{id:"4519",title:"Prof.",name:"Jaydip",surname:"Sen",slug:"jaydip-sen",fullName:"Jaydip Sen"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10653",title:"Optimization Algorithms",subtitle:null,isOpenForSubmission:!0,hash:"3cf7194a8c120e74db9dd632b9affb83",slug:null,bookSignature:"Prof. Nodari Vakhania",coverURL:"https://cdn.intechopen.com/books/images_new/10653.jpg",editedByType:null,editors:[{id:"202585",title:"Prof.",name:"Nodari",surname:"Vakhania",slug:"nodari-vakhania",fullName:"Nodari Vakhania"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10691",title:"Intelligent and Futuristic Computer Animation",subtitle:null,isOpenForSubmission:!0,hash:"5496e567e838f1eaeafba5f9a776b13a",slug:null,bookSignature:"Prof. Ahmad Hoirul Basori and Dr. Andi Besse Firdausiah Mansur",coverURL:"https://cdn.intechopen.com/books/images_new/10691.jpg",editedByType:null,editors:[{id:"13394",title:"Prof.",name:"Ahmad Hoirul",surname:"Basori",slug:"ahmad-hoirul-basori",fullName:"Ahmad Hoirul Basori"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10692",title:"Critical Systems - Towards Antifragility",subtitle:null,isOpenForSubmission:!0,hash:"78d284ad921e9677830ef0335b1f1276",slug:null,bookSignature:"Prof. Darrell Mann",coverURL:"https://cdn.intechopen.com/books/images_new/10692.jpg",editedByType:null,editors:[{id:"297423",title:"Prof.",name:"Darrell",surname:"Mann",slug:"darrell-mann",fullName:"Darrell Mann"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10695",title:"Computational Fluid Dynamics",subtitle:null,isOpenForSubmission:!0,hash:"1f8fd29e4b72dbfe632f47840b369b11",slug:null,bookSignature:"Dr. Suvanjan Bhattacharyya",coverURL:"https://cdn.intechopen.com/books/images_new/10695.jpg",editedByType:null,editors:[{id:"233630",title:"Dr.",name:"Suvanjan",surname:"Bhattacharyya",slug:"suvanjan-bhattacharyya",fullName:"Suvanjan Bhattacharyya"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10857",title:"Augmented Reality",subtitle:null,isOpenForSubmission:!0,hash:"5d66e2c09cddac7cc377ffb103aa7ef9",slug:null,bookSignature:"Dr. Dragan Mladen Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/10857.jpg",editedByType:null,editors:[{id:"101330",title:"Dr.",name:"Dragan",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10858",title:"MOOC (Massive Open Online Courses)",subtitle:null,isOpenForSubmission:!0,hash:"d32f86793bc72dde32532f509b1ec5b0",slug:null,bookSignature:"Dr. Dragan Mladen Cvetković",coverURL:"https://cdn.intechopen.com/books/images_new/10858.jpg",editedByType:null,editors:[{id:"101330",title:"Dr.",name:"Dragan",surname:"Cvetković",slug:"dragan-cvetkovic",fullName:"Dragan Cvetković"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10859",title:"Data Mining",subtitle:null,isOpenForSubmission:!0,hash:"63a4e514e537d3962cf53ef1c6b9d5eb",slug:null,bookSignature:"Prof. Ciza Thomas",coverURL:"https://cdn.intechopen.com/books/images_new/10859.jpg",editedByType:null,editors:[{id:"43680",title:"Prof.",name:"Ciza",surname:"Thomas",slug:"ciza-thomas",fullName:"Ciza Thomas"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:28},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:9},{group:"topic",caption:"Business, Management and Economics",value:7,count:3},{group:"topic",caption:"Chemistry",value:8,count:11},{group:"topic",caption:"Computer and Information Science",value:9,count:9},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:9},{group:"topic",caption:"Engineering",value:11,count:24},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:4},{group:"topic",caption:"Materials Science",value:14,count:7},{group:"topic",caption:"Mathematics",value:15,count:2},{group:"topic",caption:"Medicine",value:16,count:46},{group:"topic",caption:"Neuroscience",value:18,count:3},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:4},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Robotics",value:22,count:2},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:2}],offset:12,limit:12,total:9},popularBooks:{featuredBooks:[{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8564",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",isOpenForSubmission:!1,hash:"98d7f080d80524285f091e72a8e92a6d",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9629",title:"Electroencephalography",subtitle:"From Basic Research to Clinical Applications",isOpenForSubmission:!1,hash:"8147834b6c6deeeec40f407c71ad60b4",slug:"electroencephalography-from-basic-research-to-clinical-applications",bookSignature:"Hideki Nakano",coverURL:"https://cdn.intechopen.com/books/images_new/9629.jpg",editors:[{id:"196461",title:"Prof.",name:"Hideki",middleName:null,surname:"Nakano",slug:"hideki-nakano",fullName:"Hideki Nakano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8760",title:"Structure Topology and Symplectic Geometry",subtitle:null,isOpenForSubmission:!1,hash:"8974840985ec3652492c83e20233bf02",slug:"structure-topology-and-symplectic-geometry",bookSignature:"Kamal Shah and Min Lei",coverURL:"https://cdn.intechopen.com/books/images_new/8760.jpg",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9161",title:"Frailty in the Elderly",subtitle:"Understanding and Managing Complexity",isOpenForSubmission:!1,hash:"a4f0f2fade8fb8ba35c405f5ad31a823",slug:"frailty-in-the-elderly-understanding-and-managing-complexity",bookSignature:"Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/9161.jpg",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8445",title:"Dam Engineering",subtitle:"Recent Advances in Design and Analysis",isOpenForSubmission:!1,hash:"a7e4d2ecbc65d78fa7582e0d2e143906",slug:"dam-engineering-recent-advances-in-design-and-analysis",bookSignature:"Zhongzhi Fu and Erich Bauer",coverURL:"https://cdn.intechopen.com/books/images_new/8445.jpg",editors:[{id:"249577",title:"Dr.",name:"Zhongzhi",middleName:null,surname:"Fu",slug:"zhongzhi-fu",fullName:"Zhongzhi Fu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8937",title:"Soil Moisture Importance",subtitle:null,isOpenForSubmission:!1,hash:"3951728ace7f135451d66b72e9908b47",slug:"soil-moisture-importance",bookSignature:"Ram Swaroop Meena and Rahul Datta",coverURL:"https://cdn.intechopen.com/books/images_new/8937.jpg",editors:[{id:"313528",title:"Associate Prof.",name:"Ram Swaroop",middleName:null,surname:"Meena",slug:"ram-swaroop-meena",fullName:"Ram Swaroop Meena"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7031",title:"Liver Pathology",subtitle:null,isOpenForSubmission:!1,hash:"631321b0565459ed0175917f1c8c727f",slug:"liver-pathology",bookSignature:"Vijay Gayam and Omer Engin",coverURL:"https://cdn.intechopen.com/books/images_new/7031.jpg",editors:[{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8158",title:"Veganism",subtitle:"a Fashion Trend or Food as a Medicine",isOpenForSubmission:!1,hash:"d8e51fc25a379e5b92a270addbb4351d",slug:"veganism-a-fashion-trend-or-food-as-a-medicine",bookSignature:"Miljana Z. Jovandaric",coverURL:"https://cdn.intechopen.com/books/images_new/8158.jpg",editors:[{id:"268043",title:"Dr.",name:"Miljana Z.",middleName:"Z",surname:"Jovandaric",slug:"miljana-z.-jovandaric",fullName:"Miljana Z. Jovandaric"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"2160",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 1",isOpenForSubmission:!1,hash:"dd9c658341fbd264ed4f8d9e6aa8ca29",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-1",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/2160.jpg",editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5314},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8564",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",isOpenForSubmission:!1,hash:"98d7f080d80524285f091e72a8e92a6d",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9629",title:"Electroencephalography",subtitle:"From Basic Research to Clinical Applications",isOpenForSubmission:!1,hash:"8147834b6c6deeeec40f407c71ad60b4",slug:"electroencephalography-from-basic-research-to-clinical-applications",bookSignature:"Hideki Nakano",coverURL:"https://cdn.intechopen.com/books/images_new/9629.jpg",editors:[{id:"196461",title:"Prof.",name:"Hideki",middleName:null,surname:"Nakano",slug:"hideki-nakano",fullName:"Hideki Nakano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8760",title:"Structure Topology and Symplectic Geometry",subtitle:null,isOpenForSubmission:!1,hash:"8974840985ec3652492c83e20233bf02",slug:"structure-topology-and-symplectic-geometry",bookSignature:"Kamal Shah and Min Lei",coverURL:"https://cdn.intechopen.com/books/images_new/8760.jpg",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9161",title:"Frailty in the Elderly",subtitle:"Understanding and Managing Complexity",isOpenForSubmission:!1,hash:"a4f0f2fade8fb8ba35c405f5ad31a823",slug:"frailty-in-the-elderly-understanding-and-managing-complexity",bookSignature:"Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/9161.jpg",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"2160",title:"MATLAB",subtitle:"A Fundamental Tool for Scientific Computing and Engineering Applications - Volume 1",isOpenForSubmission:!1,hash:"dd9c658341fbd264ed4f8d9e6aa8ca29",slug:"matlab-a-fundamental-tool-for-scientific-computing-and-engineering-applications-volume-1",bookSignature:"Vasilios N. Katsikis",coverURL:"https://cdn.intechopen.com/books/images_new/2160.jpg",editors:[{id:"12289",title:"Prof.",name:"Vasilios",middleName:"N.",surname:"Katsikis",slug:"vasilios-katsikis",fullName:"Vasilios Katsikis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7031",title:"Liver Pathology",subtitle:null,isOpenForSubmission:!1,hash:"631321b0565459ed0175917f1c8c727f",slug:"liver-pathology",bookSignature:"Vijay Gayam and Omer Engin",coverURL:"https://cdn.intechopen.com/books/images_new/7031.jpg",editors:[{id:"273100",title:"Dr.",name:"Vijay",middleName:null,surname:"Gayam",slug:"vijay-gayam",fullName:"Vijay Gayam"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"3568",title:"Recent Advances in Plant in vitro Culture",subtitle:null,isOpenForSubmission:!1,hash:"830bbb601742c85a3fb0eeafe1454c43",slug:"recent-advances-in-plant-in-vitro-culture",bookSignature:"Annarita Leva and Laura M. R. Rinaldi",coverURL:"https://cdn.intechopen.com/books/images_new/3568.jpg",editors:[{id:"142145",title:"Dr.",name:"Annarita",middleName:null,surname:"Leva",slug:"annarita-leva",fullName:"Annarita Leva"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"8472",title:"Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health",subtitle:null,isOpenForSubmission:!1,hash:"8855452919b8495810ef8e88641feb20",slug:"bioactive-compounds-in-nutraceutical-and-functional-food-for-good-human-health",bookSignature:"Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu",coverURL:"https://cdn.intechopen.com/books/images_new/8472.jpg",editedByType:"Edited by",editors:[{id:"197731",title:"Dr.",name:"Kavita",middleName:null,surname:"Sharma",slug:"kavita-sharma",fullName:"Kavita Sharma"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8760",title:"Structure Topology and Symplectic Geometry",subtitle:null,isOpenForSubmission:!1,hash:"8974840985ec3652492c83e20233bf02",slug:"structure-topology-and-symplectic-geometry",bookSignature:"Kamal Shah and Min Lei",coverURL:"https://cdn.intechopen.com/books/images_new/8760.jpg",editedByType:"Edited by",editors:[{id:"231748",title:"Dr.",name:"Kamal",middleName:null,surname:"Shah",slug:"kamal-shah",fullName:"Kamal Shah"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9536",title:"Education at the Intersection of Globalization and Technology",subtitle:null,isOpenForSubmission:!1,hash:"0cf6891060eb438d975d250e8b127ed6",slug:"education-at-the-intersection-of-globalization-and-technology",bookSignature:"Sharon Waller, Lee Waller, Vongai Mpofu and Mercy Kurebwa",coverURL:"https://cdn.intechopen.com/books/images_new/9536.jpg",editedByType:"Edited by",editors:[{id:"263302",title:"Dr.",name:"Sharon",middleName:null,surname:"Waller",slug:"sharon-waller",fullName:"Sharon Waller"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8564",title:"Cell Interaction",subtitle:"Molecular and Immunological Basis for Disease Management",isOpenForSubmission:!1,hash:"98d7f080d80524285f091e72a8e92a6d",slug:"cell-interaction-molecular-and-immunological-basis-for-disease-management",bookSignature:"Bhawana Singh",coverURL:"https://cdn.intechopen.com/books/images_new/8564.jpg",editedByType:"Edited by",editors:[{id:"315192",title:"Dr.",name:"Bhawana",middleName:null,surname:"Singh",slug:"bhawana-singh",fullName:"Bhawana Singh"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9629",title:"Electroencephalography",subtitle:"From Basic Research to Clinical Applications",isOpenForSubmission:!1,hash:"8147834b6c6deeeec40f407c71ad60b4",slug:"electroencephalography-from-basic-research-to-clinical-applications",bookSignature:"Hideki Nakano",coverURL:"https://cdn.intechopen.com/books/images_new/9629.jpg",editedByType:"Edited by",editors:[{id:"196461",title:"Prof.",name:"Hideki",middleName:null,surname:"Nakano",slug:"hideki-nakano",fullName:"Hideki Nakano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9685",title:"Agroecosystems",subtitle:"Very Complex Environmental Systems",isOpenForSubmission:!1,hash:"c44f7b43a9f9610c243dc32300d37df6",slug:"agroecosystems-very-complex-environmental-systems",bookSignature:"Marcelo L. Larramendy and Sonia Soloneski",coverURL:"https://cdn.intechopen.com/books/images_new/9685.jpg",editedByType:"Edited by",editors:[{id:"14764",title:"Dr.",name:"Marcelo L.",middleName:null,surname:"Larramendy",slug:"marcelo-l.-larramendy",fullName:"Marcelo L. Larramendy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9524",title:"Organ Donation and Transplantation",subtitle:null,isOpenForSubmission:!1,hash:"6ef47e03cd4e6476946fc28ca51de825",slug:"organ-donation-and-transplantation",bookSignature:"Vassil Mihaylov",coverURL:"https://cdn.intechopen.com/books/images_new/9524.jpg",editedByType:"Edited by",editors:[{id:"313113",title:"Associate Prof.",name:"Vassil",middleName:null,surname:"Mihaylov",slug:"vassil-mihaylov",fullName:"Vassil Mihaylov"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9280",title:"Underwater Work",subtitle:null,isOpenForSubmission:!1,hash:"647b4270d937deae4a82f5702d1959ec",slug:"underwater-work",bookSignature:"Sérgio António Neves Lousada",coverURL:"https://cdn.intechopen.com/books/images_new/9280.jpg",editedByType:"Edited by",editors:[{id:"248645",title:"Dr.",name:"Sérgio António",middleName:null,surname:"Neves Lousada",slug:"sergio-antonio-neves-lousada",fullName:"Sérgio António Neves Lousada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9161",title:"Frailty in the Elderly",subtitle:"Understanding and Managing Complexity",isOpenForSubmission:!1,hash:"a4f0f2fade8fb8ba35c405f5ad31a823",slug:"frailty-in-the-elderly-understanding-and-managing-complexity",bookSignature:"Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/9161.jpg",editedByType:"Edited by",editors:[{id:"233998",title:"Ph.D.",name:"Sara",middleName:null,surname:"Palermo",slug:"sara-palermo",fullName:"Sara Palermo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8158",title:"Veganism",subtitle:"a Fashion Trend or Food as a Medicine",isOpenForSubmission:!1,hash:"d8e51fc25a379e5b92a270addbb4351d",slug:"veganism-a-fashion-trend-or-food-as-a-medicine",bookSignature:"Miljana Z. Jovandaric",coverURL:"https://cdn.intechopen.com/books/images_new/8158.jpg",editedByType:"Edited by",editors:[{id:"268043",title:"Dr.",name:"Miljana Z.",middleName:"Z",surname:"Jovandaric",slug:"miljana-z.-jovandaric",fullName:"Miljana Z. Jovandaric"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"1303",title:"Motion Planning",slug:"motion-planning",parent:{title:"Robotic Mapping",slug:"robotic-mapping"},numberOfBooks:1,numberOfAuthorsAndEditors:24,numberOfWosCitations:5,numberOfCrossrefCitations:5,numberOfDimensionsCitations:7,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"motion-planning",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"6322",title:"Advanced Path Planning for Mobile Entities",subtitle:null,isOpenForSubmission:!1,hash:"438f519ccb7ac4196660ada6b648e15f",slug:"advanced-path-planning-for-mobile-entities",bookSignature:"Rastislav Róka",coverURL:"https://cdn.intechopen.com/books/images_new/6322.jpg",editedByType:"Edited by",editors:[{id:"112777",title:"Dr.",name:"Rastislav",middleName:null,surname:"Róka",slug:"rastislav-roka",fullName:"Rastislav Róka"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:1,mostCitedChapters:[{id:"58388",doi:"10.5772/intechopen.72574",title:"Path Planning Based on Parametric Curves",slug:"path-planning-based-on-parametric-curves",totalDownloads:697,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Lucía Hilario Pérez, Marta Covadonga Mora Aguilar, Nicolás Montés\nSánchez and Antonio Falcó Montesinos",authors:[{id:"213131",title:"Dr.",name:"Lucía",middleName:null,surname:"Hilario Pérez",slug:"lucia-hilario-perez",fullName:"Lucía Hilario Pérez"},{id:"213132",title:"Dr.",name:"Marta Covadonga",middleName:null,surname:"Mora",slug:"marta-covadonga-mora",fullName:"Marta Covadonga Mora"},{id:"213144",title:"Dr.",name:"Nicolás",middleName:null,surname:"Montés Sánchez",slug:"nicolas-montes-sanchez",fullName:"Nicolás Montés Sánchez"},{id:"221922",title:"Dr.",name:"Antonio",middleName:null,surname:"Falcó Montesinos",slug:"antonio-falco-montesinos",fullName:"Antonio Falcó Montesinos"}]},{id:"57484",doi:"10.5772/intechopen.71486",title:"Path Planning in Rough Terrain Using Neural Network Memory",slug:"path-planning-in-rough-terrain-using-neural-network-memory",totalDownloads:440,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Nancy Arana-Daniel, Roberto Valencia-Murillo, Alma Y. Alanís,\nCarlos Villaseñor and Carlos López-Franco",authors:[{id:"162391",title:"Dr.",name:"Nancy",middleName:null,surname:"Arana-Daniel",slug:"nancy-arana-daniel",fullName:"Nancy Arana-Daniel"},{id:"164571",title:"Dr.",name:"Carlos",middleName:null,surname:"Lopez-Franco",slug:"carlos-lopez-franco",fullName:"Carlos Lopez-Franco"},{id:"212726",title:"Dr.",name:"Roberto",middleName:null,surname:"Valencia-Murillo",slug:"roberto-valencia-murillo",fullName:"Roberto Valencia-Murillo"},{id:"212727",title:"Dr.",name:"Alma Y.",middleName:null,surname:"Alanis",slug:"alma-y.-alanis",fullName:"Alma Y. Alanis"},{id:"220834",title:"Dr.",name:"Carlos",middleName:null,surname:"Villaseñor",slug:"carlos-villasenor",fullName:"Carlos Villaseñor"}]},{id:"58361",doi:"10.5772/intechopen.72573",title:"Path Planning on Quadric Surfaces and Its Application",slug:"path-planning-on-quadric-surfaces-and-its-application",totalDownloads:408,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Chi-Chia Sun, Gene Eu Jan, Chaomin Lu and Kai-Chieh Yang",authors:[{id:"36311",title:"Dr.",name:"Chaomin",middleName:null,surname:"Luo",slug:"chaomin-luo",fullName:"Chaomin Luo"},{id:"220894",title:"Prof.",name:"Gene Eu (Ching Yuh)",middleName:"Eu",surname:"Jan",slug:"gene-eu-(ching-yuh)-jan",fullName:"Gene Eu (Ching Yuh) Jan"},{id:"221450",title:"Dr.",name:"Chi-Chia",middleName:null,surname:"Sun",slug:"chi-chia-sun",fullName:"Chi-Chia Sun"},{id:"221451",title:"MSc.",name:"Kai-Chieh",middleName:null,surname:"Yang",slug:"kai-chieh-yang",fullName:"Kai-Chieh Yang"}]}],mostDownloadedChaptersLast30Days:[{id:"57409",title:"Consensus-Based Multipath Planning with Collision Avoidance Using Linear Matrix Inequalities",slug:"consensus-based-multipath-planning-with-collision-avoidance-using-linear-matrix-inequalities",totalDownloads:499,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Innocent Okoloko",authors:[{id:"211140",title:"Dr.",name:"Innocent",middleName:null,surname:"Okoloko",slug:"innocent-okoloko",fullName:"Innocent Okoloko"}]},{id:"58388",title:"Path Planning Based on Parametric Curves",slug:"path-planning-based-on-parametric-curves",totalDownloads:697,totalCrossrefCites:2,totalDimensionsCites:4,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Lucía Hilario Pérez, Marta Covadonga Mora Aguilar, Nicolás Montés\nSánchez and Antonio Falcó Montesinos",authors:[{id:"213131",title:"Dr.",name:"Lucía",middleName:null,surname:"Hilario Pérez",slug:"lucia-hilario-perez",fullName:"Lucía Hilario Pérez"},{id:"213132",title:"Dr.",name:"Marta Covadonga",middleName:null,surname:"Mora",slug:"marta-covadonga-mora",fullName:"Marta Covadonga Mora"},{id:"213144",title:"Dr.",name:"Nicolás",middleName:null,surname:"Montés Sánchez",slug:"nicolas-montes-sanchez",fullName:"Nicolás Montés Sánchez"},{id:"221922",title:"Dr.",name:"Antonio",middleName:null,surname:"Falcó Montesinos",slug:"antonio-falco-montesinos",fullName:"Antonio Falcó Montesinos"}]},{id:"58982",title:"Multi-Path Planning on a Sphere with LMI-Based Collision Avoidance",slug:"multi-path-planning-on-a-sphere-with-lmi-based-collision-avoidance",totalDownloads:516,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Innocent Okoloko",authors:[{id:"211262",title:"Dr",name:"Innocent",middleName:null,surname:"Okoloko",slug:"innocent-okoloko",fullName:"Innocent Okoloko"}]},{id:"58561",title:"Search-Based Planning and Replanning in Robotics and Autonomous Systems",slug:"search-based-planning-and-replanning-in-robotics-and-autonomous-systems",totalDownloads:570,totalCrossrefCites:1,totalDimensionsCites:0,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"An T. Le and Than D. Le",authors:[{id:"211542",title:"Mr.",name:"Than",middleName:null,surname:"Le",slug:"than-le",fullName:"Than Le"},{id:"211558",title:"Mr.",name:"An",middleName:"T.",surname:"Le",slug:"an-le",fullName:"An Le"}]},{id:"57484",title:"Path Planning in Rough Terrain Using Neural Network Memory",slug:"path-planning-in-rough-terrain-using-neural-network-memory",totalDownloads:440,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Nancy Arana-Daniel, Roberto Valencia-Murillo, Alma Y. Alanís,\nCarlos Villaseñor and Carlos López-Franco",authors:[{id:"162391",title:"Dr.",name:"Nancy",middleName:null,surname:"Arana-Daniel",slug:"nancy-arana-daniel",fullName:"Nancy Arana-Daniel"},{id:"164571",title:"Dr.",name:"Carlos",middleName:null,surname:"Lopez-Franco",slug:"carlos-lopez-franco",fullName:"Carlos Lopez-Franco"},{id:"212726",title:"Dr.",name:"Roberto",middleName:null,surname:"Valencia-Murillo",slug:"roberto-valencia-murillo",fullName:"Roberto Valencia-Murillo"},{id:"212727",title:"Dr.",name:"Alma Y.",middleName:null,surname:"Alanis",slug:"alma-y.-alanis",fullName:"Alma Y. Alanis"},{id:"220834",title:"Dr.",name:"Carlos",middleName:null,surname:"Villaseñor",slug:"carlos-villasenor",fullName:"Carlos Villaseñor"}]},{id:"58572",title:"Design and Implementation of a Demonstrative Palletizer Robot with Navigation for Educational Purposes",slug:"design-and-implementation-of-a-demonstrative-palletizer-robot-with-navigation-for-educational-purpos",totalDownloads:721,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Dora-Luz Almanza-Ojeda, Perla-Lizeth Garza-Barron, Carlos Rubin\nMontoro-Sanjose and Mario-Alberto Ibarra-Manzano",authors:[{id:"182765",title:"Dr.",name:"Dora Luz",middleName:null,surname:"Almanza Ojeda",slug:"dora-luz-almanza-ojeda",fullName:"Dora Luz Almanza Ojeda"},{id:"191783",title:"Dr.",name:"Mario-Alberto",middleName:null,surname:"Ibarra-Manzano",slug:"mario-alberto-ibarra-manzano",fullName:"Mario-Alberto Ibarra-Manzano"},{id:"213261",title:"BSc.",name:"Perla Lizeth",middleName:null,surname:"Garza-Barrón",slug:"perla-lizeth-garza-barron",fullName:"Perla Lizeth Garza-Barrón"},{id:"223872",title:"Dr.",name:"Carlos Rubin",middleName:null,surname:"Montoro-Sanjose",slug:"carlos-rubin-montoro-sanjose",fullName:"Carlos Rubin Montoro-Sanjose"}]},{id:"63374",title:"Motion Planning for Mobile Robots",slug:"motion-planning-for-mobile-robots",totalDownloads:694,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Xiangrong Xu, Yang Yang and Siyu Pan",authors:[{id:"217380",title:"Prof.",name:"Xiangrong",middleName:null,surname:"Xu",slug:"xiangrong-xu",fullName:"Xiangrong Xu"}]},{id:"58361",title:"Path Planning on Quadric Surfaces and Its Application",slug:"path-planning-on-quadric-surfaces-and-its-application",totalDownloads:408,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Chi-Chia Sun, Gene Eu Jan, Chaomin Lu and Kai-Chieh Yang",authors:[{id:"36311",title:"Dr.",name:"Chaomin",middleName:null,surname:"Luo",slug:"chaomin-luo",fullName:"Chaomin Luo"},{id:"220894",title:"Prof.",name:"Gene Eu (Ching Yuh)",middleName:"Eu",surname:"Jan",slug:"gene-eu-(ching-yuh)-jan",fullName:"Gene Eu (Ching Yuh) Jan"},{id:"221450",title:"Dr.",name:"Chi-Chia",middleName:null,surname:"Sun",slug:"chi-chia-sun",fullName:"Chi-Chia Sun"},{id:"221451",title:"MSc.",name:"Kai-Chieh",middleName:null,surname:"Yang",slug:"kai-chieh-yang",fullName:"Kai-Chieh Yang"}]},{id:"57601",title:"Multi-Spacecraft Attitude Path Planning Using Consensus with LMI-Based Exclusion Constraints",slug:"multi-spacecraft-attitude-path-planning-using-consensus-with-lmi-based-exclusion-constraints",totalDownloads:433,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"advanced-path-planning-for-mobile-entities",title:"Advanced Path Planning for Mobile Entities",fullTitle:"Advanced Path Planning for Mobile Entities"},signatures:"Innocent Okoloko",authors:[{id:"211370",title:"Dr",name:"Innocent",middleName:null,surname:"Okoloko",slug:"innocent-okoloko",fullName:"Innocent Okoloko"}]}],onlineFirstChaptersFilter:{topicSlug:"motion-planning",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/15164/michele-coletti",hash:"",query:{},params:{id:"15164",slug:"michele-coletti"},fullPath:"/profiles/15164/michele-coletti",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()