Pharmacological neuroprotection strategies
\\n\\n
IntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\\n\\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\\n\\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\\n\\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\\n\\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\\n\\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\\n\\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\\n\\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\\n\\nFeel free to share this news on social media and help us mark this memorable moment!
\\n\\n\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/237"}},components:[{type:"htmlEditorComponent",content:'
After years of being acknowledged as the world's leading publisher of Open Access books, today, we are proud to announce we’ve successfully launched a portfolio of Open Science journals covering rapidly expanding areas of interdisciplinary research.
\n\n\n\nIntechOpen was founded by scientists, for scientists, in order to make book publishing accessible around the globe. Over the last two decades, this has driven Open Access (OA) book publishing whilst levelling the playing field for global academics. Through our innovative publishing model and the support of the research community, we have now published over 5,700 Open Access books and are visited online by over three million academics every month. These researchers are increasingly working in broad technology-based subjects, driving multidisciplinary academic endeavours into human health, environment, and technology.
\n\nBy listening to our community, and in order to serve these rapidly growing areas which lie at the core of IntechOpen's expertise, we are launching a portfolio of Open Science journals:
\n\nAll three journals will publish under an Open Access model and embrace Open Science policies to help support the changing needs of academics in these fast-moving research areas. There will be direct links to preprint servers and data repositories, allowing full reproducibility and rapid dissemination of published papers to help accelerate the pace of research. Each journal has renowned Editors in Chief who will work alongside a global Editorial Board, delivering robust single-blind peer review. Supported by our internal editorial teams, this will ensure our authors will receive a quick, user-friendly, and personalised publishing experience.
\n\n"By launching our journals portfolio we are introducing new, dedicated homes for interdisciplinary technology-focused researchers to publish their work, whilst embracing Open Science and creating a unique global home for academics to disseminate their work. We are taking a leap toward Open Science continuing and expanding our fundamental commitment to openly sharing scientific research across the world, making it available for the benefit of all." Dr. Sara Uhac, IntechOpen CEO
\n\n"Our aim is to promote and create better science for a better world by increasing access to information and the latest scientific developments to all scientists, innovators, entrepreneurs and students and give them the opportunity to learn, observe and contribute to knowledge creation. Open Science promotes a swifter path from research to innovation to produce new products and services." Alex Lazinica, IntechOpen founder
\n\nIn conclusion, Natalia Reinic Babic, Head of Journal Publishing and Open Science at IntechOpen adds:
\n\n“On behalf of the journal team I’d like to thank all our Editors in Chief, Editorial Boards, internal supporting teams, and our scientific community for their continuous support in making this portfolio a reality - we couldn’t have done it without you! With your support in place, we are confident these journals will become as impactful and successful as our book publishing program and bring us closer to a more open (science) future.”
\n\nWe invite you to visit the journals homepage and learn more about the journal’s Editorial Boards, scope and vision as all three journals are now open for submissions.
\n\nFeel free to share this news on social media and help us mark this memorable moment!
\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"5988",leadTitle:null,fullTitle:"New Insights into Morphometry Studies",title:"New Insights into Morphometry Studies",subtitle:null,reviewType:"peer-reviewed",abstract:"There have been brilliant studies in the field of morphometry in recent years. This book increases the literature on this domain by presenting some recent advances and emerging applications upon biological structures, ranging in a variety of purposes and objectives: from animal visual system to growth models, from amphibians to humans, all in a comprehensive and accessible way of information. All chapters are written by leading internationally recognized experts from academia, who explain their own topics in plain English and in a totally rigorous manner. Suitable for a wide range of expert readers, this book represents a high valuable work for scientists and advanced students working in biological and medical morphometric topics.",isbn:"978-953-51-3366-7",printIsbn:"978-953-51-3365-0",pdfIsbn:"978-953-51-4746-6",doi:"10.5772/66563",price:100,priceEur:109,priceUsd:129,slug:"new-insights-into-morphometry-studies",numberOfPages:96,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"3c8701d62860a9cdfb6d09d9ffb32493",bookSignature:"Pere M. Pares-Casanova",publishedDate:"July 12th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/5988.jpg",numberOfDownloads:7815,numberOfWosCitations:5,numberOfCrossrefCitations:6,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:9,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:20,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 17th 2016",dateEndSecondStepPublish:"December 8th 2016",dateEndThirdStepPublish:"March 6th 2017",dateEndFourthStepPublish:"June 4th 2017",dateEndFifthStepPublish:"August 3rd 2017",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"199463",title:"Dr.",name:"Pere M.",middleName:null,surname:"Pares-Casanova",slug:"pere-m.-pares-casanova",fullName:"Pere M. Pares-Casanova",profilePictureURL:"https://mts.intechopen.com/storage/users/199463/images/5840_n.jpg",biography:"Pere M. Parés-Casanova graduated in Veterinary Medicine at the “Universitat Autònoma de Barcelona” (Catalonia) in 1987. He holds a Diploma in Public Health from the “Escuela Nacional de Sanidad” (Madrid, Spain), a Master’s degree in Animal Production from the “Universitat Autònoma de Barcelona,” and a PhD degree from the same University. From 2016, he is a lecturer and course coordinator of Gross Anatomy and Imaging Diagnostics at the Department of Animal Science in the School of Agrifood and Forestry Science and Engineering of the University of Lleida (Catalonia). His current research activity concerns the structural study of domestic mammals based on morphometrics techniques, with special emphasis to pure breeds. Evaluation of the morphological effects of extreme paedomorphy and asymmetries on “toy animals” has been recently his approach, too.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Lleida",institutionURL:null,country:{name:"Spain"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"331",title:"Forestry Science",slug:"agricultural-and-biological-sciences-ecology-forestry-science"}],chapters:[{id:"55813",title:"Introductory Chapter - Morphometric Studies: Beyond Pure Anatomical Form Analysis",doi:"10.5772/intechopen.69682",slug:"introductory-chapter-morphometric-studies-beyond-pure-anatomical-form-analysis",totalDownloads:1577,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:null,signatures:"Pere M. Parés‐Casanova",downloadPdfUrl:"/chapter/pdf-download/55813",previewPdfUrl:"/chapter/pdf-preview/55813",authors:[{id:"199463",title:"Dr.",name:"Pere M.",surname:"Pares-Casanova",slug:"pere-m.-pares-casanova",fullName:"Pere M. Pares-Casanova"}],corrections:null},{id:"55631",title:"Morphometric Growth Characteristics and Body Composition of Fish and Amphibians",doi:"10.5772/intechopen.69061",slug:"morphometric-growth-characteristics-and-body-composition-of-fish-and-amphibians",totalDownloads:1954,totalCrossrefCites:2,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Describing animal growth through the nonlinear models allows a detailed evaluation of their behavior, besides revealing important information of the response to a particular treatment. In this chapter, the parameters of mathematical models (Gompertz, Von Bertalanffy, Logistic and Brody) for live weight, feed and protein intakes, total and standard lengths and nutrient deposition are described systematically and comprehensively. Also the relative growth and allometric coefficients of body components in relation to body weight of fish and amphibians are described, explaining better the use of the allometric equation and classifying the growth of the body components.",signatures:"Cleber Fernando M. Mansano, Beatrice Ingrid Macente, Kifayat\nUllah Khan, Thiago Matias T. do Nascimento, Edney P. da Silva, Nilva\nKazue Sakomura and João Batista K. Fernandes",downloadPdfUrl:"/chapter/pdf-download/55631",previewPdfUrl:"/chapter/pdf-preview/55631",authors:[{id:"202719",title:"Dr.",name:"Cleber",surname:"Mansano",slug:"cleber-mansano",fullName:"Cleber Mansano"},{id:"202722",title:"Dr.",name:"Beatrice I.",surname:"Macente",slug:"beatrice-i.-macente",fullName:"Beatrice I. Macente"},{id:"202723",title:"Dr.",name:"Kifayat U.",surname:"Khan",slug:"kifayat-u.-khan",fullName:"Kifayat U. Khan"},{id:"203431",title:"Dr.",name:"Thiago Matias T. Do",surname:"Nascimento",slug:"thiago-matias-t.-do-nascimento",fullName:"Thiago Matias T. Do Nascimento"},{id:"203432",title:"Dr.",name:"Edney P. Da",surname:"Silva",slug:"edney-p.-da-silva",fullName:"Edney P. Da Silva"},{id:"203434",title:"Dr.",name:"Nilva Kazue",surname:"Sakomura",slug:"nilva-kazue-sakomura",fullName:"Nilva Kazue Sakomura"},{id:"203435",title:"Dr.",name:"João Batista K.",surname:"Fernandes",slug:"joao-batista-k.-fernandes",fullName:"João Batista K. Fernandes"}],corrections:null},{id:"55797",title:"Morphometrics in Developmental Neurobiology: Quantitative Analysis of Growth Cone Motility in Vivo",doi:"10.5772/intechopen.69060",slug:"morphometrics-in-developmental-neurobiology-quantitative-analysis-of-growth-cone-motility-in-vivo",totalDownloads:1208,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In order for the nervous system to function properly, neurons in the brain must establish specific connections during embryonic development. Formation of neuronal circuits involves axons extending from cell bodies and navigating through diverse tissues to reach their targets in the brain. Once axons reach their target tissues, they arborize and make synaptic connections. Axon pathfinding is driven by dynamic motility behaviors expressed by terminal growth cones at the tips of the axons. Here, we applied morphometrics to determine quantitative values for six morphological and motility parameters for growth cones of optic axons navigating through the optic tract of a living brain preparation from a Xenopus laevis tadpole. Our results demonstrate an increase in length, decrease in width, increase in perimeter, decrease in area, increase in number of filopodia, and a decrease in number of lamellipodia, of the growth cones in the optic tract. Therefore, optic axonal growth cones become less circular and more elongated and protrusive during their navigation through the optic tract. Quantitatively deconstructing parameters of growth cone motility is necessary to determine molecular, cellular, and biophysical mechanisms of axon pathfinding, and to formulate computational analyses of developing neuronal connectivity in the brain.",signatures:"Anokh Sohal, James Ha, Manuel Zhu, Fayha Lakhani, Kavitha\nThiagaragan, Lauren Olzewski, Raagav Monakrishnan and Tamira\nElul",downloadPdfUrl:"/chapter/pdf-download/55797",previewPdfUrl:"/chapter/pdf-preview/55797",authors:[{id:"203351",title:"Associate Prof.",name:"Tamira",surname:"Elul",slug:"tamira-elul",fullName:"Tamira Elul"},{id:"206616",title:"MSc.",name:"Anokh",surname:"Sohal",slug:"anokh-sohal",fullName:"Anokh Sohal"},{id:"206618",title:"MSc.",name:"James",surname:"Ha",slug:"james-ha",fullName:"James Ha"},{id:"206619",title:"MSc.",name:"Manuel",surname:"Zhu",slug:"manuel-zhu",fullName:"Manuel Zhu"},{id:"206620",title:"MSc.",name:"Fayha",surname:"Lakhani",slug:"fayha-lakhani",fullName:"Fayha Lakhani"},{id:"206621",title:"Dr.",name:"Kavitha",surname:"Thiagarajan",slug:"kavitha-thiagarajan",fullName:"Kavitha Thiagarajan"},{id:"206622",title:"BSc.",name:"Lauren",surname:"Olzewski",slug:"lauren-olzewski",fullName:"Lauren Olzewski"},{id:"206623",title:"BSc.",name:"Raagav",surname:"Monakrishnan",slug:"raagav-monakrishnan",fullName:"Raagav Monakrishnan"}],corrections:null},{id:"55461",title:"MRI Morphometry of the Brain and Neurological Diseases",doi:"10.5772/intechopen.69098",slug:"mri-morphometry-of-the-brain-and-neurological-diseases",totalDownloads:1369,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The diagnosis of diseases of the brain is based on additional methods, confirming the clinical diagnosis. One of the most objective methods is magnetic resonance imaging (MRI). A detailed quantitative evaluation became possible after the introduction of MRI voxel‐morphometry–statistical analysis of structural MRI images using a computerized segmentation matter of the brain gray and white matter. The decrease in the volume of the brain, as a manifestation of cerebral atrophy, is a common feature of many neurological diseases. We performed a study of brain structures in multiple sclerosis, Parkinson’s disease, and cerebrovascular diseases. In patients with multiple sclerosis the correlation was found between the score on a scale of Expanded Disability Status Scale and the total thickness of the cerebral cortex. In our study of the brain in Parkinson’s disease, the amount of the substantia nigra was slightly lower than in the control. In patients with long‐following Parkinson’s disease, the volume of substantia nigra was significantly higher than in patients with early stage. The increased volume was determined by the accumulation of organic iron compounds as a sign of neurodegeneration.",signatures:"Sergey Kotov",downloadPdfUrl:"/chapter/pdf-download/55461",previewPdfUrl:"/chapter/pdf-preview/55461",authors:[{id:"203592",title:"Prof.",name:"Sergey",surname:"Kotov",slug:"sergey-kotov",fullName:"Sergey Kotov"}],corrections:null},{id:"55840",title:"Application of Morphometric and Stereological Techniques on Analysis and Modelling of the Avian Lung",doi:"10.5772/intechopen.69062",slug:"application-of-morphometric-and-stereological-techniques-on-analysis-and-modelling-of-the-avian-lung",totalDownloads:1707,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"For a long time, biology was a qualitative (descriptive) science. The investigations failed to fully explicate the functional designs of whole organisms and their constituent parts. About half a century ago, at an interdisciplinary meeting which was held in Feldberg (Germany), the International Society of Stereology (ISS) was formed. Mathematicians, statisticians and physical and biological scientists combined their skills to create a new scientific discipline of stereology that allowed for reliable and reproducible quantitation of structural entities of composite physical and biological materials and extrapolation of measurements made on two‐dimensional profiles/images to their three‐dimensional forms. With time, novel bias‐free sampling and quantitation techniques have been developed and tested. Presently, there is no justification for totally descriptive biological studies. Numerous books, publications, computer programmes and applications and dedicated microscopes exist for cost‐effective analysis. Within the relatively short time, it has been in existence, the ISS has actively advanced stereology which is now applied by scientists all over the world in various biological disciplines. Only basic understanding of mathematics, geometry and statistics is needed to do good stereology. Here, analysis of the avian (bird) lung is given to show the versatility and robustness of stereological techniques in analysing biological structures.",signatures:"John N. Maina",downloadPdfUrl:"/chapter/pdf-download/55840",previewPdfUrl:"/chapter/pdf-preview/55840",authors:[{id:"85320",title:"Dr.",name:"John",surname:"Maina",slug:"john-maina",fullName:"John Maina"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"2246",title:"Global Perspectives on Sustainable Forest Management",subtitle:null,isOpenForSubmission:!1,hash:"b633fc6fc6a3a8f24dd4c4373fb14cb7",slug:"global-perspectives-on-sustainable-forest-management",bookSignature:"Okia Clement Akais",coverURL:"https://cdn.intechopen.com/books/images_new/2246.jpg",editedByType:"Edited by",editors:[{id:"119660",title:"Dr.",name:"Dr. Clement A.",surname:"Okia",slug:"dr.-clement-a.-okia",fullName:"Dr. Clement A. Okia"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"616",title:"Forest Ecosystems",subtitle:"More than Just Trees",isOpenForSubmission:!1,hash:"00ecaa84de1aa2d7116ab5871b353b82",slug:"forest-ecosystems-more-than-just-trees",bookSignature:"Juan A. Blanco and Yueh-Hsin Lo",coverURL:"https://cdn.intechopen.com/books/images_new/616.jpg",editedByType:"Edited by",editors:[{id:"51995",title:"Dr.",name:"Juan",surname:"Blanco",slug:"juan-blanco",fullName:"Juan Blanco"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"617",title:"Sustainable Forest Management",subtitle:"Current Research",isOpenForSubmission:!1,hash:"a8d91cf4745e90f7510e056fd508dc46",slug:"sustainable-forest-management-current-research",bookSignature:"Jorge Martin Garcia and Julio Javier Diez Casero",coverURL:"https://cdn.intechopen.com/books/images_new/617.jpg",editedByType:"Edited by",editors:[{id:"88987",title:"Dr.",name:"Julio J.",surname:"Diez",slug:"julio-j.-diez",fullName:"Julio J. Diez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1511",title:"Deforestation Around the World",subtitle:null,isOpenForSubmission:!1,hash:"9eeb50fd58ff5ebb4151b5368105e9ef",slug:"deforestation-around-the-world",bookSignature:"Paulo Moutinho",coverURL:"https://cdn.intechopen.com/books/images_new/1511.jpg",editedByType:"Edited by",editors:[{id:"115144",title:"Dr.",name:"Paulo",surname:"Moutinho",slug:"paulo-moutinho",fullName:"Paulo Moutinho"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2073",title:"Sustainable Forest Management",subtitle:"Case Studies",isOpenForSubmission:!1,hash:"656069330afd66b7a27ca8963a544092",slug:"sustainable-forest-management-case-studies",bookSignature:"Jorge Martin-Garcia and Julio Javier Diez",coverURL:"https://cdn.intechopen.com/books/images_new/2073.jpg",editedByType:"Edited by",editors:[{id:"88987",title:"Dr.",name:"Julio J.",surname:"Diez",slug:"julio-j.-diez",fullName:"Julio J. Diez"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4757",title:"Precious Forests",subtitle:"Precious Earth",isOpenForSubmission:!1,hash:"6bd8329fb8128da2fc08c1c6d8a22613",slug:"precious-forests-precious-earth",bookSignature:"Miodrag Zlatic",coverURL:"https://cdn.intechopen.com/books/images_new/4757.jpg",editedByType:"Edited by",editors:[{id:"174414",title:"Dr.",name:"Miodrag",surname:"Zlatic",slug:"miodrag-zlatic",fullName:"Miodrag Zlatic"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1815",title:"New Advances and Contributions to Forestry Research",subtitle:null,isOpenForSubmission:!1,hash:"fb2caa8ab3683ea8aeba1810e7903a4a",slug:"new-advances-and-contributions-to-forestry-research",bookSignature:"Andrew Akwasi Oteng-Amoako",coverURL:"https://cdn.intechopen.com/books/images_new/1815.jpg",editedByType:"Edited by",editors:[{id:"119148",title:"Dr.",name:"Dr. Andrew A.",surname:"Oteng-Amoako",slug:"dr.-andrew-a.-oteng-amoako",fullName:"Dr. Andrew A. Oteng-Amoako"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5877",title:"Plant Ecology",subtitle:"Traditional Approaches to Recent Trends",isOpenForSubmission:!1,hash:"788a981ecedf0d9c0205869788524a80",slug:"plant-ecology-traditional-approaches-to-recent-trends",bookSignature:"Zubaida Yousaf",coverURL:"https://cdn.intechopen.com/books/images_new/5877.jpg",editedByType:"Edited by",editors:[{id:"196003",title:"Dr.",name:"Zubaida",surname:"Yousaf",slug:"zubaida-yousaf",fullName:"Zubaida Yousaf"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5455",title:"Global Exposition of Wildlife Management",subtitle:null,isOpenForSubmission:!1,hash:"0c60fd890b4af7771afc5211fdabe762",slug:"global-exposition-of-wildlife-management",bookSignature:"Gbolagade Stephen A. Lameed",coverURL:"https://cdn.intechopen.com/books/images_new/5455.jpg",editedByType:"Edited by",editors:[{id:"142349",title:"Dr.",name:"Lameed",surname:"Gbolagade Akeem",slug:"lameed-gbolagade-akeem",fullName:"Lameed Gbolagade Akeem"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6162",title:"New Perspectives in Forest Science",subtitle:null,isOpenForSubmission:!1,hash:"514f8da8e59157028c3707db0deec202",slug:"new-perspectives-in-forest-science",bookSignature:"Helder Filipe dos Santos Viana and Francisco Antonio García Morote",coverURL:"https://cdn.intechopen.com/books/images_new/6162.jpg",editedByType:"Edited by",editors:[{id:"37172",title:"Prof.",name:"Helder",surname:"Viana",slug:"helder-viana",fullName:"Helder Viana"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited 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Glaucoma has long been considered an irreversible progressive optic neuropathy with associated visual loss. Elevated intraocular pressure (IOP) was once considered the main modifiable risk for progression of glaucoma and has been the target for treatment. The pathogenesis of glaucoma was originally based on the mechanical and vascular dysregulation theory, however, this has evolved over the past decade. With the classification of low tension glaucoma, it is now recognized that the damage that occurs in the optic disc is not directly due to the elevated IOP and may be independent of this risk factor. Even though clinicians may aim for a target pressure, progression of optic disc cupping and visual field loss can still continue despite normal IOPs.
In contemplating a systematic approach to neuroprotection, the main areas to target include 1) neurotoxic agents such as nitric oxide and glutamate, 2) deprivation of internal neurotrophic factors 3) balancing self-repair with self-destruction in ocular nerve tissue and, 4) ocular blood flow and combating ischemia [1,2,3]. Focus in this chapter is dedicated to reviewing the mechanisms involved in the pathophysiology of neurodegeneration, target processes that offer neuroprotection, and the chemical and genetic interventions bearing potential for increasing retinal ganglion cell (RGC) survival. Glaucoma has cellular and molecular neurodegenerative pathways akin to those of other neurodegenerative disorders such as alzheimer’s and parkinsons, which increases the accessibility to possible treatment options.
Gene therapy targets increased conventional and uveoscleral outflow, reduced aqueous production and prevention of wound healing in addition to neuroprotection. Interfering with the apoptosis cycle by gene therapy has also being considered by increasing neurotrophic factors [4]. Intravitreal injections of brain-derived neurotrophic factor (BDNF), a neurotrophin that improves neurogenesis and survival are being studied. Interestingly it has recently been noted in animal models that short periods of hyperglycemia may be protective to the retinal ganglion cells during periods of elevated intra ocular pressure [5].
Neuroprotection is the strategy to prevent retinal ganglion cell death. There have been several methods, many still experimental, aimed at reducing glutamate excitotoxicity, nitric oxide, free radical production and tumour necrosis factor (TNF) inhibition [1-4,6]. With the latest research, glaucoma, which was once thought to be an optic neuropathy, then a retinal disease, is now being considered a neurodegenerative disease, like alzheimer and parkinson [7].
This chapter will review the present pathophysiology theories of neurodegeneration in glaucoma and highlight the latest updates in neuroprotection strategies, mechanisms that block apoptosis and improving the survival and functionality of the retinal ganglion cell.
The neurodegeneration seen in glaucoma is as an end result of apoptosis (programmed cell death) of the retinal ganglion cell (RGC). When the retinal ganglion cell dies, there is a degenerative change along the axon with the resulting clinical findings including thinning of the retinal nerve fiber layer (objectively measured by Optical Coherence Tomography, Heidelberg Retinal Tomography or GDx) and increased optic disc cupping. Retinal ganglion cell apoptosis results in visual field loss and ultimately loss of vision in glaucoma. There are several etiologies for retinal ganglion cell (RGC) death which occurs with and without elevated intraocular pressures.
Retinal ganglion cell apoptosis is thought to be a result of several factors:
increased intraocular pressure (IOP)
glutamate excitotoxicity
oxidative stress: free radical induced apoptosis (nitric oxide)
neurotrophic factors deprivation
glial cell activation
abnormal immune response
hypo perfusion
The glutamate and nitric oxide (NO) theories were the early proposed mechanisms for neurodegeneration. There is a proposed oxidative component which results in oxidative stress on the RGC due to increased IOP and hypoxia leading to apoptosis.
Although neurodegeneration theories were considered because of progression despite normal IOPs, increased IOP does have a role in RGC death. Increased IOP can block axonal transport of the excitotoxic transmitter, glutamate, at the level of the lamina cribrosa, leading to deprivation of neurotrophic factors. It is also theorized that a secondary release or decreased uptake of glutamate via the müller cells is another cause for retinal ganglion cell apoptosis. It has been noted that retinal ganglion cell death has been associated with elevated IOP with positive correlation with an increase in matrix metallopetidase- 9 (MMP-9) activity (P<0.001), tissue inhibitor of matrix metalloproteinase (TIMP-1) (P<0.05) and collagen 1 (P<0.01) [8].
With increased IOP, structural changes occur in the optic nerve head. There are several proposed theories for this effect. The mechanical bowing of the lamina cribrosa and loss of the axons may occur because of the hypo perfusion secondary to increased IOP. Optic nerve damage may be more prominent in hypotensive patients which may in part be due reduced perfusion and resulting oxidative stress from the induced hypoxia associated with reduced blood flow. In addition to this elevated IOP results in remodelling of the lamina cribrosa which may be a result of an increased synthesis of extracellular matrix ; matrix metalloproteases (MMP), collagen I and IV and elastin [9-11].
The upregulation of MMP may be due to either the vascular insufficiency with resulting ischemia or secondary to increased endothelin and TNF α production [12]. There is a significant correlation between MMP-9 activity and both RGC apoptosis (P <0.001) and loss of laminin (P <0.01) [8,9]. This change in the structure of the lamina cribosa may result in damage to the retinal ganglion cell axons as they traverse it [13]. Astrocyte activation can result from ischemia, increased hydrostatic pressure or damaged axons and this can propagate the process of structurally changing the lamina cribrosa, resulting in further damage to the transversing ganglion cell axons [14,15].
Glutamate is an excitatory neurotransmitter that is continuously released by photoreceptors and OFF bipolar cells in the dark which results in the dark current. Light stimuli starts the process of phototransduction which leads to reduced glutamate concentration in the synaptic cleft. Glutamate transporters allow for the uptake of glutamate by müller cells which is converted by glutamine synthetase into glutamine which is then released by the glial cells. This glutamine is taken up by the neurons and hydrolysed by glutaminase to glutamate again. Glutamate allows the influx of calcium, resulting in high intracellular calcium levels which promote apoptosis. Glutamate in excess is neurotoxic, due to its induced excitotoxicity. The glutamate-glutamine cycle allows for natural homeostasis between the neurons and the glial cells (Figure 1).
Glutamate is released from degenerating cells or reduced uptake from müller’s cells can increase the presence of glutamate. RGC may undergo apoptosis directly because of increased glutamate excitotoxicity. Müller cells can be injured by the excess glutamate which results in a secondary RGC death [16].
Glutamate ionotropic receptors are found on the post synaptic bipolar, horizontal, amacrine and ganglion cells. They are gating cation channels that are classified into 3 groups; N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainite receptors. In view of this glutamate receptor antagonists have been found to reduce the neurotoxic effect of increased glutamate levels.
The glutamate-glutamine cycle (RGC= Retinal Ganglion cell, GLAST = Glutamate Aspartate transporter, EAAT-1 =Excitatory Amino Acid Transporter))
Increased glutamate has been noted in the vitreous of glaucoma patients [17]. However the glutamate transporters; glutamate aspartate transporter (GLAST) and excitatory amino acid transporter-1 (EAAT-1) are localized exclusively to müller’s cells and glutamate transporter -1 (GLT-1) and excitatory amino acid transporter- 2 (EAAT-2) in the brain, decreased with increasing IOPs [18,19,20] (Figure 1). Therefore, the increase IOP effect on the glutamate transporters can further aggravate glutamine neurotoxicity.
Mice deficient in excitatory amino acid carrier-1 (EAAC1) or GLAST had RGC apoptosis in the absence of elevated IOP. Neuronal EAAC1 does not play a direct role in glutamate transport but transports cysteine much more than GLAST. This is important for the glutathione synthesis. Lack of glutathione made the RGCs more susceptible to oxidative stress [21].
The NMDA ionotropic glutamate receptor has been shown to have an important role in the mechanisms of certain CNS disorders, eg alzheimer’s and parkinson’s disease as seen in rat and human models [22,23,24]. Glutamate opens calcium and sodium channels after binding to the NMDA receptor, which results in a high intracellular influx of calcium which starts the cascade of apoptosis. Therefore, NMDA receptor blockers have been investigated for counteracting possible glutamate excitotoxicity.
Memantine, is a NMDA receptor blocker which is approved in the USA for dementia associated with alzheimer’s disease. Although oral memantine clinically showed a protective effect on visual function and structural damage on macaque monkeys, it did not persist in long term treatment (>5 months) on ERG findings [25,26]. It has been used at doses of 4mg/kg po daily reaching concentrations of 0.3-1.8uM in the monkey vitreous [25,26]. The second phase III clinical trial showed that although the progression of disease was significantly lower in patients receiving the higher dose of memantine compared to patients receiving the low dose of memantine, there was no significant benefit compared to patients receiving placebo [27].
Latest animal studies have shown that using memantine in monkeys will result in an overall higher mean multifocal visual evoked potential (VEP) amplitudes than the non treated memantine monkeys when experimental glaucoma has been induced [28]. However it was not significant from baseline in the former. The use of the GDx in future studies will also allow more sensitive changes in retinal nerve fiber layer to be detected however, this may not directly be translated into functional damage, which in humans can be assesed with visual fields.
This NMDA antagonist acts at the polyamine binding site of the NMDA receptor (NR2B subunit), blocking voltage dependent calcium channels. It has been shown to be neuroprotective in cultured neurons of brain and retina from excitotoxic and ischemia damage at doses of 1-10mg/kg [29]. Eliprodil has shown reduction in the NMDA currents by 78% in a glutamate induced cytotoxicity model [30]. Although there has been promise of this drug in animal studies, clinical trials have not been undertaken for glaucoma in humans.
Nitric oxide (NO) is a neurotransmitter, vasodilator and neuromodulator and can be neurotoxic. Nitric oxide is found at the post junctional area of glutaminergic junctions (rods, bipolar, amacrine and ganglion cells) and acts as an intracellular mediator for glutamate. Excessive production of nitric oxide by astrocytes has been shown to play a role in cell death in both the optic nerve head and the RGC [2,3,6,31,32]. Reactive oxidative species (ROS) may play a role in neurodegeneration as a result of apoptosis (Figure 2).
Nitric oxide is produced by nitric oxide synthase (NOS-2). NOS has 3 isoforms inducible NO (iNO), endothelial NO (eNO) and neuronal NO (nNO). These oxidize L-arginine to L-citrulline, producing NO. Nitric oxide freely diffuses to adjacent neurons and combines with O2 – to form peroxynitrite anions (ONOO-) which is a potential toxin, setting into motion neuronal apoptosis. It can be induced by injury or cytokines, such as interleukin 1 beta, tumour necrosis factor alpha, resulting in high concentrations of nitric oxide [32,33]. Increased levels of NOS are seen in the optic nerve head of glaucoma patients [32]. Tumour necrosis factor (TNF) α is upregulated in the glaucomatous optic nerve head and induces NOS in the astrocytes [34].
Multiple mechanisms for neurodegeneration which may be aggravated by vascular dysregulation, hypoxia and elevated IOP
nNO and iNO are expressed in reactive astrocytes. Increased NO reacts with a superoxide anion which can be toxic to the axons of the retinal ganglion cell. Motallebipour et al, showed a genetic association between iNO and primary open angle glaucoma (POAG) using genetic analysis and nuclear factor [35]. iNO is located in the astrocytes and microglial in the optic nerve head and expresses more activity with exposure to increased intraocular pressure and cytokines. This results in increased in NO production and the induction of the apoptotic cascade [36]. The NO oxide has its effect in both the astrocytes of the optic nerve head and the pericytes of the vasculature [32].
The endothelial NO synthase (eNOS) is expressed in the trabecular membrane and schlem’s canal cells. eNOS produces nitric oxide which regulates the vascular tone causing smooth muscle relaxation and relaxation of the trabecular meshwork which improves aqueous humour outflow [37]. Elevation of the IOP increases the shear stress which activates eNOS which results in increase in the pressure dependent outflow.
Krauss 2011 and Impagnatiello 2011 have had success in lowering IOP in preclinical trials with a nitric oxide donating prostaglandin F2 agonist (BOL-303259-X) more than with latanoprost (prostaglandin F2 agonist) alone [38,39]. Fabrizi 2012, also had some success with combining a carbonic anhydrase inhibitor with a nitric oxide moiety, NCX250 in lowering IOP compared with the a carbonic anhydrase inhibitor alone [40].
α2 adrenergic agonists are a known group of anti glaucoma drugs that inhibit adenylate cyclase, reducing cAMP, thereby decreasing aqueous production. They also act by increasing uveoscleral outflow. α2A receptors can be found in non pigmented ciliary epithelium, α2B receptors on neuronal dendrites and α2C receptors on photoreceptors cell bodies and inner segments [41]. α2 agonists have been shown to have secondary neuroprotective effects [42,43,44].
α2 adrenergic receptors can modulate the release of neurotransmitters such as glutamate [45]. NMDA receptors when stimulated results in an increase in intracellular Ca2+ and an inward current in the RGC. Brimonidine, an α2 agonist, can block the NMDA receptors which results in controlling the intracellular calcium, hereby allowing neuroprotection [23,46]. Brimonidine is also thought to up regulate brain derived neurotrophic factor (BDNF), activating anti apoptotic genes and the cell survival signaling pathway. It is also thought to modulate the N methyl-D-aspartate receptors [43,46-48].
Brimonidine is also known to upregulate not only BDNF, but prosurvival factors, such as anti apoptotic factors B-cell lymphoma -2 (Bcl-2) and B-cell lymphoma extra large (bcl-xl), basic fibroblastic growth factor (bFGF) and extracellular signal regulated kinases (ERKs). These actions assist in the prevention of neuronal death and promotes cell survival [49].
Beta blockers have a long history of use in reducing the IOP in glaucoma by reducing the production of aqueous humour. Levobetaxolol, timolol and metipranolol have been shown to have secondary neuroprotective effect by reducing sodium and calcium influx, which reduces the release of glutamate with levobetaxolol being more effective than timolol [50,51,52].
Betaxolol has been shown to reduce the spontaneous firing rate by suppressing glutamate-gated current and in effect Na currents in the ganglion cells [52]. By doing this it also reversibly blocks the voltage gated calcium current. High intracellular calcium can be neurotoxic. Due to the Ca2+ channel blockage activity by the selective beta 1 beta blocker, betaxolol exerts a neuroprotective effect on the retinal ganglion cells. This effect can be seen at 2-50uM concentration [53]. Timolol is not effective even in higher concentrations (100uM) and clinically betaxolol is more efficacious in preserving visual fields in glaucoma patients compared to timolol [54]. It has been demonstrated in human cryopreserved retinal arterioles that intraluminal bextaolol caused a significant greater dilatation than timolol, this may be due to the selective nature of the beta blocker [55]
Betaxolol 0.5% also upregulates the neurotrophic factor BDNF in retinal glia cells [56]. By its action on vascular smooth muscle relaxation this improves blood flow and reduces ischemia induced RGC apoptosis [52, 57]. Retinal ganglion cells protection has been shown using rat experimental model and the preservation of the a and b waves in the electroretinogram in both ischemic-reperfusion and glutamate toxicity models [56,57,58]. This has also been seen in light response experiments on tiger salamander flat mounted retinas [53].
As high intracellular calcium can be neurotoxic reducing this effect can be neuroprotective to the cells. This effect can be seen in both beta blockers and alpha agonists [2] (Table 1).
Prostaglandin analogs are known as a first line treatment for reducing the IOP. However, latanoprost and bimatoprost acid have shown a neuroprotective on hypoxic induced or glutamate exocitoxity on RGCs [58,59]. This was IOP independent and is not thought to be associated with normal mechanism to lower IOP [59]. Acting via prostaglandin F2 receptors, it has been suggested that latanoprost may have a COX 2 feedback inhibition resulting in neuroprotection [58]. It has also been shown that it inhibits inducible NOS [56]. Latanoprost may also be combined with the NO moiety as previously mentioned [38,39]. Further, it has been theorized that it may have an anti apoptotic effect through the inhibition of caspase-3 [58,60].
The hypotensive effect of carbonic anhydrase inhibitors is a result of reduction of aqueous humour production at the ciliary epithelium level. However in cultured retinal cells, RGC death is prevented by dorzolamide because of its anti-apoptotic pathway [60].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t|
Glutamate Receptor Antagonists • NMDA receptors | \n\t\t\tMemantine Eliprodil | \n\t\t\tReduces glutamate excitotoxicity and neurotoxicity | \n\t\t
\n\t\t\t\t | \n\t\t\tCombinations of nitric oxide donating prostaglandin F2 agonist and with a carbonic anhydrase inhibitor (experimental) | \n\t\t\tReduce oxidative stress | \n\t\t
\n\t\t\t\t | \n\t\t\tSelective Beta Blockade (Betaxolol) \n\t\t\t | \n\t\t\tReduces IOP Reduce glutamate production Upregulates BDNF Calcium channel blockade | \n\t\t
\n\t\t\t\t | \n\t\t\tAlpha 2 agonist (Brimonidine) | \n\t\t\tReduces IOP Reduce glutamate production Upregulates BDNF Calcium channel blockade Increases anti apoptotic genes | \n\t\t
\n\t\t\t\t | \n\t\t\tLatanoprost acid Bimatoprost acid Tafluprost acid | \n\t\t\tReduces IOP Inhibition of COX-2 activity Possible caspase 3 inhibition | \n\t\t
\n\t\t\t\t | \n\t\t\tDorzolamide | \n\t\t\tReduces IOP Reduces apoptosis | \n\t\t
Neurotrophic factors (BDNF and CNTF) | \n\t\t\tBrain Derived Neurotrophic Factor Ciliary Derived Neurotrophic Factor | \n\t\t\tsuppress the intrinsic apoptosis whilst activating the survival signals | \n\t\t
Antioxidants: Reactive Oxygen species scavengers | \n\t\t\tMelatonin Vitamin E Co Q10 cofactor Manganese Tetrakis (in vitro) | \n\t\t\tactivates anti oxidative enzymes Neutralizes free radicals. Oxidative stress can damage the trabecular meshwork, optic nerve head and retina. | \n\t\t
Immunmodulators Anti Inflammatory agents TNF- α Inhibitors | \n\t\t\tCop-1(glatiramer acetate) Ethanrecept Agmatine, an aminoguanidine Aspaminergic agent GLC756 | \n\t\t\tImmunization can modulate immune function | \n\t\t
Gene Therapy (Mitochondrial Augmentation) | \n\t\t\tCycloheximide (CHX) | \n\t\t\tinducing neuroprotective genes including bcl-2 | \n\t\t
Apoptosis Inhibitors Inhibition of cytochrome c release Caspase inhibitors | \n\t\t\tDeprenyl BIRC4 | \n\t\t\tIncrease mitochondrial expression of bcl-2 and bcl-x, suppresses bax. Improved neuronal survival | \n\t\t
\n\t\t\t\t | \n\t\t\tGingko Bilboa IOP lowering medications | \n\t\t\tImproved blood flow | \n\t\t
Pharmacological neuroprotection strategies
Numerous studies have shown that mitochondrial metabolism results in the release of reactive oxidative species that cause damage to lipids, protein, resulting in cell death and neurodegeneration [61]. Hypoxia and ischemia are found to play an important role in the cascade of events leading to oxidative stress, and stimulating delta-opioid receptors (DOR) [62]. DOR has been proven to reduce the build-up of harmful free radicals, glutamate, and pro-inflammatory cytokines [62]. It has been shown that naloxone, an opioid blocker given intraperitoneally 6mg/kg in rabbits can reduce the retinal thickness thinning caused by ischemia [63]. Morphine has been used to pharmacological pre condition rabbit retina and has been shown to reduce acute IOP induced damage [64]
Coenzyme Q10, either on its own or in combination with vitamin E (alpha -tocopherol ) have been shown to reduce intravitreal NMDA mediated damage in mice when adminsitered orally in 10mg/kg dosage [65]. In addition to its effect against oxidative stress its positive effect on the mitochondria may assist in the energy levels within the neuron, protecting it from apoptosis [66]. The RGC requires energy produced from mitochondria to ensure the conduction of currents and normal function of the RGC. Agents that promote the ganglion cell mitochondrial energy production may be neuroprotective in glaucoma. Oral alpha-lipoic acid and nicotinamide have been suggested for further assessment for their neuroprotective effect on light induced neuronal apoptosis [67].
Visual field defects have been noted to improve in patients with normal tension glaucoma after 4 weeks on gingko biloba and no ocular nor systemic adverse events occurred. Ginkgo biloba may exert multifactorial mechanisms which include increase ocular blood flow, anti oxidant activity, nitric oxide inhibition and improved cognitive function due to improved cerebral blood flow [70].
Brain derived neurotropic factor is a neurotrophin derived from the brain (produced in the lateral geniculate body of primates) which moves in a retrograde fashion to bind TrkB receptors on RGC cell body and axon. Its retrograde transport is obstructed in acute and chronic glaucoma models, hence apoptosis occurs, as its neurotrophic support is important in RGC survival [13].
Eyes with chronic glaucoma exhibit loss of physiological neurotrophin levels particularly BDNF. Intravitreal injections of neurotrophins, eg BDNF has shown a reduction in apoptotic RGC death in adult rat models [71]. A recent study considered the cost effective use of serum BDNF as a biomarker for early POAG as its levels were significantly decreased in glaucoma patients compared with controls [72].
BDNF acts through Trk B receptors; phosphorylating kinase enzyme, activating phosphoinositol 3-kinase thereby inhibiting the activation of capsase 3, an important link in the apoptosis pathway (Figure 3). Experimentally BDNF has shown little effect on RGC survival in a single dose, but repeated intravitreal injections as well as virally mediated over expression has been shown to slow RGC loss [4]. It has been used at doses of 25-100ug/kg in clinical trials [73]
Ciliary derived neurotrophic factor (CNTF) is a secretor- protein expressed in cells of all retinal layers and the optic nerve head. The protein shows increased expression in retinal and optic nerve injuries, and is reduced in the presence of increased IOP [4]. The protein demonstrates neuroprotection in virally-mediated overexpression after intravitreal injection. In one study by Pease et al, CNTF showed a 15% less axonal death in experimental induced glaucoma, which was statistically significant over combined CNTF- BDNF and BDNF alone [74]. Intraocular delivery of neurotrophins, BDNF and CNTF, intravitreal or by viral transfer may be a potential future development for neuroprotection [4].
There is an inflammatory component to the neuronal retinal degeneration in glaucoma [75-78]. Studies have proved an age related susceptibility of glaucoma victims to progressive nerve damage and RGC loss even with single digit IOP [4]. Researchers have also established elements of the complement pathway such as C1q, as markers for astrocyte destruction that may result in RGC apoptosis [78]. Thus, the future of glaucoma therapy lies in employing additional modalities based on proven mechanisms of RGC loss.
Apoptosis Pathway for Retinal Ganglion Cells
Progression of optic nerve axonal degeneration and retinal ganglion cell (RGC) apoptosis, have been shown to be responsible for progressive visual field loss in glaucoma, with or without ocular hypertension. One mechanism has been linked to tumor necrosis factor (TNF-α) in tissue around the optic nerve head demonstrated during immunostaining of mouse specimen [77]. This protein is a pro-inflammatory cytokine produced in response to trauma and inflammation and can start the apoptotic cascade [77] (Figure 3). TNF-α, secreted by damaged glials cells and through the binding of TNF receptor-1 (TNF-R1) starts the apoptotic process stimulating caspase ultimately leading to RGC death [79] (Figure 1). However the binding of the TNF-R1 receptor also triggers via heat shock proteins and activation of transcription factor NF-KB, a cell survival pathway. TNF- α levels if at best optimized (kept low) create a homeostasis that facilitates a balance between neuroprotection and neurodegeneration [75,79].
TNF- α is one of a 19-member family of ligands that exert their inflammatory activities through 29 receptors, triggering a cascade of inflammatory responses. TNF- α has been found to be up-regulated in neurodegenerative diseases such as parkinson’s and alzheimer’s disease. In studies on the brain tissue of Alzheimer’s patients, TNF- α, a mediator of chronic inflammation, has been detected in increased levels [76].
TNF- α in some studies was found in high concentration after laser-induced OHT, along with increased macrophage/microglia near the optic nerve head [77]. The levels of TNF α surpassed those in other inflammatory processes not involving ocular hypertension, validating the protein as a likely mediator of the RGC death, and hence a target for gene therapy. The increase in microglia population in the vitreous surface around the optic nerve head also alludes to an inflammation theory of glaucomatous optic nerve and RGC damage [77]. Research in alzheimer’s has established TNF-α as a mediator of chronic inflammation with detection of increased levels in the brain of victims of this neurodegenerative disorder [76]. Serum amyloid A, is another acute-phase inflammatory marker discovered in the retina and trabecular meshwork of glaucoma eyes [78]. An understanding of the molecular processes in parallel disorders will influence the outlook on the future of glaucoma management.
Agarwal et al 2012, reported on extensive research evidence in support of the role of TNF-α in glaucomatous optic nerve degeneration and RGC apoptosis [75]. Research involved eyes with POAG, NTG and exfoliative glaucoma, with cataract eyes as controls [75]. Results showed marked elevation in TNF- α in aqueous samples of all glaucoma groups compared with controls. In addition, optic nerve degeneration and RGC loss were demonstrated in eyes subject to intravitreal injection of TNF- α.
Under normal conditions there is greater expression of TNF-R1 over TNF- α. Stress factors such as trauma, ischaemia, and elevated hydrostatic pressure result in an increase in expression of TNF-R1 and TNF- α. These have been shown to have several roles including pro-apoptotic and neuroprotective properties depending on the environment in which they are expressed [Figure 3]. Experimental evidence using mouse eyes have shown that in the absence of normal glial cells, the apoptotic effect dominates. Microglial cells are thought to provide survival signals necessary for the neuroprotective effect of TNF- α. Insults such as ischemia, oxidative stress and optic nerve injury increases the expression of cell death signals and reduces the expression of the cell survival signals, thereby potentiating the harmful effects of TNF- α [61].
In contrast, normally functioning glial cells support the neuroprotective effects of TNF- α and TNF-R1. The ischaemic and hydrostatic stress in glaucoma activate microglial activity causing an inflammatory response. Activated glial cells produce TNF- α along with harmful compounds like NO and endothelin 1 (ET-1). In excessive microglial activation, up regulation of TNF α - causes RGC apoptosis in the absence of normal glial support. If there is significant microglial insult early in the event, TNF α - continues to exert apoptosis even after the stimulus is removed, as has been shown in in-vivo studies with mice, where progression of RGC death was seen on immunostaining even after normal IOPs were reached [75].
Current research targets TNF-α for neuroprotection by reducing RGC loss (Figure 3). Such agents need to have high selectivity and specificity for excessive TNF-α and TNF-1 expression while preserving local immunity. Agents such as Agmatine, an aminoguanidine, have been shown to protect RGCs against the apoptotic effects of TNF-α, but the effects on other receptors and pathways are yet to be established [44,45,75]. Agmatine has been used at a concentration of 60 mg daily in rat ocular hypertension model [31]. 10(-3) M agmatine solution 4 times a day has shown a high affinity for alpha 2 receptors on the ciliary body, where it exerts its IOP lowering effect which has been seen in the rat model [80]. Amnioguanidine also targets inducible nitric oxide synthase (iNOS) inhibitors [31,73].
Work done by Roh et. al (2012) demonstrated the ability of ethanrecept, a recombinant chimeric protein, to act as a TNFα inhibitor to reduce RGC loss in the wake of elevated TNFα [77]. This decoy protein selectively binds TNFα, sparing the RGC damage from this and other inflammatory agents such as microglia [77]. Ethanrecept is used in the treatment of juvenile idiopathic arthritis, rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis, and has shown no IOP-lowering capabilities. The drug however shows promise as a neuroprotective agent for intravitreal use in the future.
The inflammatory process in neurodegenerative diseases such as alzheimer’s and glaucoma has been found to be associated with pro-inflammatory activities mediated in part by T cell activity. Cop-1, a synthetic peptide polymer known to suppress autoimmune encephalomyelitis, modulates this T cell reaction by producing a Th2 anti-inflammatory phenotype with attenuation of normal inflammatory response in neurodegenerative diseases as well as increased neuroprotection [13, 81,82]. Cop-1, glatiramer acetate has been FDA approved in the treatment of multiple sclerosis, a demyelinating disease.
It had been noted experimentally that an eye that had recent glutamate injections had resulting large numbers of lymphocytes present, hence it was theorized that glutamate toxicity induces a T cell lymphocyte reaction [81]. Therefore, by immunizing against this with the correct antigen, theoretically could reduce the damage induced by the glutamate. Cop-1 immunization has shown some protection against glutamate toxicity and elevated IOP in mice retinal ganglion cells [81,82,83]. So T cell mediated immunoprotection may be a future option for glaucoma, however, much research is still to be done.
Opioid receptor activation has been shown to reduce the ischemic damage to the retina as demonstrated by ERG [84]. Opioid receptor stimulation and the facilitation of the actions of endogenous opioids show promise in neuroprotection of RGCs in glaucoma [84,85]. In the mice model, glaucoma was induced by raising the IOP above the systolic blood pressure (155-160mmHg) for 45 minutes to induce ischemic retinal injury [84]. The opioid antagonist naloxone (3mg/kg) was given to mice intraperitoneally 24 hours before the ischemic event. Another study group of mice had morphine (0.01-10mg/kg given intraperitoneallly 24 hours before the ischemic injury. 7 days after the injury the retina of both groups were assessed by the ERG. The mice that has morphine had greater preservation of their ERG a and b wave amplitudes 7 days after the ischemic event. Further the protective effect of morphine on preservation of ERG amplitudes was dose related with the ED50 of 0.18mg/kg [84]. However, these strategies have not yet been tested in humans or undergone randomized controlled trials.
Much research is still yet to be done on stem cells and neuroprotection. Stem cells can supply neurotrophins and modulate matrix metalloproteinases after an injury which can be neuroprotective and limit neuronal damage [86]. However in a pre-clinical model of glaucoma, intravitreal stem cell injections have been shown to enhance the survival of the RGC [23].
With emerging evidence for the molecular basis in glaucoma- pathophysiology, the disease may be interrupted by targeting key sites once the genetic expression is known. Studies of micro-RNA such as miRNA-125b has led to the understanding of the key sites for targeted down-regulation of messenger RNA which is thought to add to the oxidative stress induction of inflammation and astrogliosis in alzheimer’s disease [78]. Alzheimer’s disease, parkinson and glaucoma are thought to have a similar neurodegenerative basis (molecular and cellular pathways for neuronal cell loss) [78]. Hence gene therapy for glaucoma and other neurodegenerative disorders may be where medical management is headed. Target sites include uveoscleral outflow site, surgical (trabeculectomy) site, ciliary apparatus, retina and optic nerve head (neuroprotection) [4].
Gene therapy would be helpful in preventing neurodegeneration using anti apoptotic genes, bcl-2 and bcl-x [2]. Another mechanism is blocking the apoptotic pathway with deprenyl (monamine oxidase inhibitor). It is proposed that it stabilizes the mitochondrial membrane potential, preventing the release of cytochrome c which can activate capsases (Figure 1) [2, 87].
Targeting antioxidant genes is a promising strategy for future management of glaucomatous neurodegeneration. Researchers used cloned extracellular superoxide dismutase (ECSOD) or catalase (CAT), carried on recombinant adeno associated virus intravitreally in mice. The mice were euthanized and optic nerve volume, myelin fibre area, axonal cell loss and RGC loss evaluated Inital response showed a 15 fold increase in ECSOD and 3.3-fold in CAT [88]. After six months the authors reported 29% reduction in RGC loss, 36% in ON demyelination, and reduction in axonal loss by 44% all compared to control eyes, indicating that antioxidant gene therapy will prove an invaluable adjunct to current glaucoma therapy.
Administration of gene therapy must ideally be safe, repeatable, have low immunogenicity, and carry low infectious and mutagenic potential, modification of Koch’s postulates [4]. Because viral vectors have the ability to maintain stable DNA within the target nucleus, they are preferred over non-viral vectors.
The use of short 21 siRNA by intracameral and intravitreal injection to silence the unwanted expression of glaucoma genes particularly in the trabecular meshwork is being studied. The effects are so far temporary, and such siRNAs need the assistance of developed nanoparticles, such as magnetic nanoparticles, to enter target cells [89]. Chemical approach include the use of
The cause of glaucoma and ultimately retinal ganglion cell death is multifactorial. At present there is no cure for glaucoma and the mainstay of treatment medically and surgically is to control the IOP. However, this conventional approach of lowering IOP is merely a secondary or indirect approach to the real problem. Current studies show that glaucoma is a neurodegenerative disease with neuroprotection and possibly neuroregeneration and neuro enhancement as the future treatment modality. Modified Koch’s postulates have been applied in the experimental neuroprotective research. Ultimately the retinal ganglion cell death whether primary or secondary (bystander result) must be stopped and the neurons preserved. The clinical application of most of these experimental neuroprotective strategies still has yet to pass through randomized controlled clinical trials before they can be accepted. The future holds much promise as to possible effective neuroprotective strategies, however, much research is still yet to be done.
Low back pain is one of the most reported symptoms in adult life [1]. Eighty percent of the population has experienced at least one episode in their life. It results in major disability for patients when it becomes chronic [2].
Different etiologies were described, but in more than 75% of cases, a nonspecific cause is evoked. Several factors were implicated: age, work, smoking, obesity, and psychological.
Pure low back pain is generally related to degenerative changes in one or more structures of the spine. The most common cause is discogenic followed by facet joint arthropathy [1, 3].
Facet joint disease is a multifactorial problem implicating mechanical and inflammatory damages, and the most common underlying etiology is arthritis [2, 3, 4].
Radio frequency is a well-known therapeutic option for refractory low back pain related to facet arthropathy [3]. It is still a very controversial procedure in terms of efficiency. Some studies showed its superiority to placebo or conservative treatment where others were not conclusive [4, 5, 6]. We consider it as a safe, minimally invasive, inexpensive procedure. It is successful in well-selected patients.
The spine is a complex structure in which its integrity depends on multiple anatomical elements that are functionally and structurally related to each other. The spine is a multi-articular system. Its function is to maintain axial stability. Spinal stability is based on three connected systems: the columns, the muscles, and the spinal cord with its nerve roots [7].
The columns contain mechanical receptors that send proprioceptive information on the load, motion, and postures through the spinal nerves to the central nervous system.
Facet or zygoapophysial joints are part of the columns. They are bilateral on each level and contain synovial fluid lined with hyaline cartilage. Their role is to control the direction and the amplitude of the movements in addition to share the loads. In the physiological condition, a balanced action exists between the three columns. The posterior facets support up to the third of the load depending on the posture [3, 7].
Facet joints are symmetrical which maintain the correct function in mobility. Any changes in the symmetry predispose to instability and lead to degeneration of the joint. Degenerative disease of the facet joints is accompanied by an inflammatory reaction leading to nervous irritation and low back pain.
There are two types of innervation in the lumbar spine, the somatic and the sympathetic.
The L1–L4 dorsal rami are different from the L5. They are shorter and go backward into intertransverse spaces, whereas the L5 goes over the top of all of the sacrum. L1–L4 are divided into three branches; L5 has two branches: the medial and the intermediate [8]. The medial branch at all levels is responsible for the innervation of the facet joint. It runs on the top of the transverse process toward the articular process (Figure 1). Each medial branch covers two levels though each articular facet joint gets its innervation from the level itself and the level above [7, 8].
Anatomy of the medial branch at the level of the facet joint with schematic representation of the needle in addition to the radio-frequency probe.
Patients suffering from low back pain are initially assessed by their family physician. The majority are referred to low back pain clinic developed in our hospital. If there is a failure of conservative medical treatment for 12 weeks in the absence of red flags, patients are referred to neurosurgical evaluation. MRI or CT scan of the lumbosacral spine is always done before their first visit, in addition to the dynamic lumbosacral spine X-rays and laboratory workup. Initial findings on MRI or CT scan of the lumbosacral spine are related to facet joint arthropathy. There is a joint space narrowing with intra-articular fluid leading to T2 hypersignal on MRI [3, 9]. Osteophyte formation at the level of the superior articular facet of the lower vertebra, ligamentum flavum with recess stenosis is frequently observed. They are evaluated clinically by a multidisciplinary team (neurosurgeon, anesthesiologist pain specialist, neuropsychologist, physiotherapist, occupational therapist) after being referred from their primary care physician.
The initial evaluation is done by a neurosurgeon. Patients answer three questionnaires before their initial consultation: the visual analog scale, the McGill pain questionnaire, and the Sf-36 quality-of-life questionnaire. Those questionnaires are evaluated before the patient is seen at the office. In the absence of red flags, we developed a workflow for the management of chronic low back pain (Figure 2).
The Moncton workflow for facet radio-frequency ablation treatment.
Patient undergoes a complete neurological examination. Facet joint inflammation is suspected when there is an increase in pain on palpation of the joint or in hyperextension position and lateral torsion of the low back. Pain is induced by position changes from supine to sitting and from sitting to standing. In some patients, we may observe some radiating pain mainly to the hip and thigh. Without discogenic disease, straight leg rising is non-painful usually. Motor and sensory examination of the lower limbs is normal.
In the absence of any surgical condition but evident facet hypertrophy of the MRI or the CT, patients are referred for SPECT CT scan (single photon emission computed tomography) [9] and neuropsychological evaluation. SPECT CT scan usually shows an increase uptake at the level of facet joint and eliminates other inflammatory process mainly at the disc level. The mean waiting time between the initial evaluation and the follow-up is 6–8 weeks.
If the SPECT CT scan is normal or if there is a severe psychological problem, conservative treatment is considered. Otherwise, in case where the SPECT CT confirms the presence of facet arthropathy (Figure 3), patients are referred for facet block under fluoroscopy at the pain clinic. In case of improvement that lasts more than 3 months, reevaluation and second facet block are offered to the patient.
SPECT CT of the lumbosacral spine showing increase uptake of the right L5–S1 facet joint in favor of facet arthropathy.
In case of improvement for more than 48 h but less than 3 months, patients are considered candidates for radio-frequency ablation.
Rhizotomy is an outpatient procedure performed under local-assisted anesthesia [10]. Patients are evaluated at the office few weeks prior to the procedure; surgical consent and laboratory workup with a complete blood count in addition to PT are signed; PTT tests are done.
Patients are asked to fast 6 h prior to the procedure. All anticoagulant and anti-aggregant are stopped according to guidelines.
The procedure is done in the operating room. The anesthesiologist proceeds by inserting an intravenous access on the arrival of the patient to the OR. The patient is positioned prone on a radiolucent table with pillow under the head; the arms are above the head in a comfortable position.
Fluoroscopy is used for anteroposterior and lateral views (Figure 4). Aseptic technique is used. Once level is verified, local anesthesia using xylocaine 2% is infiltrated from the skin to the muscle aponeurosis. Under fluoroscopy, we insert a 20 gauge needle percutaneously targeting the junction of the transverse process and superior articulating facet, where the medial branch of the Luschka nerve runs innervating the facet joint. The needle is advanced until bone contact is made. Once position is verified, the patient is assessed for motor and sensory manifestations in the lower limb.
Anteroposterior and lateral per operative views for L4–L5 rhizotomy.
Using Baylis radio-frequency machine (Baylis medical), we start by a stimulation until reproducing patients pain and paraspinal lumbar muscle contraction. Radio frequency is started at 80°C for 90 s. Once 80° is reached (10–15 s), the needle is rotated progressively every 15 s to reach 360° coverage. The patient is then reassessed for motor or sensory manifestations in the lower limb.
A new stimulation trial is performed. In case there is a need to increase the stimulation two times compared to prior or there is no pain reported by the patient, the procedure is considered successful, and the needle is removed. The entry point is covered by a small dressing. If the patient still feels the pain or the pain was reproduced with the same stimulation level, the procedure is repeated for 60 s at 80°. After the second trial, when needed, the needle is removed and a dressing is applied. Patients are turned to their back and transferred to the same day care facility.
Patients are discharged the same day, 30–60 min after the procedure. They are followed at 2 and 4 weeks post procedure. Pain is reevaluated by visual analog scale and quality-of-life scale at the office (questionnaire is administered to the patient before their appointment).
In case of recurrence of pain after 2 weeks of relief, patients are rescheduled for a second radio-frequency treatment. During the second procedure, we target the same level as the first in addition to the superior level trying to cover the largest area and ablating the two medial branches innervating that facet. In case of failure at 1 month, we offer other neuromodulation procedures for the patient.
The overall complication rate is very low in radio-frequency procedure in the treatment of facet joint arthropathy [3, 10]. The main complication is injury to the nerve root at its exit if the needle is advanced beyond the bony anatomical landmark inferior to the transverse process.
Infectious rate is very low in purely aseptic technique done in the neurosurgical operating room. Dural puncture may occur if the needle is advanced medially or if the technique is not done under fluoroscopy.
The radio-frequency treatment is a minimally invasive cost-effective procedure. Although it is still very controversial, we found it as a safe and efficacious procedure to be offered for chronic low back pain patients refractory to conservative treatment. Selection criteria for the patients are very important to benefit from the procedure.
Patient’s age is 18 years and older.
Refractory low back pain to at least 3 months of conservative treatment.
Positive SPECT CT for facet joint arthropathy. Absent MRI/CT scan finding for other spinal disease.
Improvement for at least 48 h after facet joint block and absent neurocognitive diseases.
All charts of patients that benefited from the procedure were analyzed retrospectively. The procedure was done by the same neurosurgeon, but the clinical evaluation and the indication were decided at the practice of all the neurosurgical team included in this study.
The primary outcome was the pain intensity evaluated by the visual analog scale (VAS), 11 points of evaluation of the pain where 0 indicates the absence of pain and 10 is the worst pain ever.
The McGill pain questionnaire score between 20 and 30 points indicates the presence of chronic low back pain.
The SF-36 QOL questionnaire, with a score of 0, indicates severe or absent activities and worse QOL, whereas a score of 100 shows an excellent QOL.
Patients’ response to the procedure was considered by an improvement of 50% or more on the VAS and a change of 20 or more points on the SF-36 QOL score. An improvement of 25–50% on the VAS leads us to suggest a second rhizotomy procedure to increase the area of coverage and try to have a better outcome.
In total, 63 patients were treated by radio-frequency ablation of the medial branch of the facet joint in the lumbar spine between 2015 and March 2018.
All included patients had long history of low back pain refractory to medical treatment with short-term response to facet joint steroid injection block. Patients didn’t have any major psychological disease.
All included patients were adults. The mean age was 57 years (21–84 years). Forty-one patients were male, and 22 patients were females.
The mean pretreatment VAS was 8.4, the McGill pain score was between 20 and 30, and the SF-36 score was 58.6.
The post-procedure mean VAS was 3.8. Forty-four patients had an improvement of more than 50% of their pain; eight patient had an improvement of 25% of their pain, and 11 patients did not notice any changes at 2 weeks.
All the eight patients that reported 25% of improvement were scheduled for a second procedure. Six of eight reported an improvement of more than 50%, one did not notice any difference, and one returned to his previous VAS.
At 3 months, 40 patients were maintaining a VAS score of 50% or more than their initial pain score. Five patients had their pain score between 25 and 50%. And, seven patients returned to their baseline score. From all seven, four had already two radio-frequency treatments and were redirected to a neuromodulation procedure, and three had a second rhizotomy. One improved and was considered successful.
The overall patients that improved were 73%. Sixty-five percent had a major improvement, 8% moderate improvement, and 27% failed to improve after one or two trials.
In the 65% of patients, the overall SF-36 score improvement was to a mean of 77.9.
Three patients reported lower limb paresthesia post-procedure. Two of them had a complete remission of their symptoms at 2 weeks of follow-up, and the third improved after 6 weeks. No infection, no CSF leak, and no injury to the motor nerve root were observed.
Our result on low back improvement is similar to different studies at 2 and 4 weeks of the procedure [2, 11, 13].
At 3 months, we had a better outcome compared to other studies [11, 12]. All studies used the VAS for pain evaluation.
We consider the selection criteria specifically the positive SPECT CT findings in addition to the response to facet block as a major contributor in the prediction of the success of the procedure. No previous study used both criteria in conjunction. Van Wijk et al. showed the importance of the diagnostic test block, although their result was the same compared to sham at 3 months [12].
We followed the patients for 3 months, which is an intermediate time follow up as in other studies that showed the same results [11, 12, 13, 14]. We found that improving pain score and QOL for 3 months was a sufficient time to consider the procedure as efficient. The subjective satisfaction rate and the reported improvement on VAS and SF-36 score, respectively, were good indicators to maintain the procedure as one of the armamentarium in the treatment of chronic low back pain related to facet joint arthropathy; this finding is against Juch et al. findings that have a statistically positive finding without any clinical improvement [4]. Although, in their study published in JAMA, they suggested to improve the selection criteria to improve the outcome related to that procedure, our workflow chart improved the results dramatically.
Radio-frequency ablation technique is a safe and efficient procedure. Its complication rate and cost are low. It is a reproducible procedure. Careful patient selection increases its success rate.
The use of this technique for the treatment of other etiologies has been described. Its use in the management of metastatic vertebral bone disease is promising and becoming a very useful tool as a pain management procedure.
We extend our thanks to Dr. Jennifer Hakim who participated in the editing of this chapter.
All four authors have no conflict of interest.
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\n\nThe first step in obtaining funds for your Open Access publication begins with your institution or library. IntechOpen’s publishing standards align with most institutional funding programs. Our advice is to petition your institution for help in financing your Open Access publication.
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VSMCs are mostly of mesodermal origin, although some are of neuroectodermal origin, for example, VSMCs present in the aorta and in blood vessels arising from the aortic arch. VSMCs of neuroectodermal origin are implicated in defects of cardiovascular morphogenesis, such as bicuspid aortic valve, coarctation of the aorta, patent ductus arteriosus and tetralogy of Fallot. The origin, location in the vascular tree, gender, species, strain and age influence the phenotype of VSMCs and their propensity to migration and growth. In a healthy adult organism, VSMCs have a quiescent and differentiated contractile phenotype characterized by early markers (e.g., SM α-actin, SM22-α), intermediate markers (h-caldesmon, calponin) and late markers (SM myosins, smoothelin) of VSMC differentiation. 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