IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
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IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
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Designed to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
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After a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
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Our innovative Book Series format brings you:
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Topic Focused Publications - Each topic showcases high impact subject areas
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Renowned Editorial Expertise - Series Editors, Topic Editors, and a team of international Board Members that permanently support each Book Series
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Fast Publishing - quick turnaround which is unique for book publishing
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The benefit of ISSN and ISBN for increased citation and indexing possibilities
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IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
We invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
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Note: Edited in October 2021
\n'}],latestNews:[{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"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"5540",leadTitle:null,fullTitle:"Enzyme Inhibitors and Activators",title:"Enzyme Inhibitors and Activators",subtitle:null,reviewType:"peer-reviewed",abstract:"Over the recent years, medicinal chemistry has become responsible for explaining interactions of chemical molecule processes such that many scientists in the life sciences from agronomy to medicine are engaged in medicinal research. This book contains an overview focusing on the research area of enzyme inhibitor and activator, enzyme-catalyzed biotransformation, usage of microbial enzymes, enzymes associated with programmed cell death, natural products as potential enzyme inhibitors, protease inhibitors from plants in insect pest management, peptidases, and renin-angiotensin system. The book provides an overview on basic issues and some of the recent developments in medicinal science and technology. Especially, emphasis is devoted to both experimental and theoretical aspect of modern medicine. The primary target audience for the book includes students, researchers, chemists, molecular biologists, medical doctors, pharmacologists, and professionals who are interested in associated areas. The textbook is written by international scientists with expertise in biochemistry, enzymology, molecular biology, and genetics, many of which are active in biochemical and pharmacological research. I would like to acknowledge the authors for their contribution to the book. We hope that the textbook will enhance the knowledge of scientists in the complexities of some medical approaches; it will stimulate both professionals and students to dedicate part of their future research in understanding relevant mechanisms and applications of pharmacology.",isbn:"978-953-51-3058-1",printIsbn:"978-953-51-3057-4",pdfIsbn:"978-953-51-4887-6",doi:"10.5772/63325",price:119,priceEur:129,priceUsd:155,slug:"enzyme-inhibitors-and-activators",numberOfPages:268,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"5f1fa8db9cc4553ea23e011e520e689c",bookSignature:"Murat Senturk",publishedDate:"March 29th 2017",coverURL:"https://cdn.intechopen.com/books/images_new/5540.jpg",numberOfDownloads:31964,numberOfWosCitations:98,numberOfCrossrefCitations:72,numberOfCrossrefCitationsByBook:1,numberOfDimensionsCitations:181,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:351,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 19th 2016",dateEndSecondStepPublish:"June 9th 2016",dateEndThirdStepPublish:"September 5th 2016",dateEndFourthStepPublish:"November 4th 2016",dateEndFifthStepPublish:"December 4th 2016",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"14794",title:"Prof.",name:"Murat",middleName:null,surname:"Şentürk",slug:"murat-senturk",fullName:"Murat Şentürk",profilePictureURL:"https://mts.intechopen.com/storage/users/14794/images/system/14794.jpeg",biography:"Dr. Murat Şentürk obtained a baccalaureate degree in Chemistry in 2002, a master’s degree in Biochemistry in 2006, and a doctorate degree in Biochemistry in 2009 from Atatürk University, Turkey. Dr. Şentürk currently works as an professor of Biochemistry in the Department of Basic Pharmacy Sciences, Faculty of Pharmacy, Ağri Ibrahim Cecen University, Turkey. \nDr. Şentürk published over 120 scientific papers, reviews, and book chapters and presented several conferences to scientists. \nHis research interests span enzyme inhibitor or activator, protein expression, purification and characterization, drug design and synthesis, toxicology, and pharmacology. \nHis research work has focused on neurodegenerative diseases and cancer treatment. Dr. Şentürk serves as the editorial board member of several international journals.",institutionString:"Ağrı İbrahim Çeçen University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Ağrı İbrahim Çeçen University",institutionURL:null,country:{name:"Turkey"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"393",title:"Applied Microbiology",slug:"biochemistry-genetics-and-molecular-biology-enzymology-applied-microbiology"}],chapters:[{id:"52854",title:"Peptidases and the Renin-Angiotensin System: The Alternative Angiotensin-(1-7) Cascade",doi:"10.5772/65949",slug:"peptidases-and-the-renin-angiotensin-system-the-alternative-angiotensin-1-7-cascade",totalDownloads:1786,totalCrossrefCites:3,totalDimensionsCites:4,hasAltmetrics:1,abstract:"The renin-angiotensin system (RAS) constitutes a key hormonal system in the physiological regulation of blood pressure via peripheral and central mechanisms. Dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, and pharmacologic blockades of this system by the inhibition of angiotensin-converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT1R) are effective therapeutic regimens. The RAS is now defined as a system composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS comprises the ACE-Ang II-AT1R axis that promotes vasoconstriction, water intake, sodium retention and increased oxidative stress, fibrosis, cellular growth, and inflammation. The nonclassical or alternative RAS is composed primarily of the ACE2-Ang-(1-7)-AT7R pathway that opposes the Ang II-AT1R axis. In lieu of the complex aspects of this system, the current review assesses the enzymatic cascade of the alternative Ang-(1-7) axis of the RAS.",signatures:"Nildris Cruz-Diaz, Bryan A. Wilson and Mark C. Chappell",downloadPdfUrl:"/chapter/pdf-download/52854",previewPdfUrl:"/chapter/pdf-preview/52854",authors:[{id:"120145",title:"Dr.",name:"Brian",surname:"Rybarczyk",slug:"brian-rybarczyk",fullName:"Brian Rybarczyk"},{id:"191435",title:"Prof.",name:"Mark",surname:"Chappell",slug:"mark-chappell",fullName:"Mark Chappell"},{id:"195179",title:"Dr.",name:"Nildris",surname:"Cruz-Diaz",slug:"nildris-cruz-diaz",fullName:"Nildris Cruz-Diaz"}],corrections:null},{id:"52789",title:"Programmed Cell Death-Related Proteases in Plants",doi:"10.5772/65938",slug:"programmed-cell-death-related-proteases-in-plants",totalDownloads:1710,totalCrossrefCites:2,totalDimensionsCites:8,hasAltmetrics:0,abstract:"From an ancient Greek term related to the “leavening of bread” (en, in; zyme, leaven), an enzyme can be defined as a substance showing the properties of a catalyst that is produced as a result of cellular activity. Every proteinaceous enzyme that performs hydrolysis of peptide bonds is appropriately termed “protease” (peptidase). All of them share aspects of catalytic strategy, but with some variation. As a result, the proteases are grouped into six different catalytic families: serine, threonine, cysteine, aspartic, glutamic and metallopeptidases (http://merops.sanger.ac.uk/). The larger families (cysteine, serine, aspartic and metallopeptidases) have a wide range of distribution on living organism groups, and are also present in the “controversial” viruses. As a well‐represented family, the cysteine proteases play important roles in events such as signalling pathways, programmed cell death (PCD), nutrient mobilization, protein maturing, hormone synthesis and degradation. In the past two decades, an increased interest was driven to the study of the programmed cell death (PCD), mainly after the discovery of caspase‐related proteins and caspase‐like activities in organisms not metazoan. Caspases are cysteine proteases that cleave their substrate after aspartate residues and are part of signalling cascades of the apoptotic PCD process (also in inflammatory process), unique of metazoan. The caspase‐related proteins are named paracaspases and metacaspases. Paracaspases are found on metazoan and Dictyostelium, whereas the metacaspases are present on plants, fungi and groups of protozoan. On plants, PCD has features that are distinct from that of animals and is an important pathway on developmental events, defensive and stress response (biotic and abiotic). All these events have their own particularities, but the participation of proteases seems to be universal with those responsible for caspase‐like activities and metacaspases having an increasing number of reports that put them as important for plant PCD. In this chapter, we tackle important aspects of the proteases, in special that involved in plant PDC, as well as their specific regulators. Aspects of function, catalytic mechanisms and interaction with ligands will be on focus.",signatures:"Gustavo Lemos Rocha, Jorge Hernandez Fernandez, Antônia Elenir\nAmâncio Oliveira and Kátia Valevski Sales Fernandes",downloadPdfUrl:"/chapter/pdf-download/52789",previewPdfUrl:"/chapter/pdf-preview/52789",authors:[{id:"193467",title:"Ph.D.",name:"Katia",surname:"Fernandes",slug:"katia-fernandes",fullName:"Katia Fernandes"},{id:"193476",title:"Dr.",name:"Jorge H.",surname:"Fernandez",slug:"jorge-h.-fernandez",fullName:"Jorge H. Fernandez"},{id:"193477",title:"MSc.",name:"Gustavo L.",surname:"Rocha",slug:"gustavo-l.-rocha",fullName:"Gustavo L. Rocha"},{id:"193478",title:"Dr.",name:"Antonia E.A.",surname:"Oliveira",slug:"antonia-e.a.-oliveira",fullName:"Antonia E.A. Oliveira"}],corrections:null},{id:"53230",title:"Effect of High-Pressure Technologies on Enzymes Applied in Food Processing",doi:"10.5772/66629",slug:"effect-of-high-pressure-technologies-on-enzymes-applied-in-food-processing",totalDownloads:2062,totalCrossrefCites:5,totalDimensionsCites:7,hasAltmetrics:0,abstract:"High isostatic pressure (HIP) and high-pressure homogenization (HPH) are considered important physical technologies that able to induce changes on enzymes. HIP and HPH are emerging food processing technologies that involve the use of ultra high pressures (up to 1200 MPa for HIP and up to 400 MPa for HPH), where the first process is based on the principle that the maintenance of a product inside vessels at high pressures induces changes in the molecules conformation and, consequently, in the functionality of polysaccharides, proteins and enzymes. To the contrary, for HPH process, the high shear and sudden pressure drop are the responsible phenomena for the changes on the processed product. This chapter aims to evaluate comparatively the effects of HIP and HPH on the activity of enzymes currently applied in food industry and to identify the main structural changes induced by each process. The overall evaluation of the results shows that mild conditions of both processes were recently highlighted as able to improve the activity and the stability of several enzymes, whereas extreme process conditions (pressure, time and temperature) induce enzyme denaturation with consequent reduction of biological activity. Considering the complexity and diversity involved in the enzyme structure and its ability to react, it is not possible to determine specific conditions that each process is able to promote increase or reduction of enzyme activity, being necessary to evaluate HIP and HPH for each enzyme. Finally, in terms of molecular structure, the effect of HIP and HPH on enzymes can be explained by the alterations in the quaternary, tertiary and secondary structures of enzymes, which directly affects its active site configuration.",signatures:"Bruno Ricardo de Castro Leite Júnior, Alline Artigiani Lima Tribst\nand Marcelo Cristianini",downloadPdfUrl:"/chapter/pdf-download/53230",previewPdfUrl:"/chapter/pdf-preview/53230",authors:[{id:"178295",title:"Dr.",name:"Bruno Ricardo",surname:"Leite Júnior",slug:"bruno-ricardo-leite-junior",fullName:"Bruno Ricardo Leite Júnior"},{id:"193474",title:"Prof.",name:"Alline Artigiani Lima",surname:"Tribst",slug:"alline-artigiani-lima-tribst",fullName:"Alline Artigiani Lima Tribst"},{id:"193475",title:"Prof.",name:"Marcelo",surname:"Cristianini",slug:"marcelo-cristianini",fullName:"Marcelo Cristianini"}],corrections:null},{id:"54515",title:"Kinetic Modelling of Enzyme Catalyzed Biotransformation Involving Activations and Inhibitions",doi:"10.5772/67692",slug:"kinetic-modelling-of-enzyme-catalyzed-biotransformation-involving-activations-and-inhibitions",totalDownloads:4310,totalCrossrefCites:1,totalDimensionsCites:6,hasAltmetrics:0,abstract:"To achieve transition from lab scale enzyme studies to industrial applications, understanding of enzyme kinetics plays a critical role. The widely applied Michaelis Menten equation of the single substrate kinetics, sequential and double replacement mechanism of bisubstrate reaction and the relevant kinetics, inhibition and activation of enzyme are all integral parts of this discussion. In this chapter, we have discussed different types of inhibition and kinetic modelling. Systematic approach to generate data and its interpretation as well as designing of inhibitors is also explained.",signatures:"Ganapati D. Yadav and Deepali B. Magadum",downloadPdfUrl:"/chapter/pdf-download/54515",previewPdfUrl:"/chapter/pdf-preview/54515",authors:[{id:"49324",title:"Prof.",name:"Ganapati",surname:"Yadav",slug:"ganapati-yadav",fullName:"Ganapati Yadav"},{id:"193953",title:"Ms.",name:"Deepali",surname:"Magadum",slug:"deepali-magadum",fullName:"Deepali Magadum"}],corrections:null},{id:"52721",title:"Telomerase Inhibitors and Activators: Pharmaceutical Importance",doi:"10.5772/65933",slug:"telomerase-inhibitors-and-activators-pharmaceutical-importance",totalDownloads:2834,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:1,abstract:"Telomeres are specialized functional complexes that protect the ends of eukaryotic chromosomes. The telomeric DNA sequences are tandem repeats of a short hexameric sequence unit. The inability to DNA polymerase to replicate the end of the chromosome during lagging strand synthesis results in the loss of telomeric repeats when cell divides. Telomere shortening provides a barrier to cancer progression and the majority of the cancer cells depend on the activation of telomerase to gain proliferative immortality. Thus, telomerase is a molecular target for diseases since its discovery. Telomerase inhibition enables more specific ground for cancer therapy because the telomerase is not detected in most normal tissues. Some of the synthetic and natural telomerase inhibitors were tried on various cancer cells and there was a decrease in the number of cancer cells. But on the other hand, telomere shortening correlates with cellular aging. Some evidence suggests that the progressive loss of telomeric repeats of chromosomes may function as a molecular clock that triggers senescence. Telomerase-related gene mutations also result in some diseases. Because of this, telomerase activators are important for antiaging and telomerase-dependent disease treatments. This chapter summarizes the pharmaceutical importance of telomeres, telomerase structure, telomerase activators, and inhibitors.",signatures:"Ayse Gul Mutlu",downloadPdfUrl:"/chapter/pdf-download/52721",previewPdfUrl:"/chapter/pdf-preview/52721",authors:[{id:"115828",title:"Dr.",name:"Ayse Gul",surname:"Mutlu",slug:"ayse-gul-mutlu",fullName:"Ayse Gul Mutlu"}],corrections:null},{id:"52798",title:"Effect of Metal Ions, Chemical Agents and Organic Compounds on Lignocellulolytic Enzymes Activities",doi:"10.5772/65934",slug:"effect-of-metal-ions-chemical-agents-and-organic-compounds-on-lignocellulolytic-enzymes-activities",totalDownloads:2773,totalCrossrefCites:14,totalDimensionsCites:46,hasAltmetrics:0,abstract:"Lignocellulolytic enzymes have been extensively studied due to their potential for industrial applications such as food, textile, pharmaceutical, paper, and, more recently, energy. The influence of metal ions, chemical agents, and organic compounds on these enzyme activities are addressed in this chapter, based on data available in the scientific literature.",signatures:"Josiani de Cassia Pereira, Ellen Cristine Giese, Marcia Maria de Souza\nMoretti, Ana Carolina dos Santos Gomes, Olavo Micali Perrone,\nMaurício Boscolo, Roberto da Silva, Eleni Gomes and Daniela\nAlonso Bocchini Martins",downloadPdfUrl:"/chapter/pdf-download/52798",previewPdfUrl:"/chapter/pdf-preview/52798",authors:[{id:"58745",title:"Prof.",name:"Eleni",surname:"Gomes",slug:"eleni-gomes",fullName:"Eleni Gomes"},{id:"126536",title:"Dr.",name:"Marcia Maria de Souza",surname:"Moretti",slug:"marcia-maria-de-souza-moretti",fullName:"Marcia Maria de Souza Moretti"},{id:"139595",title:"Dr.",name:"Ellen",surname:"Giese",slug:"ellen-giese",fullName:"Ellen Giese"},{id:"192443",title:"Ph.D. Student",name:"Josiani",surname:"De Cassia Pereira",slug:"josiani-de-cassia-pereira",fullName:"Josiani De Cassia Pereira"},{id:"193381",title:"MSc.",name:"Ana Carolina",surname:"Dos Santos Gomes",slug:"ana-carolina-dos-santos-gomes",fullName:"Ana Carolina Dos Santos Gomes"},{id:"193382",title:"Dr.",name:"Daniela",surname:"Alonso Bocchini Martins",slug:"daniela-alonso-bocchini-martins",fullName:"Daniela Alonso Bocchini Martins"},{id:"195332",title:"Dr.",name:"Olavo",surname:"Micali Perrone",slug:"olavo-micali-perrone",fullName:"Olavo Micali Perrone"}],corrections:null},{id:"54038",title:"Natural Products as a Potential Enzyme Inhibitors from Medicinal Plants",doi:"10.5772/67376",slug:"natural-products-as-a-potential-enzyme-inhibitors-from-medicinal-plants",totalDownloads:2495,totalCrossrefCites:13,totalDimensionsCites:44,hasAltmetrics:0,abstract:"Enzyme inhibitory agents are attractive because of their application in treating different ailments. The absence of enzymes produce a number of diseases. Medicinal plants are a rich source of producing secondary metabolites which showed broad-spectrum enzyme inhibitory potential. The position of enzyme inhibitors as new drugs is vast since these compounds have been used for the treatment of various physiological disorders. Bioactive secondary metabolites can deliver excellent pharmacophore patterns for drugs related to numerous illnesses. This book chapter is planned to document the enzyme inhibitory potential of natural compounds, medicinal plant extract, and its isolated compounds.",signatures:"Abdur Rauf and Noor Jehan",downloadPdfUrl:"/chapter/pdf-download/54038",previewPdfUrl:"/chapter/pdf-preview/54038",authors:[{id:"192295",title:"Dr.",name:"Abdur",surname:"Rauf",slug:"abdur-rauf",fullName:"Abdur Rauf"}],corrections:null},{id:"52729",title:"Microbial Glycosidases for Nondigestible Oligosaccharides Production",doi:"10.5772/65935",slug:"microbial-glycosidases-for-nondigestible-oligosaccharides-production",totalDownloads:1714,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"There is much interest in the study and production of nondigestible oligosaccharides (NDOs), due to their bioactivities and beneficial effects to the human health. The main approach in the production of NDOs relies on the action of glycosidases performing hydrolysis or transglycosylation of polysaccharides and sugars. In this chapter, a description of the main microbial glycosidases used for NDOs production, their sources, their principal properties, and a description of the production processes with the better results obtained are discussed.",signatures:"Thais Bezerra, Rubens Monti, Egon B. Hansen and Jonas Contiero",downloadPdfUrl:"/chapter/pdf-download/52729",previewPdfUrl:"/chapter/pdf-preview/52729",authors:[{id:"193454",title:"Prof.",name:"Jonas",surname:"Contiero",slug:"jonas-contiero",fullName:"Jonas Contiero"}],corrections:null},{id:"52877",title:"Inhibitors and Activators of SOD, GSH‐Px, and CAT",doi:"10.5772/65936",slug:"inhibitors-and-activators-of-sod-gsh-px-and-cat",totalDownloads:3680,totalCrossrefCites:18,totalDimensionsCites:42,hasAltmetrics:0,abstract:"Reactive oxygen species (ROS) is harmful to our health, and SOD, CAT, and GPX are the major antioxidant enzymes that defend us from effects of ROS. In medicine, food, and dairy industries, antioxidant enzymes often surround complex environments. For better utilization of these enzymes, the inhibitors (including competitive inhibitors and noncompetitive inhibitors) and activators of SOD, CAT, and GPX are descripted in detail in this chapter. Also, the structure and catalytic mechanism of these antioxidants are summarized.",signatures:"Xianyong Ma, Dun Deng and Weidong Chen",downloadPdfUrl:"/chapter/pdf-download/52877",previewPdfUrl:"/chapter/pdf-preview/52877",authors:[{id:"193346",title:"Prof.",name:"Xianyong",surname:"Ma",slug:"xianyong-ma",fullName:"Xianyong Ma"},{id:"193352",title:"Dr.",name:"Dun",surname:"Deng",slug:"dun-deng",fullName:"Dun Deng"}],corrections:null},{id:"54207",title:"Enzyme Dynamic in Plant Nutrition Uptake and Plant Nutrition",doi:"10.5772/66938",slug:"enzyme-dynamic-in-plant-nutrition-uptake-and-plant-nutrition",totalDownloads:2528,totalCrossrefCites:1,totalDimensionsCites:3,hasAltmetrics:1,abstract:"Soil contains enzymes, constantly interacting with soil constituents, e.g. minerals, rhizosphere and numerous nutrients. Enzymes, in turn, catalyse important biochemical reactions for rhizobacteria and plants, stabilize the soil by degrading wastes and mediate nutrient recycling.The available enzymes inside soil could originate from plants, animals or microbes. The enzymes that are produced from these organism could exhibit intracellular activities, at the cell membrane, interacting therefore with soil and its constituents, or extracellularly (so freely available). Therefore, vis-à-vis to plant nutrition, the (extra or sub) cellular localization has a key role. Typical major enzymes available in soil can be listed as dehydrogenases, hydrogenases, oxidases, catalases, peroxidases, phenol o-hydroxylase, dextransucrase, aminotransferase, rhodanese, carboxylesterase, lipase, phosphatase, nuclease, phytase, arylsulphatase, amylase, cellulase, inulase, xylanase, dextranase, levanase, poly-galacturonase, glucosidase, galactosidase, invertase, peptidase, asparaginase, glutaminase, amidase, urease, aspartate decarboxylase, glutamate decarboxylase and aromatic amino acid decarboxylase. An interesting strategy for improving the nutritional quality of the soil would be to inoculate microorganism to soil while giving attention to mineral or other compounds that affect enzyme activity in soil. Since, some elements or compounds could show both activation and inhibitory effect, such as Fe, Na, etc. metals, the regulation of their bioavailability is crucial.",signatures:"Metin Turan, Emrah Nikerel, Kerem Kaya, Nurgul Kitir, Adem Gunes,\nNegar Ebrahim Pour Mokhtari, Şefik Tüfenkçi, M. Rüştü Karaman\nand K. Mesut ÇİMRİN",downloadPdfUrl:"/chapter/pdf-download/54207",previewPdfUrl:"/chapter/pdf-preview/54207",authors:[{id:"140612",title:"Prof.",name:"Metin",surname:"Turan",slug:"metin-turan",fullName:"Metin Turan"},{id:"186637",title:"Dr.",name:"Nurgül",surname:"Kıtır",slug:"nurgul-kitir",fullName:"Nurgül Kıtır"},{id:"186638",title:"Dr.",name:"Emrah",surname:"Nikerel",slug:"emrah-nikerel",fullName:"Emrah Nikerel"},{id:"186643",title:"Dr.",name:"Adem",surname:"Güneş",slug:"adem-gunes",fullName:"Adem Güneş"},{id:"194478",title:"Dr.",name:"Leyla",surname:"Tarhan",slug:"leyla-tarhan",fullName:"Leyla Tarhan"},{id:"199306",title:"Dr.",name:"Bahar",surname:"Soğutmaz",slug:"bahar-sogutmaz",fullName:"Bahar Soğutmaz"},{id:"199307",title:"Dr.",name:"Negar Ebrahim Pour",surname:"Mokhtari",slug:"negar-ebrahim-pour-mokhtari",fullName:"Negar Ebrahim Pour Mokhtari"}],corrections:null},{id:"54390",title:"Enzyme Inhibitors and Activators",doi:"10.5772/67248",slug:"enzyme-inhibitors-and-activators",totalDownloads:6090,totalCrossrefCites:13,totalDimensionsCites:17,hasAltmetrics:0,abstract:"Enzymes are very effective biological catalysts that accelerate almost all metabolic reactions in living organisms. Enzyme inhibitors and activators that modulate the velocity of enzymatic reactions play an important role in the regulation of metabolism. Enzyme inhibitors are also useful tool for study of enzymatic reaction as well as for design of new medicine drugs. In this chapter, we focused on the properties of enzyme inhibitors and activators. Here we present canonical inhibitor classification based on their kinetic behavior and mechanism of action. We also considered enzyme inhibitors that were used for design of various types of pharmacological drugs and natural inhibitors as a plausible source for design of future drugs. Mechanisms of action of enzyme activators and some features of allosteric modulators are considered.",signatures:"Olga D. 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\r\n\tNext-generation textiles represent an exciting and interesting topic within the textiles sector. They are an intersection set between life science (for example medicine, microbiology, and comfort or strain) and technical applications (textile chemistry, engineering, and testing and certification). Developments in one of these areas affect the other one; for example, the invention of superabsorbent and gel-forming materials affected the production of a new type of baby diapers. Next-generation textiles can also be considered an important part of technical textiles, being used for different purposes such as chemical and biohazard protection. They present an important aspect from an economic point of view and the necessity for their production has been increasing; for example, a huge necessity for smart medical textiles comes from the increase of the elderly population in developed countries. In the last few decades, the rapid development of command cotton fabrics also occurred. This affects all textile sectors, for example, biodegradable fibers for implantations, three-dimension spacer fabrics, and reduction of bacterial growth by using silver ion-based textiles finishing. In this and other ways, the fields concerning the next-generation textiles have been growing rapidly and are becoming a more complex area to understand.
",isbn:"978-1-80355-883-7",printIsbn:"978-1-80355-882-0",pdfIsbn:"978-1-80355-884-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,hash:"093f9e26bb829b8d414d13626aea1086",bookSignature:"Dr. Hassan Ibrahim",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11124.jpg",keywords:"Next-Generation Textile, Intelligent Textile, Smart Textile, Technical Textile, Next-Generation Material, Medical Textile, Sustainable Textile, Nanofiber, Fabric, Smart Material, Biodegradable Fiber, Technological Innovation",numberOfDownloads:27,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 5th 2021",dateEndSecondStepPublish:"February 24th 2022",dateEndThirdStepPublish:"April 25th 2022",dateEndFourthStepPublish:"July 14th 2022",dateEndFifthStepPublish:"September 12th 2022",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Hassan Ibrahim was the Egyptian National Representative of the Chemistry and Human Health Division Committee (VII) at the International Union of Pure and Applied Chemistry (IUPAC) in 2018-2019 and is currently a member of several national committees of pure and applied chemistry. He has been awarded the best Ph.D. thesis in 2010 from the national research center, Cairo, Egypt.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"90645",title:"Dr.",name:"Hassan",middleName:null,surname:"Ibrahim",slug:"hassan-ibrahim",fullName:"Hassan Ibrahim",profilePictureURL:"https://mts.intechopen.com/storage/users/90645/images/system/90645.jpeg",biography:"Dr. Hassan Ibrahim is an associate professor of Textile Chemistry and Technology at National Research Center, Cairo, Egypt. He received his Ph.D in Organic Chemistry in 2011 from Ain Shams University. He published 24 technical papers, one review article, and one book chapter with international publishers. He supervised 8 PhD and M.Sc. thesis, and participated in 14 national and international projects dealing with organic and environmental chemistry, hazardous wastes, medical textiles, nanotechnology, and electrospun nanofibers formation. He has expertise in applied chemistry and technology of organic chemistry, especially in carbohydrates, polymers, pollution prevention, preparation, and applications of nanoparticles (polymer chemistry, chemistry of chitosan, chitosan modification, nanoparticles preparation, and electrospinning technique). He built this model after years of research and teaching at university and research centers. He was the Egyptian National Representative of the Chemistry and Human Health Division Committee (VII) at the International Union of Pure and Applied Chemistry (IUPAC) in 2018-2019, and is currently a member of several national committees of pure and applied chemistry. 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1. Introduction
According to the literature and current scenario it’s a well-known fact that environmental and genetic factors modulate the multistep process of carcinogenesis. Genetic events lead to the disruption of normal regulatory mechanism that control basic cellular function of the body including cell division, differentiation and cell death [1]. Boyd and Reade (1988) described the mechanisms involved in carcinogenesis of the oral mucosa and distinguished between three major groups: chemical mechanisms, physical mechanisms, and viral mechanisms. Later Hanahan and Weinberg (2000) described six hallmarks of cancer (hallmarks I): acquisition of growth signaling autonomy (oncogenes), growth-inhibitory signals (tumor suppressor genes), evasion of apoptosis, cellular immortalization, angiogenesis, and finally, invasion and metastasis [2]. A decade later, an updating review (henceforth termed hallmarks II) added two emerging hallmarks: reprogramming energy metabolism and evading immune response, and two enabling traits: genome instability and mutation, and tumor-promoting inflammation [3].
Oral squamous carcinogenesis is the sixth most common cancer worldwide and commonest cancer in India, accounting for 50–70% of total cancer mortality rate. It predominantly affects anterior tongue, cheek, floor of mouth, retro molar area, gingiva or the buccal mucosa [4]. In carcinogenesis multiple genetic events alter the normal functions of both oncogenes and tumor suppressor genes. However, the importance of both the known gene alterations is unidentified and is still not fully understood. The histologic progression of oral carcinogenesis from hyperplasia to dysplasia, followed by severe dysplasia and eventual invasion and metastases, are believed to reflect the accumulation of these changes [5, 6] (Figure 1). Genetic alterations occurring during the carcinogenesis may present in the form of point mutations, amplifications, rearrangements, and deletions [5].
Figure 1.
Molecular model of oral carcinogenesis. The diagram shows the genetic progression from dysplasia to oral squamous cell carcinoma (OSCC), through changes in the p or q arm of chromosomes 3, 4, 8, 9, 11, 13, and 17 [2].
2. The genetic theory of cancer
2.1 Alteration of regulatory pathways during cancer development
Oral carcinogenesis is a complex, multistep process in which genetic events within signal transduction pathways governing normal cellular physiology are quantitatively or qualitatively altered.
Under normal conditions, cell biology of oral epithelia is tightly controlled by excitatory and inhibitory pathways which include cell division, differentiation, and senescence [1]. Cellular pathways of the oral keratinocyte may be diverse and contain the same fundamental elements. Binding of an extracellular ligand to a cell surface receptor forms a receptor-ligand complex that generates excitatory or inhibitory signals which are transferred intracellularly and further nuclear messengers can either directly alter cell function or can stimulate the transcription of genes which can affect protein synthesis [1] (Figure 2).
Figure 2.
Signal—transduction pathway.
On contrary, oral cancer is the result of an accumulation of changes in these excitatory and inhibitory cellular signals that can occur at any level of a given pathway. Oral epithelial cells collect these alterations or mutations from cellular signals and become functionally independent from the surrounding oral epithelium made up of normal oral keratinocyte neighbors. These tumor cell divide more rapidly, sequester blood vessels to feed that growth, delete or amplify signals to produce abnormal structural or functional changes, and start invading normal tissue at local or distant sites [6].
Oncogenes and tumor suppressor genes constitute the cellular growth-regulatory genes which are widely expressed in normal cells and their protein products are required for cell to work normally. Any alteration or inappropriate expression of these genes can induce neoplasia [7].
The genetic damage of these genes found in cancer cells is of two sorts:
The Former typically results in a gain of function, whereas latter causes loss of function [8].
The hallmark of cancer is rapid and uncontrolled growth. Cell cycle regulatory molecules (cyclin-CDK complex and retinoblastoma protein RB) play a key role in pathogenesis of head and neck cancers. Phosphorylation of RB by the cyclin/CDK there is a release of E2F, which transcribe the necessary components of the cell to continue through the G1/S transition. Specifically, RB function is mediated by cyclin E/CDK2 activity. In contrast, CDK4 and CDK6 act upstream of RB and inhibit RB function by phosphorylation [5]. In head and Neck cancers, both up and down regulation of RB function has been observed conferring a greater degree of malignancy and aggressiveness, dependent upon cellular context. Downregulation of RB function—cell cycle to remain unchecked and leads to continual cell division and cell proliferation; up-regulation of RB leading to a decrease in pro-apoptotic signals that are triggered during the cell cycle. In either case, changes in the RB pathway alter cell-cycle transition and allow for greater cancer cell survival [1].
3. Oncogenes and oncoprotein
Oncogenes can be classified according to the roles of their normal counterparts (protooncogenes) in the biochemical pathways that regulate growth and differentiation. These include the following
Growth factors (TGF, FGF, PDGF)
Cell surface receptors (EGFR, FGFR)
Intracellular signal transduction pathways (RAS)
DNA binding nuclear proteins transcription factors (MYC, FOS, JUN)
Cell cycle proteins (cyclins and cyclin dependent protein kinases)
Inhibitors of apoptosis (bcl-2)
Oncogenes are defined as “altered growth-promoting regulatory genes, or proto-oncogenes that govern the cell’s signal transduction pathways” [5]. These genes were initially discovered in retroviruses which cause cancers in birds and cats by virtue of a highly tumorigenic ‘molecular hitchhiker’, a mutated gene (oncogene) not native to the virus but picked up from a homologue in the eukaryotic genome. Alteration or mutation of these proto-oncogenes results in either an overproduction or a “gain-of-function” alteration in these excitatory proteins. Although oncogenes alone are not sufficient to transform a normal oral keratinocyte to a malignant one, they are initiators of the process [6].
Aberrant expression of several oncogenes play a crucial role in development of oral carcinogenesis which includes proto-oncogene epidermal growth factor receptor (EGFR/c-erb 1), members of the ras gene family, c-myc, int-2, hst-1, PRAD-1, and bcl-1 (Figure 3) [6].
Figure 3.
Oral cancer progression model. The histopathologic progression of normal oral mucosa from hyperplasia to malignancy and metastasis appears driven by interplay of activation of oncogenes in early cellular transformation and inactivation of tumor suppressor genes closer to the initiation of malignancy and metastasis.
The potential of proto-oncogenes to participate in tumorigenesis arises from the fact that their protein products are relays in the elaborate biochemical circuitry that governs the phenotype of vertebrate cells polypeptide hormones that act on the surface of the cell, receptors for these hormones, proteins convey signals from the receptors to the deeper cell machinery, and nuclear functions that orchestrate the genetic response to afferent commands [5].
Three biochemical mechanisms which proto-oncogenes act are [8]:
The first mechanism is phosphorylation of proteins, with serine, threonine, and tyrosine as substrates.
The second mechanism by which the genes act is transmission of signals by GTPases. The role of these signaling devices in tumorigenesis was first appreciated through the discovery of RAS oncogenes, which encode a previously unknown variety of GTPase.
The third mechanism consists of control of transcription from DNA. A still growing variety of transcription factors (FOS and MYC) are encoded by proto-oncogenes which may also participate directly in the replication of DNA.
3.1 Growth factor receptors and mechanisms
Activation of growth factor receptors in human tumors include mutations, gene rearrangements, and overexpression. Signaling pathways involved in the development of both cancer and stem cells are: the JAK/STAT pathway, NOTCH signaling pathway, the MAP-Kinase/ERK pathway, the PI3K/AKT pathway, the NFkB pathway, the Wnt pathway and the TGFβ pathways.
In the normal forms of growth factor receptors, the kinase is transiently activated by binding of the growth factors ligand to receptor, leads to rapid receptor dimerization and tyrosine phosphorylation of several substrates that are a part of the signaling cascade. The oncogenic growth factor receptors cause dimerization and activation without binding to the specific growth factor ligand. Hence, the mutant receptors deliver continuous mitogenic signals to the cell [1].
In oral carcinogenesis deregulation of growth factors receptors occurs through increased production and autocrine stimulation. Aberrant expression of transforming growth factor alpha (TGF-α) and beta (TGF-β) occur in carcinogenesis. TGF-α work in association with EGFR and TGF-β follows a pathway along with SMAD2 and 3.
TGF-α is reported to occur early in oral carcinogenesis, following the histological progression of hyperplastic epithelium first, and later in the invasive carcinoma within the inflammatory cell infiltrate, especially the eosinophils, surrounding the infiltrating epithelium. TGF-α stimulates cell proliferation by binding to EGFR and stimulates angiogenesis and has been reported to be found in “normal” oral mucosa in patients who subsequently develop a second primary carcinoma.
Microscopically “normal” oral mucosa of head and neck cancer patients who later develop second primary carcinomas overexpresses TGF-α suggesting a ‘premalignant” lesion having rapid proliferation and genetic instability of the epithelium. Prognostically patients with oral tumors overexpressing TGF-α along with EGFR have been shown to have a significantly shorter survival than patients overexpressing EGFR alone [6].
TGFβ1 signals through the TGFβ receptors and these transduce the signal by phosphorylating SMAD2 and SMAD3, which, together with SMAD4, regulate the transcription of target genes.
Recently, a connection of TGFβ signalling pathway and nuclear factor-κB (NF-κB)99 has been studied, it’s a transcription factor that provides an important survival signal to cells. Cohen et al. showed that abrogation of the TGF-β pathway was associated with activation of NF-κB, and this intriguing finding suggests that decreased TGFβ signalling is linked to NF-κB activation [9].
3.2 Cell surface receptors
Binding of cell surface receptor with ligands translates signals which are present extracellularly through the cell membrane by activating a cascade of biochemical reactions. Mutations or amplifications of genes encoding growth factor receptors can result in an increased number of receptors or production of continuous ligand-independent mitogenic signals.
EGFR, a 170,000-Da phosphoglycoprotein, is believed to be an important oncoprotein in oral cancer. Currently, three mechanisms have been postulated to activate the EGFR gene in carcinogenesis:
Deletion or mutations in the N-terminal ligand-binding domain.
Overexpression of the EGFR gene concurrent with the continuous presence of EGF or TGF-α.
Deletion in the C-terminus of the receptor that prevents downregulation of the receptor after ligand binding.
In human oral carcinogenesis EGFR is overexpressed as this gene is amplified. Therefore, it has been identified that in comparison to the normal counterpart, malignant oral keratinocytes possess 5–50 times more EGF receptor. Moreover, in oral carcinogenesis the mechanism of signal transduction is either because of overexpression of normal receptors due to mutated gene or because of the formation of many new receptors is not understood yet. Henceforth, oral tumors, having EGFR overexpression, have been shown to exhibit a higher response to chemotherapy than EGFR-negative tumors, presumably because of higher intrinsic proliferative activity leading to higher sensitivity to cytotoxic drugs [6].
3.3 Intracellular signal transduction pathways (RAS)
Like growth factor receptors, intracellular messengers can be intrinsically activated, thereby delivering a continuous rather than a ligand-regulated signal [6]. An oncogene can be activated either by gene amplification and/or mutation. In OSCC, the ras is one of the most frequently genetically altered oncogene. The mutations of three isoforms of ras gene such as Hras, Kras and Nras produce the same phenotype in the in vitro transformation assays. Mutations of the Hras appear to be highly prevalent in OSCC when compared to the Kras and Nras have been reported approximately from 0 to 55%.
3.3.1 Mechanism of ras activation
These genes encode closely related proteins that are located on the cytoplasmic side of the cell membrane and transmit messages from the cell surface receptors to intracellular regulatory enzymes [6].
RAS present on the cytoplasmic side of cell membrane get activated by growth factors through enhanced exchange of guanine nucleotide by forming Grb2 SOS complex. The molecular mechanism underlying in the functions activation of ras depends on the whole super family of small G-proteins because there exist a switch between GTP bound active and GDP-bound inactive state [10].
In normal human cell, an equilibrium is strictly maintained by the activity of GAPs (GTPase activating proteins) and GEFs (Guanine nucleotide exchange factors) between the active and inactive state because ras proteins have a minimal and a measurable activity on their own. The GAPs accelerate the GTP hydrolysis of ras and the antagonist GEFs such as ras-GRFs and ras-GRPs catalyze and weakens the GDP replacing with GTP. In a cell where ras is mutated, the equilibrium between the GTP and GDP-bound state is impaired. The ras is mutated predominantly at codon G12, G13 and Q61. In K-RAS and H-RAS because of point mutations GAP catalyzed hydrolysis of GTP to GDP, thereby generate constantly active ras and is responsible for the activation of downstream effectors whereby cell undergoes aberrant malfunctioning leading to malignancy (Figure 4) [10].
Figure 4.
Mechanisms of the ras activation.
3.3.2 Ras and its major signaling pathways
The ras oncogenes are associated with proteins that are involved in the transduction of extracellular growth, differentiation and survival signals. Ras activate receptor tyrosine kinases (RTKs), which further activate two key signal transduction components:
Small GTPase
Lipid kinase PI(3)K.
The activated ras stimulates mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/Akt pathways. The key downstream steps involve phosphorylation by RAF1 kinase on two distinct serine residues MEK1/2. The MEK1/2 further phosphorylates specific threonine and tyrosine residues in the activation loops of ERK1/2 and leads to growth and differentiation. On the other hand ras transduces PI3K/Akt signaling pathway which lead to cell cycle proliferation and survival [10].
3.4 DNA binding nuclear proteins transcription factors (MYC, FOS, JUN)
Transcription factors, or proteins that stimulate other genes to be activated, are also altered in oral cancer. A growing number of the known proto-oncogenes encode nuclear proteins. These nuclear proteins are further regulated by receptor activated second messenger pathways. Neutralization of these encoded genes result in cell cycle arrest which prevents mitogenic and differentiation responses to growth factors. C-myc is a gene which helps regulate cell proliferation and apoptosis and is frequently overexpressed in oral cancers as a result of gene amplification. C-myc is often overexpressed in poorly differentiated tumors, although more recently c-myc has been shown to be overexpressed in moderate and well differentiated oral carcinomas, in which cell proliferation far outweighed the number of apoptotic cells present. For apoptosis, c-myc requires p53 for regulating cell proliferation. c-Myc interacts with retinoblastoma tumor suppressor gene Rb-1 nuclear protein pR6, preventing its transcription, and thus inhibiting cell proliferation. However, on phosphorylation of pR6, c-Myc is increased and cell proliferation proceeds. Another transcription factor which is also amplified in head and neck cancers is PRADl (also CCNDl or cyclin Dl) which acts too as a cell cycle promoter [5, 6, 8].
Particular order of oncogene activation has not been shown in oral cancers; instead the accumulation of activated oncogenes should be of primary importance. The importance of the currently identified oncoproteins to oral carcinogenesis is under investigation. Other oncogenes linked to oral cancer development are hst-1, k-2, bcl-1, sea, men-1, and eM1s-1.3.4. Oncogenes alone, however. Not sufficient to result in oral cancer but appear to be initiators of the process and should work along with the inactivation of tumor suppressor genes. The critical event in the transformation of a “premalignant” cell to a malignant cell is the inactivation of cellular negative regulators, tumor suppressor genes.
3.5 Cell cycle proteins (cyclins and cyclin dependent protein kinases)
The cell cycle is a mammalian cells proliferation regulation process and has 4 functional phases:
S phase (DNA replication)
G2 phase (cells prepare for mitosis)
M phase (DNA and cellular components division into two daughter cells)
G1 phase (cells commit and prepare for another round of replication).
S and M phases are the major and common process in all cell cycles for replication of cells. It requires interplay of expression of cyclins and cyclin dependent kinases in response to growth factors.
3.5.1 Cdks, the cell cycle
Cdk2 and cdk1, together, direct S and G2 phase transit, while cdk1 governs the G2/M transition and mitotic progression. Cdks can be divided into two groups:
‘Cell cycle’ cdks, which orchestrate cell cycle progression.
‘Transcriptional’ cdks, which contribute to mRNA synthesis and processing.
The first group encompasses cyclin D-cdk4 and 6, as well as cyclin E-cdk2 complexes, which sequentially phosphorylate the retinoblastoma protein (RB), to facilitate the G1/S transition. Cyclin A-cdk 2 and 1 are required for orderly S phase progression, whereas cyclin B-cdk1 complexes control the G2/M transition and participate in mitotic progression [11].
The second group includes cyclin H-cdk7 and cyclin T-cdk9 (pTEFb). It phosphorylates the carboxy-terminal domain of RNA polymerase II to promote elongation of mRNA transcription. Cyclin T-cdk9 also regulates mRNA processing [12].
3.5.2 Cdk’s and cancer
CDK’s and cyclins are the biochemicals play a pivotal role in cell cycle progression and transcription. Errors and dysregulation like amplification, mutation, deletion and hypermethylation of cyclins and its cdk partners activity results in loss of cell cycle check points and apoptotic activity which is a major cause for proliferative disorders such as cancer and which has been directly linked to the molecular pathology of cancer [11].
Cell cycle progression through the G1 phase is regulated by the action of cyclin D-cdk4, cyclin D-cdk6, and cyclin E-cdk2. This transition is mediated through the RB, which is regulated through sequential phosphorylations by CDK. Various genetic and epigenetic alterations in human cancer including mutations and amplification of Cdk and positive regulatory Cyclin subunits, lead to a hyperactivation of Cdk regulatory pathways. Henceforth, alteration in cell cycle checkpoints causes abnormal cell proliferation and results in tumor progression. Although mutations of cdk genes in tumor cells are rather infrequent with the exception of Cdk4 and Cdk6 amplification, overexpression or hyperactivation of basic cell cycle regulators is a general feature of human tumors like leukemia or carcinomas and were associated with poor prognosis [11].
3.6 Inhibitors of apoptosis (Bcl-2)
Apoptosis “programmed cell death’—is a physiologic process of cell to undergo death following sequence of events once the function is over. Any alterations in the mechanism of cell undergoing apoptosis not only contribute to abnormal proliferation of cell but also enhance resistance to anticancer therapies, such as radiation and cytotoxic agents. One of the suggested mechanisms for developing resistance to cytotoxic antineoplastic drugs is the alteration in expression of B-cell lymphoma-2 (Bcl-2) family members.
A balance between newly forming cells and old dying cells is maintained by Bcl-2 family of proteins which consists of 25 pro- and anti-apoptotic members. When there is alteration or disbalance in ratio of distribution of pro and antiapoptotic proteins resulting in the overexpression of anti-apoptotic Bcl-2 family members, apoptotic cell death can be prevented. Targeting the anti-apoptotic Bcl-2 family of proteins can improve apoptosis and thus overcome drug resistance to cancer chemotherapy [6].
Two major pathways of apoptosis are the intrinsic and extrinsic cell-death pathways.
The intrinsic cell death pathway/mitochondrial apoptotic pathway: mainly triggers apoptosis in response to internal stimuli and is activated by a wide range of signals, including radiation, cytotoxic drugs, cellular stress, DNA damage and growth factor withdrawal. This mechanism involves the release of proteins cytochrome c from the mitochondrial membrane space which in turn activates pro caspase-9 and induces apoptosis.
The extrinsic cell-death pathway: pathway functions independently of mitochondria and executes cascade activation of caspases. Activation of cell-surface death receptors, such as Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors, directly activate the caspase cascade via an “initiator” caspase (caspase-8) the role of which is to cleave other pro-caspases into active “executioner” caspases which induces degradation of cytoskeleton and nucleus [13].
3.6.1 Role of Bcl-2 in oral carcinogenesis
Bcl-2 family members can be divided into three subfamilies based on structural and functional features [13].
Bcl-2 homology—the anti-apoptotic subfamily contains the Bcl-2, Bcl-XL, Bcl-w, Mcl-1, Bfl1/A-1, and Bcl-B proteins, which suppress apoptosis and contain all four Bcl-2 homology domains.
Multidomain proteins—some pro-apoptotic proteins, such as Bax, Bak, and Bok, contain Bcl-2 homology domains.
BH3-only proteins—pro-apoptotic proteins, such as Bim, Bad, and Bid, contain only the BH3 domain.
Recent studies have shown that Bcl-2 expression is upregulated in oral SCC. Bcl-2 inhibits cell death via inhibiting apoptosis. Hence, Bcl-2-mediated inhibition of apoptosis may be an important factor in the pathogenesis of oral SCC. Bax forms heterodimers with Bcl-2 and when present in excess, Bax overrides the anti-apoptotic activity of Bcl-2.
P53 tumor-suppressor protein is a direct transcriptional activator of the human Bax gene suggesting that p53 may, in some instances, induce apoptosis via Bax-mediated suppression of Bcl-2 activity. In mutagenesis experiments, single amino acid substitutions in Bcl-2 homology domains disrupted Bcl-2-Bax heterodimers. The Bcl-2 mutants that failed to complex with Bax could no longer inhibit apoptosis. According to the study done by Oltvai et al. (1993) it was suggested that anti-apoptotic activity of Bcl-2 was inhibited by Bax, whereas the findings of Yin et al. (1994) is converse to that of the previous findings, i.e. that the function of Bcl-2 is to inhibit the apoptotic activity of Bax. But it was further hypothesized that the possible mechanism was the formation of Bcl-2-Bax heterodimers which inhibits both apoptotic and anti-apoptotic activity and is only seen when there is a functional excess of Bax or Bcl-2, respectively.
Bcl-x and Bcl-2 form heterodimers with Bad. This dimerization displaces Bax from Bcl-x, and Bcl-2 thereby enhances apoptosis. Therefore, the Bcl-2 family of related proteins (as with the Myc family) functions in part through protein-protein interactions.
In conclusion, Bcl-2-mediated inhibition of apoptosis may be an important factor in the pathogenesis of oral SCC. Furthermore, by blocking apoptosis, Bcl-2 can increase tumor cell resistance to anti-neoplastic drugs.
4. Tumor suppressor genes
Genes that encode the proteins for negative signal transduction pathways and modulate excitatory pathways and negate their effect in a “checks and balances” have been called as growth regulatory genes, recessive oncogenes or anti-oncogenes, but they are most often referred to as tumor suppressor genes. Negative regulatory pathways allow the cell to perform its function in the face of changing internal and external stresses [1, 14].
As been mentioned earlier in the chapter “Oncogenes alone are not sufficient to cause oral cancer and appear to be initiators of the process”.
The transformation of a premalignant cell to a malignant cell is due to the inactivation of tumor suppressor gene which is a major event leading to the development of malignancy.
This mechanism of inactivation is may be due to point mutations, deletions, hypermethylation and rearrangements in gene copies. It was identified that many tumor suppressor genes were initially identified in pediatric tumors that formed early in life because one mutated tumor suppressor gene was inherited [1].
This mechanism led the evolution of “Knudson two hit hypothesis” This theory suggested a genetic model for retinoblastoma development. According to this RB gene mutation is inherited is described as the first hit and the tumor-restricted mutation as the second hit. This model further includes genetic aberrations, such as inactivation of a tumor suppressor and activation of an oncogene, as hits. Currently an extensive research on “chromosomal walking” is highlighted in pediatric tumors were the first tumor suppressor genes isolated with large chromosomal alterations. Therefore, although the identification of these “cancer genes” is one of the primary focuses of molecular biologists today, still far less is known about tumor suppressor genes [1].
4.1 Function of p53 as a tumor suppressor gene
The many roles of p53 as a tumor suppressor include the ability to induce cell cycle arrest, DNA repair, senescence, and apoptosis. Due to many genotoxic or chemical insults when genomic DNA damage is being identified, p53 gene activated and stop cell to divide further at the G1-S boundary and it repairs rather than replicates the error in the genetic code. If the chromosomal damage is too great, p53 gene activate apoptotic pathways [15].
4.2 Mutant form of p53
Mutation of p53 allows tumors to pass through the G1-S boundary and propagate the genetic alterations that may lead to other activated oncogenes or inactivated tumor suppressor genes. In addition to the loss of function that a mutation in TP53 may cause, many p53 mutants are able to actively promote tumor development by other means like:
Dominant negative manner
Gain of function
4.2.1 Dominant negative manner
In a heterozygous situation, where both wildtype (WT) and mutant alleles exist, mutant p53 can antagonize the activity of WT p53 tumor suppressor functions in a dominant negative (DN) manner. The transcriptional activity of WT p53 depends on forming tetramer where mutant p53 interfered in DNA binding activity of WT p53. However, such a heterozygous state is often transient, as TP53 mutations are frequently followed by loss of heterozygosity (LOH) during cancer progression as WT p53 allele is either deleted or mutated [14].
4.2.2 Gain of function
This term refers to the acquisition of oncogenic properties by the mutant form of p53 protein, compared with the mere inactivation of the protein. During tumorigenesis both the dominant negative and GOF effects may play a significant role in missense mutations of TP53 protein [15].
4.3 Mechanistic views of how mutant p53 exerts its function
Various mechanisms by which mutant p53 works in tumor progression:
GOF properties acquired by mutant p53 drive cells toward migration, invasion, and metastasis. Recent work demonstrates that mutant p53 can augment cell migration and invasion. It was studied that “oncogenic” Ras and “Tumor Suppressor” mutant p53 activities occurs in early neoplasms to promote growth and survival, they play an equally important role at late stages of tumor progression in empowering TGFβ-induced metastasis.
EMT—metastasis follow the properties of epithelial to-mesenchymal transition (EMT), including loss of cell-cell adhesion and an increase in cell motility., Mutant p53 was found to promote EMT by facilitating the function of the key transcriptional regulators of this process, TWIST1 and SLUG whereas WT p53 was shown to inhibit EMT mechanism.
Tp63—an additional mechanism through which mutant p53 was shown to augment cell invasion is via the inhibition of transcriptional activity of TAp63α, but is unable to inhibit this function of TAp63γ indicating a protooncogenic activity of TP 53 [14].
It appears that in certain cancers, p53 is mutated late in the tumorigenesis process or plays a significant role in those advanced stages, whereas other studies indicates its expression in early stages of tumor progression. Therefore, it was hypothesized that TP53 mutations at early stages of tumorigenesis results in uncontrolled proliferation, a feature of both benign and malignant tumors, whereas mutations at later stages synergize with additional oncogenic events to drive invasion and metastasis, the hallmark of malignant tumors. p53 inactivation as a single event results in the high proliferation rate. Inactivation of p53 in conjunction with oncogenic H-Ras expression activates the expression of a large set of chemokines and interleukins reported to promote angiogenesis, invasion, and metastasis.
In general, tumor suppressor genes are thought to act recessively so that both copies of the gene must be inactivated for malignancy to occur. LOH and p53 mutations have been reported in several tumors. There is also controversy about the relation between mutated p53 and detection of its expression by immunohistochemistry. Some authors have commented on high correlation between p53 expression and point missense mutation, whereas others have reported discrepancy in oral cancer and lack of expression of p53 as immunocytochemistry have been attributed to insensitive methods of detecting p53 mutation. In Li-Fraumeni syndrome, mutant p53 is unstable, like the wild-type p53 protein, which suggests that some other event may be necessary for stability, and that stability of p53 is not intrinsic to the mutant p53 structure but might vary in different cell backgrounds. This mechanism can be highlighted by p53 and mdm2 relation because when normal p53 is bound to mdm2 it is targeted for destruction by the ubiquitin dependent pathway. However, it appears that mutant p53 fails to stimulate transcription of mdm2 and therefore mutant p53 is not degraded. Another mechanism tells that if E6 protein forms complexes with wild-type p53 and promotes p53 degradation this could account for the lack of concordance between p53 mutation frequency and LOH [16].
Other tumor suppressor genes include doc-1, the retinoblastoma gene, and APC.
5. Role of HPV in pathogenesis of OSCC
The role of HPV in pathogenesis of human malignancies has become convincingly established. HPV is a strictly epitheliotropic, circular double-stranded DNA virus that is known to be the primary cause of cervical cancer and currently establishing important role in oral carcinogenesis. There are more than 100 subtypes of HPV, some of which are involved in oral carcinogenesis and have been designated as high-risk HPVs. Approximately 85% of squamous cell carcinoma patients. The viral DNA gets incorporated into the host genome and is responsible for malignant transformation. The virus contains two oncogenes, E6 and E7, E1 and E2 open reading frames will be interrupted and can lead to overexpression of E6 and E7 proteins. This E7 protein binds to underphosphorylated form of retinoblastoma results in the enhanced phosphorylation and degradation. Degraded form of pRb displaces E2F form of transcription factor and subsequent activation of gene promoting cell proliferation. E6 protein degrades p53 protein causing perturbation of cell cycle regulation in the infected cells which is considered to be the onset of HPV-mediated carcinogenesis. The virus is not easily cultured, therefore determining the role of virus in pathogenesis of OSCC is usually determined by detection of the viral DNA genome or expression of the viral genes using PCR methods. E6 and E7 have a crucial role in cervical cancer were also involved in HPV mediated carcinogenesis of the upper aerodigestive tract (Figures 5 and 6) [9, 17, 18].
Figure 5.
Cell cycle deregulation by human papilloma virus activated by E6 and E7.
Figure 6.
Proposed molecular model for the genetic events in squamous cell carcinoma of the head and neck [19, 20].
6. Conclusions
Cellular signaling pathways are not isolated from each other but are interconnected to form complex signaling networks. Any change or diversification in this cellular signaling network such as increased production of growth factor or cell surface receptors, increase transcription or translation or intracellular messenger levels will give rise to abnormal proliferation of cell and is one of the reason for multifactorial oral carcinogenesis These changes can, in turn, cause a activation of protooncogene or loss of tumor suppressor activity which give rise to a phenotype capable of increasing cellular proliferation, weakening cell cohesion, and causing local infiltration and metastasis.
\n',keywords:"carcinogenesis, protooncogene, oncogene, tumor suppressor gene, intercellular signaling, cell surface receptors, growth factors",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/67447.pdf",chapterXML:"https://mts.intechopen.com/source/xml/67447.xml",downloadPdfUrl:"/chapter/pdf-download/67447",previewPdfUrl:"/chapter/pdf-preview/67447",totalDownloads:3730,totalViews:0,totalCrossrefCites:2,totalDimensionsCites:2,totalAltmetricsMentions:0,impactScore:1,impactScorePercentile:70,impactScoreQuartile:3,hasAltmetrics:0,dateSubmitted:"October 12th 2018",dateReviewed:"March 5th 2019",datePrePublished:"May 31st 2019",datePublished:"March 18th 2020",dateFinished:"May 31st 2019",readingETA:"0",abstract:"Oral carcinogenesis is a molecular and histological multistage process featuring genetic and phenotypic molecular markers which involves enhanced function of several protooncogenes, oncogenes and/or the deactivation of tumor suppressor genes, resulting in the over activity of growth factors and its cell surface receptors, which could enhance messenger signaling intracellularly, and/or leads to the increased production of transcription factors. Alone oncogenes are not responsible for carcinogenesis, genes having tumor suppressor activity, leads to a phenotypic change in cell which is responsible for increased cell proliferation, loss of cellular cohesion, and the ability to infiltrate local tissue and spread to distant sites. Understanding the molecular interplay of both onco and tumor genes will allow more accurate diagnosis and assessment of prognosis, which might lead the way for novel approaches to treatment.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/67447",risUrl:"/chapter/ris/67447",book:{id:"8211",slug:"squamous-cell-carcinoma-hallmark-and-treatment-modalities"},signatures:"Anshi Jain",authors:[{id:"280692",title:"Dr.",name:"Anshi",middleName:null,surname:"Jain",fullName:"Anshi Jain",slug:"anshi-jain",email:"dranshijain@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The genetic theory of cancer",level:"1"},{id:"sec_2_2",title:"2.1 Alteration of regulatory pathways during cancer development",level:"2"},{id:"sec_4",title:"3. Oncogenes and oncoprotein",level:"1"},{id:"sec_4_2",title:"3.1 Growth factor receptors and mechanisms",level:"2"},{id:"sec_5_2",title:"3.2 Cell surface receptors",level:"2"},{id:"sec_6_2",title:"3.3 Intracellular signal transduction pathways (RAS)",level:"2"},{id:"sec_6_3",title:"3.3.1 Mechanism of ras activation",level:"3"},{id:"sec_7_3",title:"3.3.2 Ras and its major signaling pathways",level:"3"},{id:"sec_9_2",title:"3.4 DNA binding nuclear proteins transcription factors (MYC, FOS, JUN)",level:"2"},{id:"sec_10_2",title:"3.5 Cell cycle proteins (cyclins and cyclin dependent protein kinases)",level:"2"},{id:"sec_10_3",title:"3.5.1 Cdks, the cell cycle",level:"3"},{id:"sec_11_3",title:"3.5.2 Cdk’s and cancer",level:"3"},{id:"sec_13_2",title:"3.6 Inhibitors of apoptosis (Bcl-2)",level:"2"},{id:"sec_13_3",title:"3.6.1 Role of Bcl-2 in oral carcinogenesis",level:"3"},{id:"sec_16",title:"4. Tumor suppressor genes",level:"1"},{id:"sec_16_2",title:"4.1 Function of p53 as a tumor suppressor gene",level:"2"},{id:"sec_17_2",title:"4.2 Mutant form of p53",level:"2"},{id:"sec_17_3",title:"4.2.1 Dominant negative manner",level:"3"},{id:"sec_18_3",title:"4.2.2 Gain of function",level:"3"},{id:"sec_20_2",title:"4.3 Mechanistic views of how mutant p53 exerts its function",level:"2"},{id:"sec_22",title:"5. Role of HPV in pathogenesis of OSCC",level:"1"},{id:"sec_23",title:"6. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'Shah S, Pathak P, Gulati N. Cell signaling pathways in oral cancer: A review. Journal of Applied Dental and Medical Sciences. 2015;1(1):69-75'},{id:"B2",body:'Sayáns MP, Martín JMS, Angueira FB, López MDR, Rey JMG, García AG. Genetic and molecular alterations associated with oral squamous cell cancer (review). Oncology Reports. 2009;22:1277-1282'},{id:"B3",body:'Fouad YA, Aanei C. Revisiting the hallmarks of cancer. 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Genes & Cancer. 2011;2(4):466-474'},{id:"B15",body:'Chandra A, Sebastian BT, Agnihotri A. Oral squamous cell carcinoma pathogenesis and role of p53 protein. Universal Research Journal of Dentistry. 2013;3(3):128-130'},{id:"B16",body:'Bose P, Brockton NT, Dort JC. Head and neck cancer: From anatomy to biology. International Journal of Cancer. 2013;133:2013-2023'},{id:"B17",body:'Gudiseva S, Katappagari KK, Kantheti LPC, Poosarla C, Gontu SR, Baddam VRR. Molecular biology of head and neck cancer. Journal of Dr. NTR University of Health Sciences. 2017;6(1):1-7'},{id:"B18",body:'Naik VK, Adhyaru P, Gudigenavar A. Tumor suppressor gene in oral cancer. Clinical Cancer Investigation Journal. 2015;4(6):697-702'},{id:"B19",body:'Mendes RA. Oncogenic pathways in the development of oral cancer. Journal of Carcinogenesis and Mutagenesis. 2012;3(2):1-2'},{id:"B20",body:'Field JK. The role of oncogenes and tumour-suppressor genes in the aetiology of oral, head and neck squamous cell carcinoma. Journal of the Royal Society of Medicine. 1995;88:1-4'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Anshi Jain",address:"dranshijain@gmail.com",affiliation:'
Department of Oral Pathology and Microbiology, ITS CDSR, Muradnagar, Ghaziabad, India
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1. Introduction
The field of electrical neuromodulation was developed under the hypothesis that the activation of large, myelinated nerve fibers could modulate sensory nociceptive signals carried by A-delta and C nerve fibers into the dorsal horn in the spinal cord. The gate control theory (GCT) formulated by Melzack and Wall [1], served as inspiration for the use of peripheral nerve stimulation and spinal cord stimulation (SCS) to treat pain. The simplicity of the proposed mechanism, based on the understanding of pain in 1965, granted researchers with the ability to formulate finite mathematical and complex computational models to assess the effects of different variables of the electrical signal on the neuronal conduction. The GCT’s enduring value in neuromodulation for more than 50 years is due to its simplicity and utility as a working tool to postulate therapies to patients in pain. Unfortunately, as the German psychologist Wolfgang Köhler explains: “premature simplifications and systematization in science, could ossify science and prevent vital growth” [2].
The early 1990s marked the beginning of a revolution in the field of neuroscience in understanding the mechanism of pathological pain from a molecular perspective. The use of animal models has helped unravel the role of neuroinflammatory processes driven by glial cells in the development and maintenance of chronic neuropathic pain. Those advances though, were largely neglected in the field of electrical neuromodulation, which remained focused on the effects of electrical signals on neuronal conduction, ignoring the benefit of understanding how these signals could affect biological processes at the neuron-glia interaction. The differential electrophysiological characteristics of neurons and glial cells is now at the core of our quest to understand how electrical signals affect such biological processes. To begin with, the resting membrane potential of these cell populations is different, driven by the fact that the main neuronal intracellular cation is potassium, while sodium is the predominant one in glial cells [3]. Considering the critical roles that various specialized glial cell populations play in the intimate communication between neurons and glial cells, it is pertinent to briefly describe these roles. Following peripheral injury, persistent release of neurotransmitters at the synaptic cleft activates microglial and astrocyte membrane receptors generating transcriptional changes that generate the synthesis and release of pro-inflammatory and anti-inflammatory cytokines. Astrocytes are critical to maintain homeostasis at the synapse. The synaptic cleft is surrounded by astroglial perisynaptic processes in what is now known as the tripartite synapse. Perisynaptic glial processes are densely packed with numerous transporters, which provide proper homeostasis of ions and neurotransmitters in the synaptic cleft, for local metabolism support, and for release of astroglia-derived scavengers of oxygen species [4]. For example, membrane ionotropic and metabotropic glutamate receptors in the astrocyte regulate glutamate concentration. Interestingly, a single astrocyte provides processes that extend over distance to surround over 100,000 synapses. During intense neuronal firing, the release of neurotransmitters, such as glutamate and GABA, induces the elevation of calcium ion concentrations in glial cells, causing Ca2+-dependent release of molecules that affects neural excitability and synaptic transmission and plasticity. Even more thought-provoking is that although astrocytes are unable to generate action potentials, they can raise intracellular calcium concentrations that spread from astrocyte to astrocyte through gap channels that allow propagation of so-called calcium waves as a way of cell-to-cell communication. The presence of Ca2+mobilizations mediated by astrocytes implies that glial cells have some excitability and neuromodulator activities [5]. Finally, oligodendrocytes provide myelin to hundreds of surrounding axons and are known to affect the conduction velocity of action potentials propagating along the axons they surround when electrically stimulated [6].
An important distinction between glial cells and neurons is that glial cells depolarize following electrical stimulation, but do not generate action potentials. In 1981, Roitbak and Fanardjian [7] demonstrated in a live feline model that changes in the frequency and intensity of the applied pulsed electrical signals could lead to differential degrees of astrocytic depolarization. Another interesting clue on how electrical signals could affect glial cells was provided by Agnesi et al. [8], in an experiment with anesthetized rats that showed that changing the repolarization of an electrical stimulation signal from monophasic to a biphasic led to different degrees of glutamate release by the stimulated astrocytes.
The complexity of changes in neuron-glial biological processes triggered by pain and further modulation by electrical stimulation demands the use of experimental animal models. Testing such hypotheses in humans would require large-scale, well-controlled clinical trials because of the heterogeneity of genetics and pain etiology in the general population [9].
The notable anatomical, biological, and physiological resemblances between humans and animals, predominantly mammals, have encouraged researchers to investigate a large range of mechanisms and assess novel therapies in animal models before applying their discoveries to humans.
Scientists cross-examine organisms at multiple levels: molecules, cells, organs, and physiological functions in healthy or diseased conditions. Advance molecular technologies are required to get a complete portrayal and understanding of the mechanisms. Certain aspects of the responses can be evaluated using in vitro approaches (e.g., cell culture). On the other hand, the exploration of physiological functions and systemic interactions between organs requires a whole organism.
This chapter explores the efforts of diverse research groups to understand from a behavioral and molecular perspective, how spinal cord stimulation affects pathological pain by utilizing animal models. This research may provide strong hypotheses on what may be happening in humans and ways to continue improving therapeutic efficacy.
The following sections provide a description of existing, well-validated models for pain caused by neuropathies, inflammation, and ischemic conditions. Due to technical limitations, most of these are based on Rattus norvegicus, although recently models in a larger animal (Ovis aries) have been developed.
2. Animal models of SCS for neuropathic pain
Neuropathic pain is caused by damaged somatosensory neural circuits that have developed into a disease condition as a result of an injury that compromised nerve fibers. Chronic neuropathic pain affects hundreds of millions of people around the world and is one of the main sources of work-related disabilities, contributing to the socioeconomical burden on individuals as well as health systems [10]. SCS is largely indicated for chronic neuropathic pain conditions, thus the development of various animal models that resemble clinical conditions play a critical role in our understanding of the electrophysiological and molecular changes in the establishment and persistence of neuropathic pain.
2.1 SCS in partial nerve injury models
Prior to the development of the chronic constriction injury (CCI) model, animal models of pain often were lacking in their ability to accurately mimic human peripheral neuropathological conditions or did not reflect conditions involving injuries which spared a portion of a nerve’s functioning [11]. The CCI model most commonly used was described by Bennet and Xie in 1988 [11]. The procedure typically involves exposing the common sciatic nerve under anesthesia at the level of the mid-thigh and freeing approximately 7 mm of the sciatic nerve from adhering tissue at a location proximal to the sciatic nerve’s trifurcation. Once exposed, four sutures are tied loosely around the sciatic nerve approximately 1-2 mm apart from one another. These ligatures are tied loose enough to just barely constrict the diameter of the sciatic nerve (as observed under 25x-40x magnification), thus preserving partial nerve functioning [11, 12, 13, 14, 15, 16]. Constriction of the sciatic nerve was observed histologically beneath all 4 ligature areas as early as one day following the CCI procedure. From days 2-21, adjacent constriction areas tended to progressively merge and were accompanied by thinning of the affected sciatic nerve area. Two to four months after the CCI procedure, thinning of the ligated area was still present, but the swellings typically observed in the area had dissipated.
Importantly, this CCI model has proven to be effective in eliciting a neuropathic pain state as measured by a variety of methods, including von Frey mechanical, chemogenic, and heat and cold thermal stimulation. CCI surgery typically resulted in increased paw sensitivity following von Frey stimulation by Day 2 post-lesion using both the up-down method of analysis [12, 15, 16] and the ascending filament method of analysis [12, 13, 14]. The CCI model is also sensitive to chemogenic pain. Following the application of a noxious substance (a 50% mustard oil solution) to the affected hind paw, CCI rats exhibited exaggerated physical responses and an increase in the amount of time they held their hind paw above the floor of the apparatus [11]. CCI rats also showed hypersensitivity to noxious heat sources, such as radiant beams of light being applied to the affected hind paw [11, 16] and increased allodynic responses to cold, such as a slightly chilled metal floor [11].
Although most applications of the CCI model with SCS have been performed in rats, an ovine model has also been effectively demonstrated [17]. In rats, application of SCS with pulsed signals at 50 Hz frequency, 0.2 ms pulse width (PW), and intensity at 66% of the motor threshold (MT) for 30 minutes [12, 14] decreased pain sensitivity following CCI, but did not return pain levels back to pre-injury control levels. Similar results were obtained when SCS was applied for 180 minutes in rats with CCI lesions using the following SCS parameters: 50 Hz frequency, 0.2 ms PW at 80% of the MT [12]. Lowering the intensity to 20-40% of the MT eliminated the beneficial effect of SCS. Electrodes in these rat studies were aimed at the T11-L1 regions of the spinal cord. In sheep, SCS parameters were set at 40 Hz frequency, 120 μs PW and 0.1 V intensity on a continuous setting for one week with electrodes placed at the L2-L3 region. SCS also attenuated pain responses following CCI in sheep, though also failed to return pain levels back to pre-lesion levels [17]. Most SCS studies following CCI typically utilized conventional (also called tonic) SCS at a stimulating frequency of 50 Hz. However, a more detailed investigation of frequency on treatment outcomes (in which frequency varied from 1 Hz to 150 Hz) found a response curve that suggested that while the GCT could account for a subset of efficacious SCS responses, it is unlikely to be the only mechanism underlying the beneficial effects of SCS [18].
In addition to demonstrating that SCS was effective in decreasing pain sensitivity, the CCI model also has proven valuable in elucidating the biological mechanisms behind the increase in pain following injury and the beneficial effect of SCS. After CCI lesions, rats exhibited an increase in the toll-like receptor 4 and nuclear factor κβ [15, 16], which subsequently could increase the release of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. SCS significantly reduced these CCI-induced increases, perhaps by inhibiting the activation of glial cells. Indeed, the co-administration of the microglial inhibitor minocycline was shown to decrease CCI-induced pain and prolonged the effect of SCS [12]. However, this same study also showed an increase in the microglial-reactive marker OX-42 and the astrocyte reactive marker GFAP in the lumbar region of CCI-lesioned rats following SCS treatment. This paradoxical increase may limit the effectiveness of SCS and may partially explain why SCS is not effective in all patients and why pain relief often does not return to baseline levels following SCS. Other studies utilizing SCS in CCI-lesioned rats have identified roles of the adenosine and GABAergic systems in mediating the beneficial effects of SCS. Administration of adenosine or the adenosine A1 receptor agonist R-N6-phenylisopropyladenosine (R-PIA), decreased pain in CCI rats [14]. In addition, giving sub-effective doses of R-PIA to non-responders to SCS during stimulation led to effective pain relief. Zhang et al. [18] also found that administration of bicuculline, a GABAA receptor antagonist, decreased inhibitory responses to SCS.
Although the CCI model has provided significant value in (1) serving as a valid model of neuropathic pain, (2) demonstrating that the use of SCS is effective in reducing neuropathic pain, and (3) advancing our understanding of the biological mechanisms underlying SCS, its use has perhaps been surpassed in recent years by another animal model of partial nerve injury called partial sciatic nerve ligation (PSNL). Most PSNL studies utilize the Seltzer technique [19]. The procedure typically involves exposing the sciatic nerve under anesthesia at high-thigh level. The sciatic nerve is freed from adhering tissue at a location near the trochanter just distal to the point at which the posterior biceps semitendinosus nerve branches off the common sciatic nerve. Once the sciatic nerve is properly exposed, a suture with a curved cutting mini needle is inserted into the nerve. Unlike the CCI procedure, which involves a loose ligation of the sciatic nerve, the PSNL procedure involves tightly ligating approximately 1/3 to 1/2 of the dorsal nerve thickness [19, 20]. As with the CCI procedure, the goal is to partially reduce, but not completely block sciatic nerve functioning.
Similar to the CCI model, the PSNL model also successfully induces a neuropathic pain state as measured by a variety of methods. The primary method is to assess mechanical allodynia using von Frey filaments [21, 22, 23]. Following PSNL surgery, rats show a decreased paw withdrawal response following mechanical stimulation of the affected paw, as compared to control rats, pre-surgery baseline levels, and paw withdrawal thresholds (PWT) following stimulation of the contralateral, unaffected paw [23, 24]. This increased pain sensitivity usually develops by Day 2 post-PSNL lesion [21] and is still typically observed after two weeks post-PSNL lesion [20, 24, 25]. Meuwissen et al. [26] recorded decreased PWT over 40 days following the PSNL lesion. Although the PSNL technique overall has been successful in inducing a neuropathic pain state, it should be noted that there is a wide range of pain responsiveness across studies, with some studies reporting 100% of subjects exhibiting hyperalgesia with von Frey testing of the affected hind paw [20, 24] and other studies reporting less than 40% of subjects showing hyperalgesia [27, 28]. Increased paw sensitivity to thermal stimuli has also been observed following the presentation of both heat stimuli (e.g., a radiant light beam) and cold stimuli, such as a cold spray directed at the affected paw [19, 29]. However, the degree of thermal sensitivity can vary depending upon the location of the PSNL ligature. Other studies have also confirmed hypersensitivity to pain following PSNL surgery by using a pneumatic pressure device [30] and by observing gait/posture [31]. Overall, the PSNL technique has proven successful at inducing a neuropathic pain state as assessed by numerous methodologies.
The PSNL model has also proven effective at evaluating SCS treatment for chronic neuropathic pain. Both tonic and burst SCS attenuated the pain sensitivity observed in rat PSNL neuropathic pain models [20, 24]. In rats, tonic SCS (50 Hz frequency, 0.2 ms PW, intensity at 66% of the MT) attenuated PSNL-induced hyperalgesia following 30 minutes of stimulation [23, 32, 33] and 60 minutes of stimulation [20, 22, 24]. Though tonic SCS successfully decreased pain sensitivity, SCS treatment typically did not return pain levels in rats back to pre-injury control levels. In a mouse model, SCS treatment following PSNL lesions proved particularly efficacious, with 80% of mice in one study [34] and 100% of mice in another study [25] responding positively to tonic SCS treatment. In this latter study, unlike the typical rat study, the mice returned to baseline levels of paw withdrawal following SCS treatment.
Although most rat studies investigating the effect of SCS following PSNL lesions have utilized conventional stimulation parameters and have shown a significant benefit of tonic SCS treatment, it is clear that not all PSNL rat subjects benefit from SCS treatment, leading researchers to investigate different SCS parameters in hopes of improving efficacy. Some factors that have proved to have significant impact on SCS efficacy following PSNL lesions include: (1) electrode placement, (2) stimulus intensity, (3) timing of treatment, and (4) utilizing a burst (vs tonic) stimulation pattern. Electrodes placed at the T13 level of the spinal cord typically yielded more efficacious treatment outcomes than electrodes placed at the T11 area [28, 31, 35] or L5 and L6 regions [36]. In a study that directly compared the efficacy of electrode location at T13 and T11 [21], the T13 placement yielded significantly better pain relief than placement at T11 with 63% vs 15% improvement, respectively, following 15 minutes of electrical stimulation and 48.5% vs. 18.4% improvement, respectively, following 30 minutes of electrical stimulation. Lowering the intensity to 30-50% of the MT reduced the beneficial effect of tonic SCS [24]. In terms of timing, early SCS treatment given within 24 hours of lesion led to significantly better treatment outcomes than late SCS given 16 days post-lesion [32]. Interestingly, an early round of SCS treatment followed by a subsequent late round of SCS treatment increased the efficacy of the late SCS treatment [37]. Lastly, burst stimulation typically led to similar response rates as tonic stimulation [20, 22, 26]. However, burst stimulation patterns did produce slightly different outcomes. For instance, one study [24] found that tonic SCS was most effective at 66% of the MT, while burst SCS was most effective at 50% of the MT. In addition, burst stimulation took longer following stimulus onset to achieve therapeutic benefits, but the benefits of the burst stimulation lasted longer after the stimulation was turned off [38]. Burst SCS stimulation also led to greater performance than tonic SCS on a mechanical conflict avoidance system (MCAS) task which measured the cognitive-motivational aspects of pain, rather than the more typical mechanical allodynic physical response to pain [26]. These results suggest that although equally efficacious, tonic, and burst SCS stimulation may work, at least in part, by different biological mechanisms.
Given the beneficial effect of SCS treatment following PSNL lesions, many PSNL studies have sought to investigate the biological mechanisms behind it. Many studies have utilized a paradigm in which sub-effective doses of pharmaceutical treatments are given to SCS non-responders to determine if the combination of these treatments can yield beneficial effects. Song et al. [29] showed that sub-effective doses of the muscarinic agonist oxotremorine turned SCS non-responders into SCS responders, suggesting that the cholinergic system (particularly M2 and M4 muscarinic receptors) plays an important role in SCS efficacy. A subsequent study by these same authors [39] indicated an important serotonergic role in the pain-relieving effect of SCS, particularly the 5-HT2A and 5-HT4 serotonin receptor subtypes. Similarly, blocking NMDA receptors with sub-effective doses of ketamine followed by 30 minutes of SCS also turned SCS non-responders into SCS responders, indicating that the glutamate system also plays an important role in the beneficial effects of SCS [22]. While blocking the excitatory glutamatergic system likely plays a role in successful SCS treatment, enhancing the inhibitory GABAergic system might also play a significant role in successful SCS treatment [27, 32]. SCS treatment decreased intracellular GABA levels in SCS responders but not SCS non-responders [32], while increasing extracellular GABA levels in the spinal cord [27]. Lastly, SCS stimulation in PSNL rats also led to an increase in levels of c-fos, suggesting immediate early gene modulation may trigger longer term changes which could explain pain relief both during and after SCS stimulation [40]. Overall, PSNL has proven to be a valuable tool in examining the biological mechanisms behind the beneficial treatment effects of SCS.
2.2 SCS in the spared nerve injury model
The Spared Nerve Injury (SNI) was developed by Decosterd and Woolf in 2000 [41] to evaluate peripheral neuropathic pain in the rat model. The SNI is considered superior to previous denervation and partial denervation models due to its specificity of the affected region, as well as its prompt and long-lasting effect. Unlike other models that were designed to test acute nociceptive pain through behavioral and electrophysiological measurements, denervation and partial denervation models induce sensations such as hypersensitivity that more accurately reflect true clinical chronic pain conditions.
The SNI procedure targets the sciatic nerve at its point of trifurcation (Figure 1A) in the hindlimb of the rat. Located directly under the biceps femoris muscle, the nerves are exposed and identified as the tibial, common peroneal, and sural branches (Figure 1B). Distal to the point of trifurcation and in the direction of the terminal end, both the tibial and common peroneal branches are individually ligated with silk sutures (Figure 1C). Then, 2–4 mm of nerve is sectioned and removed to ensure a complete disruption of nerve transmission (Figure 1D). The incision is then closed, leaving the sural branch fully intact and undisturbed. Minor amendments, such as carefully separating the gluteus superficialis and biceps femoris muscles instead of cutting through to expose the sciatic nerve, were made in some later studies in attempt to reduce unnecessary tissue damage [42]. Hypersensitivity is rapidly established in this model, with behavioral onset occurring at just 24 hours post-induction, lasting no less than 6 months, with peak sensitivity around 2 weeks [41]. The duration of the SNI effectiveness allows for considerable flexibility when considering study design. Per the original study, non-responders are virtually nonexistent so long as the model is induced correctly.
Figure 1.
(A) A scheme depicting the anatomical innervation of the sciatic nerve into the spinal cord of the rat. (B-D) Photographic sequence of the localization, ligation, and sectioning of the tibial and peroneal nerves. (E) Map of nerve coverage to plantar hind paw surfaces.
As shown in Figure 1E, the hind paw of the rat is subdivided into three zones which are innervated by the sciatic and saphenous nerves. Transecting two of the three sciatic nerve branches, allows for precise and consistent behavioral testing of the lateral portion of plantar surface, corresponding to the sural nerve. This model permits mechanical and thermal allodynia, as well as thermal hyperalgesia to be evaluated [41] and has been used extensively in basic science studies investigating the use spinal cord stimulation (SCS) for the treatment of neuropathic pain.
In 2015, the SNI-SCS model was taken a step further when Tilley et al. [42] developed a model of continuous stimulation in an awake and freely moving rat, allowing stimulation to be delivered for 72 continuous hours. This method allowed for more clinically relevant testing since human patients receive continuous stimulation. A miniaturized four-electrode cylindrical lead was implanted in the epidural space of the rat and anchored into the musculature in the back (Figure 2). The lead exited through the incision and was secured through a custom-made harness and tubing up to a circuit board and stimulator suspended in a swivel so that the full assembly could turn and move with the rat. The rat cage lid was modified to allow free movement of the tubing. In later studies, the lead has been attached to an ethernet port secured to the rat harness with a coiled ethernet cord running to the stimulator connector suspended in the swivel [43]. Mechanical (von Frey filament) and cold thermal (acetone drop) allodynia were tested in this study. SCS was set at 50 Hz frequency, 20 μs PW, and at 70% of the MT. While there was no apparent improvement in cold allodynia following SCS, mechanical allodynia was significantly alleviated 24 and 72 hours after the start of SCS. A follow-up genomic study revealed the biological processes uniquely modulated by the SNI model and SCS in the spinal cord and dorsal root ganglion tissues (Table 1) [44]. The primary affected processes in both types of tissues included inflammatory response, ion channel regulation, and immune response.
Figure 2.
Left: A diagram of the setup for continuous SCS setup reported in references [42, 44]. a: plexiglass lid, b: supporting floor, c: counterweight swivel system, d: connecting board/stimulator (IPG), e: connecting cable, f: harness with lead connector. Right: a lateral x-ray image showing a quadripolar SCS lead placed in the dorsal epidural space of a rat.
FDR p-value (increase/decrease)
Relevant Biological Processes Modulated by SCS in the SNI model
Spinal Cord
0.063 (↑)
Inflammatory response; Immune related
0.097 (↓)
Ion channel regulation (Voltage gated); Generation of neurons; synaptic transmission
0.057 (↓)
Vesicle transport; regulation of calcium ion
0.064 (↓)
Cell growth; cell activity pathways such as MAPKK, JUN kinase
0.011 (↑)
Ribosomal proteins, 50% unknown proteins
0.069 (↓)
Ion transport (cation and anion); GABA signaling, neuron development
0.011 (↓)
Transmembrane/transporter activity, mostly ion transport; proton transport
0.011 (↓)
Cell regulation changes; neuron differentiation and development
0.016 (↑)
Activation of immune response
Dorsal Root Ganglion
0.012 (↓)
Ion transmembrane transport
0.012 (↓)
Mitochondrial respiratory chain; regulation of superoxide, mechano-sensory perception of pain
0.009 (↑)
Inflammatory response: cytokine and apoptosis regulation; Immune response to stimulus
0.009 (↑)
Innate immune response; Adaptive immune response
0.009 (↑)
Regulation of immune response: T-cell activation and differentiation
0.074 (↑)
Histone acetylation; regulation of neuron migration; regulation of rho GTPase activity
Gene ontology biological processes modulated in the ipsilateral dorsal quadrant of the spinal cord (directly under the electrode) and ipsilateral L5 dorsal root ganglion demonstrating molecular changes caused by SCS therapy with the SNI model. Reelevant processes obtained after WGCNA and gene ontology analyses performed on microarray results. Only modules with significant False Discovery Rate (FDR) p-values are shown. Data from reference [44].
Following the initial development of the SNI model, Li et al. [35] tested variations in an effort to optimize the model specifically for SCS studies. The study included the original SNI procedure, peroneal axotomy, tibial axotomy, tibial tight ligation (no sectioning), and partial tibial ligation (1/3 to 1/2 of its diameter ligated, without sectioning). SCS was delivered through an implanted 2 mm disc cathode placed on the dura at the T11 level. The 4 mm anode was placed on the chest wall, subcutaneously. Stimulation parameters were set at 50 Hz frequency, 0.2 ms PW, and amplitude at 90% of the MT. SCS was delivered for a 30-minute duration. Measuring mechanical allodynia via von Frey filament testing, authors found that all variations of the model produced allodynia within one week, lasting for at least 3 weeks. All variations except the partial tibial ligation lasted 7-10 weeks. Paw posture was noted as one difference between models, where peroneal axotomy resulted in an inverted position of the paw which tended to be dragged behind the rat. The other variations presented an eversion posture, with the partial tibial ligation being less prominent. Contrary to the original study, where no non-responders were reported and the contralateral hypersensitivity rate was zero, Li et al. found only 53% of SNI operated rats developed hypersensitivity and 25% had some hypersensitivity in the contralateral paw. Response to SCS showed the SNI group with the smallest responder rate at just 8%, compared to the 40-50% responder rate of the variation groups. The researchers concluded there was an inverse relationship between degree of hypersensitivity and efficacy of SCS, agreeing with previous literature in similar models [45], and that these variations of the SNI may provide better models for use in SCS animal studies. However, it should be mentioned that some later studies report higher responder rates to the original variation of the SNI model and subsequent SCS treatment.
Most recently, Sluka and coworkers [46] evaluated tonic SCS on multiple pain models, including the SNI. Implanting an epidural lead and corresponding neurostimulator, the rats were stimulated for 15 minutes per day at 60 Hz, 0.25 ms PW, and at 90% of the MT. Two weeks after SNI induction, the effect of SCS was evaluated. They found that neuropathic pain was alleviated by tonic SCS, measured by von Frey filaments, with significantly increased withdrawal thresholds. Twenty-four hours after stimulation was turned off, behavioral testing revealed that the effect of SCS was lost. The authors attribute the analgesic effect of tonic SCS on the SNI model to the activation of large Aβ dorsal column axons (supporting the GCT), as well as the electrochemical alteration of cell membranes and the involvement of neurotransmitters, receptors, and glial cells.
Previously, this group looked at frequency-dependent outcomes of SCS, particularly regarding opioid receptors [47] and glial cell activation with SCS [48]. In the opioid receptor study [47], SNI-induced rats were administered naloxone or naltrindole (both opioid antagonists), or were made morphine tolerant. Rats then received SCS at 4 Hz, 60 Hz, or no SCS daily for 6-hour periods, lasting 4 days for each treatment. Testing for mechanical allodynia, they found naloxone prevented the analgesic effect produced by 4 Hz and 60 Hz stimulation, though a higher dose was required to block the effect of 60 Hz. Interestingly, naltrindole had no effect on 4 Hz SCS, but successfully impeded the effect of 60 Hz SCS. When testing the morphine-tolerant rats, they found that 4 Hz SCS did not have the same analgesic effect that it did in normal rats, while 60 Hz stimulation remained efficacious. This work resulted in the understanding that the frequency of SCS may determine the mechanism by which pain relief is achieved, and in this case, engaging different opioid receptors.
Glial activation, via immunohistochemical staining with known markers (GFAP, MCP-1, and OX-42), was measured in a separate study using 30-minute and 6-hour SCS durations and varying the intensity (as percent of the MT) [48]. Two weeks after the SNI was induced, mechanical hypersensitivity increased, as expected, as well as glial cell activity. The results indicated that withdrawal thresholds were positively correlated with increasing SCS duration (6 h vs 30 min) and by stimulating at higher intensities (90% vs 75% vs 50% MT). Glial cell activation was significantly decreased in both 4 and 60 Hz SCS, delivered for 6 hours at 90% MT.
Additional studies focused on the question of frequency importance in SCS, utilizing the SNI as a pain model. Song et al. investigated conventional 50 Hz (200 μs PW, 80% MT) SCS compared to high frequency (HF) SCS at lower intensity (500, 1000, and 10000 Hz; 24 μs PW, 40–50% MT) [49]. A miniaturized 4-electrode plate lead was implanted into the epidural space of the T13 vertebral level. Performing behavioral testing for mechanical hypersensitivity (von Frey filaments) and thermal hypersensitivity (ethyl chloride spray for cold, modified Hargreaves test for heat), they found no significant difference in the overall analgesic effect of conventional SCS versus SCS at higher frequencies. They did, however, found that conventional SCS had significant effect on increasing the gracile nucleus neuron discharge rate. HF SCS had no effect whatsoever. These results suggest that conventional and HF SCS have different mechanisms of action.
Building on the idea that SCS can be designed to modulate neuron-glial interactions, Vallejo et al. [50] utilized the SNI model with continuous SCS to evaluate a differential target multiplexed programming (DTMP) approach compared to high rate and low rate SCS. The DTMP approach utilizes multiple signals that are intended to target neuron and glial cells differentially. It was found that all SCS treatments resulted in significant reduction of mechanical hypersensitivity, but the DTMP approach provided more significant improvement as well as reduced thermal hypersensitivity (hot/cold plate test) after 48 hours of continuous stimulation. RNA-sequencing was performed to confirm the phenotypes. Figure 3 provides a heatmap illustrating the significant effect of DTMP on sets of genes (modules) with similar expression patterns obtained through a Weighted Gene Co-expression Network Analysis (WGCNA) showing that the effect of DTMP SCS correlated stronger with the expression patterns of modules in naïve rats, compared to the pattern of untreated animals (No-SCS). In a follow up study, Cedeño et al. [51] demonstrated that the DTMP approach modulated neurons and glial cells (microglia, astrocytes, and oligodendrocytes) in a differential manner by using set of genes that were uniquely expressed (cell-specific transcriptomes) by each of the type of neural cell. The effect of DTMP on each of these cell-specific transcriptomes correlated strongly with the expression pattern of naïve animals, indicating a return of gene expression toward the state of naïve (healthy) animals.
Figure 3.
Heat map of mean module eigengene values for modules with significantly different comparisons (FDR-p < 0.2) between SNI untreated animals (No-SCS) and naïve animals. A total of 23 modules out of the total 39 are affected. Asterisks (*) indicate significantly different module eigengene values when comparing the SCS treatment to untreated animals (No-SCS). R is the Pearson coefficient for the correlation between eigengene values for naïve and each of the other groups. A negative value indicates an opposite trend. DTMP: differential target multiplexed programming; LR: low rate; HR: high rate; SCS: spinal cord stimulation. Reproduced from reference [50].
2.3 SCS in the spinal nerve ligation model
The spinal nerve ligation model (SNL) is one of the most popular preclinical models of neuropathic pain due to its reproducibility and lack of autotomy. During the surgery, initially described by Kim and Chung [52], the L5 spinal nerve is ligated with a 6-0 silk suture at a point just distal to the dorsal root ganglion (DRG), and cut distally, after the removal of the paraspinal muscles at the level of the L5 spinous process down to the sacrum, and the removal of the L6 transverse process.
Since the introduction of paresthesia-free stimulation parameters in the clinical setting, questions were raised on the value of the GCT as a practical construction to generate models to optimize SCS parameters. To find answers to some of these questions, Guan and coworkers have used the SNL model [53] to understand the specific effects of different components of the electrical signals in SCS treatment. Before paresthesia-free SCS, common frequencies used in clinical and animal models ranged from 50 to 60 Hz, since referred to as conventional SCS. Due to the lack of agreement regarding the optimal frequency and stimulation intensity to maximize analgesia, these authors hypothesized that kilohertz-level SCS and conventional 50Hz SCS might differently activate gate-control mechanisms and affect peripheral afferent conduction properties [53].
Using the SNL rodent model of neuropathic pain, the authors evaluated intensity-dependent (20%, 40%, and 80% MT) pain inhibition of SCS at various frequencies (50 Hz, 1 kHz, and 10 kHz) while maintaining the PW constant (24 μs). They further compared the effects of conditioning stimulation of the dorsal column, the primary structure targeted by SCS, at 50 Hz and 1 kHz on the conduction property of afferent Aα/β-fibers and inhibition of dorsal horn wide dynamic range (WDR) neuronal responses.
In their experiments, Guan and coworkers [53] advanced a custom-made quadripolar epidural SCS electrode up to the T10-12 spinal levels, via a small laminectomy at the level of T13. Mechanical hypersensitivity was assessed by determining the PWT using von Frey filaments. To further evaluate clinical conditions in the SNL model, the authors choose stimulation intensities set at either 20%, 40%, or 80% of the MT to test the effect of the described frequencies on pain-like behavior. Stimulation was conducted for 30 mins on days 12, 13, and 14 (week 1) and days 19, 20, and 21 (week 2) post-SNL. Behavioral testing was done at time 0, 15 (within the activation of SCS), 30 (end of stimulation), and 60 min. A cross-over design was implemented to avoid the order effect while switching the different frequencies.
Interestingly, rats exposed to 10 kHz SCS at 80% MT often exhibited signs of discomfort. For comparison, a small number of animals were implanted, but not stimulated, and served as a stimulation sham. When stimulation was applied at 20% MT, the effect was marginal for all the tested frequencies. The average mean PWT across the three treatment days was increased from the pre-stimulation level in all SCS groups but was statistically significantly higher than that of sham stimulation only in the 1 kHz and 10 kHz groups. Notably, there was a trend for SCS induced inhibition to increase gradually from the first to the third treatment in all groups. When using 80% MT the mean PWT was significantly increased from the first day of stimulation in both the 1 kHz and the 10kHz SCS groups. Of notice, the mean PWT in the 1 kHz and 10 kHz were both higher than that of the 50 Hz group on the first day of stimulation. The inhibitory effect of 50 Hz stimulation increased progressively during the second and third days of stimulation. The authors concluded that the SCS analgesia in SNL rats depends on both intensity and frequency, and high-intensity kilohertz level SCS provides earlier inhibition of mechanical hypersensitivity than conventional 50 Hz SCS. These results imply that analgesia from kilohertz and 50 Hz SCS may involve different mechanisms.
In a follow-up report, Guan and coworkers [54] explored how charge delivery affects pain inhibition by different frequencies at intensities that seem to be below the sensory threshold (40% MT), and which component of stimulation runs the therapeutic actions. Epidural electrodes were implanted 5 to 7 days post-SNL, in a similar fashion described by this group previously [53]. Based on the frequency, PW, and intensity, the authors calculated the charge-per-pulse, duty time, and charge-per-second. Then, four patterns of high-dose subthreshold active recharge biphasic signals at different frequencies with similar duty times were produced by adjusting the PW (200 Hz with 1 ms PW, 500 Hz with 0.5 ms PW, 1.2 kHz with 0.2 ms PW, and 10 kHz with 0.024 ms PW). Finally, the authors included one 50 Hz with 0.2 ms PW at subthreshold and a sham (no SCS) group. Because clinical and animal data suggest that subthreshold SCS may have a slower onset, stimulation was carried for 120 mins (one session per day) from days 14 to 17 (week 1). The behavioral response was determined by measuring the PWT 30 mins pre-SCS, at 0, 30, and 60 mins during SCS, and 0, 30, and 60 mins post-SCS to evaluate carry-over effects. In those groups that showed increased tolerance to mechanical hypersensitivity, the peak effect appeared at 60 to 90 mins after initiation of SCS and faded shortly after the stimulation was completed. The onset of significant PWT increase was observed from day one in the 200 Hz and 10 kHz groups and was observed on day two in the 1.2 kHz group. Although 200 Hz SCS had the longest PW, the highest charge-per-pulse and the lowest charge-per-second, and 10 kHz had the shortest PW, the lowest charge-per-pulse, and the highest amplitude and charge-per-second, the two groups provided comparable improvements in PWT. These findings suggest that the efficacy of the inhibitory effect is not correlated to the difference in individual SCS parameters (frequency, PW) but is positively correlated with the electrical dose. Probably, the most interesting finding is that at subthreshold SCS amplitudes, mechanical hypersensitivity was not only inhibited by 10 kHz but also at lower frequencies (200 Hz). The authors concluded that using low-frequency subthreshold SCS and longer PWs, could be a more energy-efficient stimulation paradigm for inhibition of mechanical hypersensitivity when compared with 10 kHz SCS.
2.4 SCS in a chemotherapy-induced neuropathic pain model
The administration of chemotherapy agents for the treatment of cancer often results in the onset of neuropathic pain due to peripheral nerve damage. Recently, Sivanesan et al. [55] reported on the efficacy of SCS in reducing mechanical and thermal hypersensitivity in a rodent model of chemotherapy-induced peripheral neuropathy (CIPN). The chemotherapeutic paclitaxel (PTX), common in the treatment of ovarian, breast, and lung cancers, can induce painful peripheral neuropathy even at therapeutic dosages. Often this pain is severe enough to necessitate a reduced dose of PTX and persists after cessation of the drug in nearly a third of cases. Other chemotherapeutic agents, including platinum-based agents, and proteasome inhibitors like bortezomib, are also known to induce similar neuropathies [56].
Induction of the model began by acclimation of a group of adult male rats that were divided into three groups: (1) SCS + PTX, (2) PTX, or (3) naïve. Behavioral testing consisted of assessments of mechanical hypersensitivity (von Frey filaments) and thermal hypersensitivity (via dry ice application) of the hind paws.
Animals assigned to receive SCS underwent a T13 laminectomy and were implanted with a quadripolar miniaturized lead in the dorsal epidural space corresponding to the T13-L1 spinal cord. Stimulation parameters were set to conventional settings with 50 Hz frequency, 0.2 ms PW, and current intensity at 80% MT. Subsequently, animals in the PTX and SCS + PTX groups were administered 1-2 mg/kg PTX, via intraperitoneal (i.p.) injection, every other day for four days. Naïve animals received i.p. injections of the vehicle used in the PTX groups. SCS was administered daily for 6-8 hours over the course of two weeks. To substantiate whether SCS can avert the development of CIPN, PTX was administered at the same time as the stimulation. Implanted animals that did not receive SCS treatment were included as control animals.
Rats developed hypersensitivity one week after the first administration of PTX that was sustained for 25 days. Interestingly, early administration of SCS attenuated the development of mechanical hypersensitivity associated with neuropathic pain-like behavior induced by administration of PTX (Figure 4). SCS did not fully recover to the PWT in naïve animals, but the preemptive effect of SCS is noteworthy. Early application of SCS also prevented the development of cold hypersensitivity. It is also important to note that the analgesic effect of SCS persisted for at least 2 weeks after stopping SCS treatment.
Figure 4.
Mechanical hypersensitivity (left) and cold thermal hypersensitivity (right) of animals treated with SCS (SCS + PTX), untreated (PTX) and naïve. The patterned box indicates the time of PTX administration. The black box indicates the time of SCS administration. * indicates significant differences (p < 0.05) relative to naïve, # indicates significant differences (p < 0.05) relative to PTX + SCS. Values obtained from reference [55].
L3-L6 spinal cord tissue was harvested 17 days after SCS was applied, and RNA in the samples was sequenced to investigate changes in gene expression and biological processes of treated, untreated, and naïve animals. It was found that some genes associated with mechanosensation, neuroimmune response, and glial activation were affected by the CIPN model. The authors hypothesized that repetitive dosing of SCS increased the expression of genes that enhance adenosine-related activity, which has been shown to enhance pain inhibition by SCS when using the CCI model [14]. The authors also observed that SCS downregulated GABA reuptake-related genes, which is consistent with a previous observation in rats after sciatic nerve injury [57]. They postulated that downregulation of genes such as Gat3 (a GABA transporter expressed by glial cells) by SCS may increase GABAergic signaling that inhibits neurotransmission in CIPN rats. The GABAergic inhibition of excitatory neurotransmitters may involve then the suppression of calcium influx into presynaptic terminals, which is regulated by astrocytes.
2.5 SCS in a model of painful diabetic neuropathy
Originally developed in the early 1960’s for studying diabetes mellitus, the streptozotocin (STZ)-based painful diabetic neuropathy model (SPDN) uses an antibiotic derived from Streptomyces achromogenes to selectively kill insulin secreting β-cells in the pancreas [58]. The results replicate symptoms seen in type 1 diabetes including dysregulation of blood glucose, decreased body weight, and peripheral artery disease leading to painful diabetic neuropathy.
Early investigations with this model to study the effects of SCS were conducted by Wu et al. [59] to explore the effect of SCS on blood flow in the periphery. Adult male rats were divided into two groups: (1) diabetic rats and (2) non-diabetic rats. Diabetic rats were injected with 50 mg/kg streptozotocin i.p., while the non-diabetic animals were injected with an equivalent volume of vehicle (citrate buffer). Animals were monitored weekly for weight loss and blood glucose levels. After four weeks, animals were tested for vasodilation in response to SCS provided via a spring-loaded unipolar ball electrode placed on the right or left side of the subdural face of the dorsal columns at the L2-L3 spinal segments. SCS was set to 50 Hz frequency, 0.2 ms PW, with monophasic rectangular pulses. Current was applied for 2 minutes at 30, 60, or 90% of the MT. It was found that MT in diabetic rats was significantly higher than in non-diabetic rats, and that SCS at the largest intensity attenuated SCS-induced vasodilation in diabetic rats. Furthermore, increasing SCS from 30% to 90% of MT increased blood flow in non-diabetic rats but not in diabetic rats. The study suggested that SCS-induced vasodilation improves peripheral blood flow, although this seems partially impaired in the diabetic animals.
In a later study, van Beek et al. [60] utilized the SPDN model to explore the effect of increasing the stimulation frequency on mechanical hypersensitivity induced by the model. In this study the dosage of STZ was increased to 65 mg/kg, to ensure the development of type-1 diabetes in four days instead of four weeks. Animals were implanted with a quadripolar lead via a T13 laminectomy into the dorsal epidural space of the T10-T12 spinal cord. Stimulation parameters were set to 200 μs PW, intensity at 67% MT and frequency at either 5, 50, or 500 Hz. Sham-stimulated animals were used as controls. SCS sessions were 40 minutes/day for four consecutive days. It was found that SCS at all frequencies alleviated mechanical sensitivity similarly, but stimulation at 500 Hz elicited a delayed response.
In other study, van Beek et al. [61] utilized the SPDN model to evaluate the long-term efficacy (10 weeks) of conventional SCS treatment. As before, the SPDN model was induced in male rats using an i.p. injection of 65 mg/kg STZ. Animals were monitored for weight loss and blood glucose to establish response to the model. An internally implanted pulse generator fitted with a quadripolar lead was required due the longer duration of the study. The quadripolar lead was implanted via a L1 laminectomy into the dorsal epidural space of the L2-L5 spinal cord. Stimulation parameters were 50 Hz frequency, 210 μs PW, intensity at 67% of the MT, 12 h/day for four weeks. A group of implanted SPDN animals sham for SCS were included as a control. The results indicate that long-term conventional SCS decreases mechanical hypersensitivity even after cessation of SCS in the SPDN model (Figure 5).
Figure 5.
Effect of conventional SCS on mechanical hypersensitivity in a diabetic neuropathic pain model. * indicates a significant difference (p < 0.05) relative to No-SCS. Values obtained from reference [61].
3. Animal models of SCS for inflammatory pain
The injection of a chemical inflammatory agent in a skin dermatome has been effectively used for the study of the mechanism of acute and persistent inflammatory pain [62]. Such agents include solutions of formalin, complete Freund’s adjuvant, or carrageenan (CAR). The CAR model has been adapted to study the effect of SCS in inflammatory pain in the limbs of rodents. Cui et al. [63] reported the first account of the utilization of a carrageenan-based model of chronic nociceptive pain coupled to SCS. The pain model was adapted from Woolf and Doubell [64] and consisted of the injection, under standard halothane anesthesia, of 0.15 mL solution of carrageenan lambda (in 0.9% saline to a concentration of 1%) in the mid plantar part of the hind paw. The inflammatory agent induces an edema at the site of injection and decreases the threshold for paw withdrawal or vocalization to mechanical stimuli in the affected area. Adult male Sprague-Dawley rats epidurally implanted, under anesthesia, with a monopolar cathode (2 x 3 mm2) placed retrograde in the L1-L3 vertebral region via a laminectomy in T11. The anode was placed subcutaneously in the supravertebral region adjacent to the cathode. Rats were allowed to recover for 3 days post-surgery before any experimentation. Current-controlled SCS was applied using a pulsed signal with a width of 200 μs at a frequency of 50 Hz. The intensity was set to 67% of the MT and was on average 1.0 (± 0.3) mA. These parameters correspond to those used clinically during conventional SCS therapy. Treatment was applied for 30 minutes at 3 h, 1, 3, 5, 7 and 9 days after injection of the CAR solution. SCS was also applied to another group of animals 3 days (30 minutes/day) before injection besides the timepoints after injection. The study also included control animals that were injected with CAR but were not implanted with the SCS system, and animals that were subjected to SCS but were not injected with CAR. The extent of local inflammation was determined by measuring the circumference of the metatarsal region and mechanical sensitivity was measured by recording paw withdrawal or vocalization upon applying pressure to the affected paw. A pressure gauge measured the force (in g) that elicited the withdrawal or vocalization response.
The mean circumference of the edema at the paw was around 30 mm before injection (no edema) and increased to a maximum at around 43 mm 3 hours after injection. The edema gradually decreased back to baseline at day 7-9 post-injection. The mean paw withdrawal/vocalization threshold was 215-220 g before CAR injection and decreased to 77 g at 3 hour after CAR injection. Mechanical hypersensitivity reduced gradually and reached baseline at around day 7 post-injection. The reduction in mechanical hypersensitivity correlated well with the reduction in the edema (Figure 6). The application of 30 min of SCS at every time point produced a significant increase of the size of the edema until day 5 post-injection (Figure 7). However, mechanical sensitivity was only significantly increased by SCS at the 3h point after CAR injection. At day 3, mechanical sensitivity was reduced significantly relative to the pre-stimulation value and was similar at days 7 and 9 post-injection. Authors reported that application of SCS pre-emptively did not provide a beneficial effect. Application of SCS in the absence of the inflammatory insult did not produce significant changes in circumference size and mechanical sensitivity.
Figure 6.
Correlation between edema size resulting from CAR injection as measured by the mean circumference of the metatarsal level of the paw and the change in the threshold force (g) that elicits paw withdrawal or vocalization. Labels by every post-injection point indicates the time point. The values at days 7 (7d) and 9 (9d) post-injection are the same as the pre-injection values. Values obtained from reference [63].
Figure 7.
Change in the edema size (left) and mechanical hypersensitivity (right) as a result of 30 minutes/day of SCS. A positive change in withdrawal threshold is equivalent to a reduction in hypersensitivity. * indicates a significant difference (p < 0.05). Values obtained from reference [63].
Authors concluded that this model is a representation of subacute pain between the third day post CAR injection and the 14th day, which is concomitant to the invasion of different types of inflammatory cells, while the stage previous to the third day post-injection represents an acute pain phase. It was surprising to observe that the SCS signal applied in this study increased the size of the edema as well as mechanical sensitivity in the early stage of the acute phase. However, the increase in hypersensitivity was not likely causal to the edema, and rather may be due to plasticity changes in the dorsal horn as a result of the stimulating signal and the acute inflammatory process. Once the inflammatory processes have settled in during the subacute phase, authors hypothesized that SCS provides an analgesic effect due to the inhibition of neuronal hyperexcitability due to A fiber-mediated wind up.
Years later, the same group reported [49] on using the CAR-based inflammatory pain model to assess the effect of signal rate at low intensities in the acute stage of the model. This was motivated by a shift in SCS paradigm resulting from the clinical introduction of a SCS therapy that provided pain relief at intensities below the perception threshold, thus removing the need for paresthesia overlap of the painful dermatome required by conventional SCS which operates at low frequency (50 Hz), in contrast to the high frequency (10 kHz) used by the novel therapy. The authors utilized signals at 50 Hz (conventional frequency), and 10 kHz, which is referred to as high frequency SCS (HF SCS). In the same report, the authors also studied the effects on HF SCS (500 Hz, 1 kHz, and 10 kHz) on the SNI model, which was allowed to develop more chronically (2 weeks after nerve injury) before SCS intervention. In this work, authors used male adult Wistar rats, which were injected with 0.15 mL of a 1% saline solution of CAR in the hind paw as previously described [63]. Animals were implanted with a SCS system consisting of a paddle lead with four circular poles (0.9-1.0 mm diameter) spaced by 1.8-2.0 mm, which was introduced epidurally via laminectomy at the T13 vertebral level and placed anterograde to cover the T10-T12 levels. This was a variation from the previous report [63]. Animals were left to recover from surgery for 48 hours before any additional experimental intervention. Pain-like behavior was tested before injection (baseline, before stimulation and after 120 minutes of SCS at days 1, 2 and 3 after CAR injection. The test consisted of applying force progressively with clamping forceps (algometer) terminated in a blunt tip in the affected paw until the animal withdraws the paw. The algometer was equipped with a pressure gauge that reads the force exerted (in g) at the threshold of paw withdrawal. In contrast to the previous study by this group, the circumference of the metatarsal level of the paw was not measured, so the effect of SCS frequency on the edema was not determined. SCS was distributed to the four contacts in the paddle lead using adjacent bipoles (+-+-, rostral to caudal). Conventional SCS (50 Hz) used monophasic pulses 200 μs wide and current-controlled intensity set to 80% of the MT, corresponding to intensities in the 0.48 to 0.64 mA range. The HF-SCS (10 kHz) monophasic pulses were 24 μs wide with intensities set in the range 0.3-0.4 mA, which correspond to 40-50% of the MT, which were defined as subparesthetic based on observation of behavioral responses. Untreated animals served as control. Mean paw withdrawal threshold was 72 g before injection and decreased to around 19 g 1 day after CAR injection. As expected, for this model, the mean withdrawal threshold gradually increased reaching around 30 g and 56 g at days 2 and 3 post-injection, respectively (Figure 8).
Figure 8.
Effect of SCS treatments on acute inflammatory pain. Values obtained from reference [49].
Neither conventional SCS nor HF-SCS provided a significant improvement of acute inflammatory pain over the course of 3 days, although it is worth mentioning that, in contrast, their previous work reported a significant difference at 3 days post CAR injection. The authors did not comment on their counter results, but is plausible that the position of the lead, which was reported to be a differing factor may have influenced the outcome. A lumbar location may modulate neural circuits of the hind paw more effectively than a thoracic location used in this study. The findings for the acute inflammatory pain were similar to what was found when healthy animals were subjected to SCS and a test of acute pain (pinch force with a pointy tip in the algometer), but in contrast to the results observed in the neuropathic chronic pain model, in which 120 minutes of both conventional and HF-SCS treatments reduced mechanical hypersensitivity significantly. Thus, it can be concluded from the study that neither HF-SCS nor conventional SCS provide relief from acute inflammatory pain (as well as acute nociceptive pain), in agreement with previous clinical and well-controlled observations [65, 66, 67] and had led to the establishment of a segmental mechanism of action in which SCS works by modulating conduction of dorsal column fibers within a particular segmental circuitry that has reached a level of central sensitization during the establishment of chronic pain due to a peripheral injury, such as in the SNI model of neuropathic pain tested.
Recently, Sato et al. [46] reported the utilization of a CAR-based model to study the effect of conventional SCS on joint inflammatory pain. This group had previously found [68] that the unilateral intraarticular anterior injection of 0.1 mL of a 3% solution of lambda carrageenan (type IV, dissolved in 0.9% saline) into the left knee joint of rats induces pain-like behavior that manifests as increased thermal (hot) and mechanical hyperalgesia in the ipsilateral hind paw and knee. The model can be used to evaluate acute or chronic onset of inflammatory pain. In their recent work, they implemented this joint inflammatory pain model to test the effect of short doses (15 min/day) of conventional SCS (60 Hz, 250 μs PW, intensity at 90% of the MT) on thermal and mechanical hyperalgesia using an acute stage of the model. The SCS system had been previously described [48, 69] and consisted of a stimulation lead epidurally introduced, under anesthesia, via laminectomy at the T13 vertebral level and positioned rostrally. The authors did not provide details on the lead design and final position of it relative to spinal levels within the epidural space. Lead wires were tunneled to an internal neurostimulator (Interstim iCon, model 3058, Medtronic Inc., Minneapolis, MN) implanted subcutaneously in the left flank. This allowed animals to roam freely in their cages while being stimulated. Animals were tested for both paw and knee withdrawal to noxious mechanical stimuli before CAR injection, and 30 min before and after SCS (15 min) on days 1, 2, 3, and 4 after injection. Paw withdrawal thresholds were obtained using von Frey filaments with bending force in the range 1-402 mN applied to the plantar surface of the paw ipsilateral to the affected joint. Measurements in the contralateral paw served as internal controls. Knee withdrawal thresholds were measured by compressing the affected extended knee with a pair of calibrated forceps (30 mm2 tip) until the knee was withdrawn due to the applied force. Mean paw and knee withdrawal thresholds are shown in Figure 9.
Figure 9.
Effect of SCS treatments on acute inflammatory joint pain as reflected in the ipsilateral paw and knee. All post-SCS values are significantly increased (p < 0.05) relative to Pre-SCS values. Pre-SCS values are significantly reduced relative to pre-injection. There is no significant difference between treatment days. Values obtained from reference [46].
An acute application of conventional SCS, as applied in this work, improved mean withdrawal thresholds significantly relative to the pre-SCS state, implying that conventional SCS may be used to treat acute inflammatory pain. The study did not address the effects of a chronic inflammatory state, which is achievable with this CRA model. Similar to what was reported for effects on the SNI neuropathic pain model, the effect is reversible and reproducible over the different days of treatment. It has been established that SCS modulates inflammatory processes in the stimulated area of the spinal cord that contain neural circuits associated with the painful areas. These neural circuits contain neurons and other abundant non-neuronal cells that are highly involved in the establishment and chronification of pain, even at early stages. It is quite interesting to note that the effect of SCS sets in as early as 1 day to alleviate hyperalgesia associated with acute knee inflammation, which was not observed by Linderoth and coworkers when inflammation was elicited in the hind paw [49, 63]. It is plausible that the circuits operating in the thoracic region for inflammation of the hind paw are not as effective for SCS, in contrast to treat inflammation of the knee joint.
4. Animal models of SCS for ischemic pain
It has been established that SCS modulates vasodilation in the lower limbs and feet dermatomes associated with vertebral segments being stimulated [70]. This has justified SCS as an alternative treatment for nociceptive pain and associated symptoms related to advanced cases of peripheral arterial occlusion disease (PAOD), which leads to ischemia and the subsequent neuropathy due to the lack of blood supply to nerve terminals. Other clinical uses of SCS related to vasodilation modulation include Rynaud’s syndrome and angina pectoris. In the absence of a pain model related to PAOD, animal models that measure the modulation of blood flow and vasodilation have been used to demonstrate the mechanism of action of SCS treatment of peripheral vascular diseases. Although there is no evidence that SCS is effective on acute nociceptive pain, the modulation of vasodilation is hypothesized as the mechanism of action for relieving ischemic conditions and recover the flow of nutrients into the affected nerve terminals. Linderoth and Foreman’s groups have collaborated to measure the effect of low rate SCS on blood flow changes in the skin dermatomes of the hind paws of anesthetized rats. In one experiment [71], a spring-loaded monopolar ball cathode was placed in the subdural surface of the L1-L3 dorsal columns (left or right) of anesthetized rats to assess the role of SCS in modulating the sympathetic autonomous system. SCS monophasic pulses (50 Hz, 200 μs PW, 66% of the MT) were applied for 2 minutes. Blood flow was monitored using laser-based doppler probes placed in the glabrous surfaces of the hind paws ipsilateral and contralateral to the stimulation. Another group of animals was subjected to total sympathectomy, while the other was subjected to the ganglionic transmission blocker hexamethonium. In a separate experiment [72], the effect of SCS on the sympathetic nervous system was determined by evaluating the role of ganglionic transmission (with hexamethonium blockade), alpha-adrenergic receptors (phentolamine or prazosin blockade), beta-adrenergic receptors (propanolol blockade), and adrenal catecholamine secretion (adrenal demedullation) in paralyzed anesthetized animals. The left L1-L2 vertebral region was stimulated epidurally with a monopolar ball cathode (0.9 mm diameter) that delivered pulses at 50 Hz, 200 μs PW, and 0.6 mA of intensity. Blood flow was monitored using laser Doppler probes in each hind paw. Although both studies concurred that SCS increases peripheral blood flow in the ipsilateral limb by about 200% concomitant to a reduction of flow resistance of ~50%, there were disagreements in the role of sympathetic contributions, which prompted the formulation of a second hypothesis involving the antidromic activation of the release of vasodilators, such as calcitonin gene-related peptide (CGRP) and nitric oxide. A further report [73] explored the effect of SCS pulse rate on blood flow, finding that pulsing at 500 Hz provided a significant increase of vasodilation relative to pulsing at 200 Hz and 50 Hz at similar pulse widths and intensities. The frequency effect seems to be related to increased release of CGRP, induced by activation of fibers containing the capsaicin receptor (TRPV-1). In conclusion, the reduction of nociceptive lower limb pain due to ischemia has been indirectly associated with SCS-induced vasodilation that provides an increase in blood flow and the concomitant decrease of flow resistance in the affected limb. It is plausible that vasodilation is due to the release of agents CGRP and nitric oxide from the stimulated fiber afferents and at some extent by modulation of the sympathetic nervous system.
5. Translational equivalence of animal models
Besides rodent (mostly rat) models, there have been reports of SCS effects on ovine models of neuropathic pain. As presented in section 2.1 above, Reddy et al. [17] reported on the utilization of female sheep to develop a CCI model to study the effect of tonic SCS. The advantage of using a large animal model is that it provides a way to bridge the translation of SCS parameters toward clinical application for longer exposures in anatomical environments that are more similar to that of humans. These authors found that the model provided a significant reduction of mechanical hypersensitivity upon continuous SCS for one week. A closer examination of the reported data for 5 animals, reveals that one of them was a non-responder to the pain model since there was not a decrease of the limb withdrawal threshold (WT). If data from this animal is discarded, the CCI model reduced the WT to a mean 51% (± 6%) relative to the mean WT of the control measurements in the contralateral limb. The mean WT of the responders after SCS corresponded to 85% (± 13%) of the mean WT of the control. This is consistent with the findings in rodents, although a direct comparison is not possible because there are not reports on rodent CCI models with continuous SCS.
Vallejo et al. [74] reported on a comparison of the effect of SCS based on the DTMP approach on a rat and sheep models after 24 and 48 h of continuous treatment. The pain model in the rats was the SNI as previously described [42, 43], while the sheep model is the equivalent peroneal nerve injury (PNI) developed by Wilkes et al. [75] and adapted for SCS by implanting a cylindrical octapolar human-grade lead (1.3 mm diameter) in the L1-L3 epidural space. DTMP consisted of multiplexing 4 pulsed signals with frequencies in the 50 Hz to 1.2 kHz and PW of 200 μs at an intensity of 50% of the MT. Mechanical hypersensitivity was obtained before starting SCS, as well as at 24 h and 48 h of continuous SCS, using an electronic von Frey anesthesiometer. In order to compare rodent and ovine results, the WT were normalized to the pre-SCS values (Figure 10). Rodent data is for individual subjects (N = 13). Ovine data is from two sheep that were evaluated in a crossover experiment, in which one sheep was stimulated while the other one served as a No-SCS control. After a one-week break for washing out the effects of SCS, the animal that had not been treated was subjected to SCS while the other one was the No-SCS control. This process was repeated until obtaining a set of six measurements.
Figure 10.
Top row: Mechanical hypersensitivity of rats subjected to SCS with a DTMP approach in comparison with untreated animals (No SCS) and corresponding areas under the curve (AUC). Bottom row: equivalent measurement obtained from sheep. * denotes significant differences (p < 0.05) between treated and untreated animals.
DTMP significantly relieved mechanical hypersensitivity in the rat model equivalent to 78.6% at 24h and 77.3% at 48 h in the rat model relative to the pre-SCS and No-SCS measurements. Similar effects were seen in the sheep model where the decrease in mechanical hypersensitivity was 84.8% at 24h and 73.7% at 48 h. These results demonstrate translational equivalence between two animal models of neuropathic pain for the first time.
6. Conclusion
Certain limitations exist in the development of animal models that simulate human pathological conditions of pain. For instance, the most common clinical indication for SCS has become the treatment of intractable neuropathic pain of the lower back and legs, largely associated with failed surgical spine interventions (failed back surgery syndrome, FBSS), which causes axial back pain that radiates to the limbs in a unilateral or bilateral manner. The existing rat models of neuropathic pain, which are described in this chapter, are mostly peripherally induced (nerve injury) and test the manifestation of mechanical hypersensitivity in the paws, not necessarily in the leg of the animals. An animal model that resembles FBSS has yet to be developed. Such peripheral nerve injury models, however, resemble symptoms found in other pain-related syndromes such as complex regional pain syndrome (CRPS), which are also indicated for SCS treatment in humans. Despite these limitations, the existing models have proven extremely useful to understand the effects of various modalities of SCS on pain-like behavior of the animals, and more importantly, on the mechanistic understanding of SCS via the molecular analysis of samples obtained from neural tissues (spinal cord, DRG) that cannot be obtained in clinical assessments. Such molecular evaluations have made use of pharmacological approaches that use the coadministration of neurotransmitters agonists and antagonists, opioids, receptor blockers, etc., as well as immunohistochemical analysis that target cellular markers of glial activation. Recent approaches are most robust and utilize high throughput transcriptomic and proteomic analysis in combination with many bioinformatic tools that provide an understanding of the effects of SCS on complex biological processes that involve a multitude of proteins and their encoding genes. These advancements should provide the field with tools to enhance current therapies and improvements on pain diagnostics that could ultimately lead to an integral and personalized treatment of painful conditions in humans. Animal models will continue to play a crucial role in the development of the science and technology of electrical neuromodulation for treating pain.
Acknowledgments
The authors want to acknowledge our colleagues, Dana Tilley, William Smith, Ashim Gupta, Cynthia Cass, Maggie DeMaegd, Randi Wilson, Louis Vera-Portocarrero, Melanie Goodman-Keiser, Samuel Thomas, Alejandro Vallejo, and Tina Billstrom who have provided their help in developing our own SCS animal models.
Conflict of interest
DLC and RV are consultants and scientific advisors for Medtronic Inc. They are also coinventors in patents related to differential target multiplexed (DTM) spinal cord stimulation.
\n',keywords:"spinal cord stimulation, animal models, neuropathic pain, inflammatory pain, ischemia",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75497.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75497.xml",downloadPdfUrl:"/chapter/pdf-download/75497",previewPdfUrl:"/chapter/pdf-preview/75497",totalDownloads:217,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 22nd 2021",dateReviewed:"February 4th 2021",datePrePublished:"March 2nd 2021",datePublished:"March 9th 2022",dateFinished:"March 2nd 2021",readingETA:"0",abstract:"Spinal cord stimulation (SCS) is an electrical neuromodulation technique with proven effectiveness and safety for the treatment of intractable chronic pain in humans. Despite its widespread use, the mechanism of action is not fully understood. Animal models of chronic pain, particularly rodent-based, have been adapted to study the effect of SCS on pain-like behavior, as well as on the electrophysiology and molecular biology of neural tissues. This chapter reviews animal pain models for SCS, emphasizing on findings relevant to advancing our understanding of the mechanism of action of SCS, and highlighting the contribution of the animal model to advance clinical outcomes. The models described include those in which SCS has been coupled to neuropathic pain models in rats and sheep based on peripheral nerve injuries, including the chronic constriction injury (CCI) model and the spared nerve injury model (SNI). Other neuropathic pain models described are the spinal nerve ligation (SNL) for neuropathic pain of segmental origin, as well as the chemotherapy-induced and diabetes-induced peripheral neuropathy models. We also describe the use of SCS with inflammatory pain and ischemic pain models.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75497",risUrl:"/chapter/ris/75497",signatures:"Joseph M. Williams, Courtney A. Kelley, Ricardo Vallejo, David C. Platt and David L. Cedeño",book:{id:"10549",type:"book",title:"Preclinical Animal Modeling in Medicine",subtitle:null,fullTitle:"Preclinical Animal Modeling in Medicine",slug:"preclinical-animal-modeling-in-medicine",publishedDate:"March 9th 2022",bookSignature:"Enkhsaikhan Purevjav, Joseph F. Pierre and Lu Lu",coverURL:"https://cdn.intechopen.com/books/images_new/10549.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-805-8",printIsbn:"978-1-83968-804-1",pdfIsbn:"978-1-83968-806-5",isAvailableForWebshopOrdering:!0,editors:[{id:"231585",title:"Associate Prof.",name:"Enkhsaikhan",middleName:null,surname:"Purevjav",slug:"enkhsaikhan-purevjav",fullName:"Enkhsaikhan Purevjav"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"337591",title:"Ph.D.",name:"David L.",middleName:null,surname:"Cedeño",fullName:"David L. Cedeño",slug:"david-l.-cedeno",email:"dclumbrera@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"337596",title:"Dr.",name:"Ricardo",middleName:null,surname:"Vallejo",fullName:"Ricardo Vallejo",slug:"ricardo-vallejo",email:"vallejo1019@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"346305",title:"Dr.",name:"Joseph M.",middleName:null,surname:"Williams",fullName:"Joseph M. Williams",slug:"joseph-m.-williams",email:"jwilliam@iwu.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Illinois Wesleyan University",institutionURL:null,country:{name:"United States of America"}}},{id:"346306",title:"Ms.",name:"Courtney A.",middleName:null,surname:"Kelley",fullName:"Courtney A. Kelley",slug:"courtney-a.-kelley",email:"cklumbrera@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Illinois Wesleyan University",institutionURL:null,country:{name:"United States of America"}}},{id:"346307",title:"Mr.",name:"David C.",middleName:null,surname:"Platt",fullName:"David C. Platt",slug:"david-c.-platt",email:"dcplatt26@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Illinois Wesleyan University",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Animal models of SCS for neuropathic pain",level:"1"},{id:"sec_2_2",title:"2.1 SCS in partial nerve injury models",level:"2"},{id:"sec_3_2",title:"2.2 SCS in the spared nerve injury model",level:"2"},{id:"sec_4_2",title:"2.3 SCS in the spinal nerve ligation model",level:"2"},{id:"sec_5_2",title:"2.4 SCS in a chemotherapy-induced neuropathic pain model",level:"2"},{id:"sec_6_2",title:"2.5 SCS in a model of painful diabetic neuropathy",level:"2"},{id:"sec_8",title:"3. Animal models of SCS for inflammatory pain",level:"1"},{id:"sec_9",title:"4. Animal models of SCS for ischemic pain",level:"1"},{id:"sec_10",title:"5. Translational equivalence of animal models",level:"1"},{id:"sec_11",title:"6. Conclusion",level:"1"},{id:"sec_12",title:"Acknowledgments",level:"1"},{id:"sec_15",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Melzack R, Wall PD. Pain mechanisms: A new theory. Science 1965; 150: 971-979'},{id:"B2",body:'Köhler W. 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Department of Psychology, Illinois Wesleyan University, USA
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Openness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
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