Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse
Identifieur interne : 001C86 ( Istex/Corpus ); précédent : 001C85; suivant : 001C87Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse
Auteurs : Erwan Bezard ; Mohamed Jaber ; François Gonon ; Alain Boireau ; Bertrand Bloch ; Christian E. GrossSource :
- European Journal of Neuroscience [ 0953-816X ] ; 2000-08.
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Abstract
Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5‐day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH‐immunoreactive neurons (−70.2%) and striatal dopamine content (−38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.
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DOI: 10.1046/j.1460-9568.2000.00180.x
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Gross</name><affiliation><mods:affiliation>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:0767F6689204C21A242EBC8E6FC5D4CC9D81D477</idno><date when="2000" year="2000">2000</date><idno type="doi">10.1046/j.1460-9568.2000.00180.x</idno><idno type="url">https://api.istex.fr/document/0767F6689204C21A242EBC8E6FC5D4CC9D81D477/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001C86</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001C86</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse</title><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation><mods:affiliation>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Jaber, Mohamed" sort="Jaber, Mohamed" uniqKey="Jaber M" first="Mohamed" last="Jaber">Mohamed Jaber</name><affiliation><mods:affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Gonon, Francois" sort="Gonon, Francois" uniqKey="Gonon F" first="François" last="Gonon">François Gonon</name><affiliation><mods:affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Boireau, Alain" sort="Boireau, Alain" uniqKey="Boireau A" first="Alain" last="Boireau">Alain Boireau</name><affiliation><mods:affiliation>CNS Programme, Rhône‐Poulenc Rorer, CRVA, 13 quai Jules Guesde, 94403 Vitry sur Seine Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Bloch, Bertrand" sort="Bloch, Bertrand" uniqKey="Bloch B" first="Bertrand" last="Bloch">Bertrand Bloch</name><affiliation><mods:affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</mods:affiliation></affiliation></author><author><name sortKey="Gross, Christian E" sort="Gross, Christian E" uniqKey="Gross C" first="Christian E." last="Gross">Christian E. Gross</name><affiliation><mods:affiliation>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">European Journal of Neuroscience</title><idno type="ISSN">0953-816X</idno><idno type="eISSN">1460-9568</idno><imprint><publisher>Blackwell Science Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2000-08">2000-08</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="2892">2892</biblScope><biblScope unit="page" to="2900">2900</biblScope></imprint><idno type="ISSN">0953-816X</idno></series><idno type="istex">0767F6689204C21A242EBC8E6FC5D4CC9D81D477</idno><idno type="DOI">10.1046/j.1460-9568.2000.00180.x</idno><idno type="ArticleID">EJN180</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0953-816X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson's disease</term><term>compensation</term><term>cytochrome oxidase</term><term>dopamine transporter</term><term>immunohistochemistry</term><term>tyrosine hydroxylase</term><term>voltammetry</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5‐day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH‐immunoreactive neurons (−70.2%) and striatal dopamine content (−38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Erwan Bezard</name><affiliations><json:string>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</json:string></affiliations></json:item><json:item><name>Mohamed Jaber</name><affiliations><json:string>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</json:string></affiliations></json:item><json:item><name>François Gonon</name><affiliations><json:string>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</json:string></affiliations></json:item><json:item><name>Alain Boireau</name><affiliations><json:string>CNS Programme, Rhône‐Poulenc Rorer, CRVA, 13 quai Jules Guesde, 94403 Vitry sur Seine Cedex, France</json:string></affiliations></json:item><json:item><name>Bertrand Bloch</name><affiliations><json:string>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</json:string></affiliations></json:item><json:item><name>Christian E. Gross</name><affiliations><json:string>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>compensation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>cytochrome oxidase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopamine transporter</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>immunohistochemistry</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>tyrosine hydroxylase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>voltammetry</value></json:item></subject><articleId><json:string>EJN180</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5‐day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH‐immunoreactive neurons (−70.2%) and striatal dopamine content (−38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.</abstract><qualityIndicators><score>8</score><pdfVersion>1.2</pdfVersion><pdfPageSize>612 x 791 pts</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1804</abstractCharCount><pdfWordCount>7689</pdfWordCount><pdfCharCount>46539</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>266</abstractWordCount></qualityIndicators><title>Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse</title><refBibs><json:item><author><json:item><name>M. Abercrombie</name></json:item></author><host><volume>94</volume><pages><last>247</last><first>239</first></pages><author></author><title>Anat. 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neurosurgery</json:string></scienceMetrix></categories><publicationDate>2000</publicationDate><copyrightDate>2000</copyrightDate><doi><json:string>10.1046/j.1460-9568.2000.00180.x</json:string></doi><id>0767F6689204C21A242EBC8E6FC5D4CC9D81D477</id><score>0.15817074</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/0767F6689204C21A242EBC8E6FC5D4CC9D81D477/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/0767F6689204C21A242EBC8E6FC5D4CC9D81D477/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/0767F6689204C21A242EBC8E6FC5D4CC9D81D477/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Blackwell Science Ltd</publisher><pubPlace>Oxford, UK</pubPlace><availability><p>WILEY</p></availability><date>2000</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse</title><author xml:id="author-1"><persName><forename type="first">Erwan</forename><surname>Bezard</surname></persName><affiliation>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">Mohamed</forename><surname>Jaber</surname></persName><note type="biography">Present address: INSERM 259, Université Victor Segalen, Rue Camille Saint‐Saëns, BP, 59, 33076 Bordeaux Cedex, France.</note><affiliation>Present address: INSERM 259, Université Victor Segalen, Rue Camille Saint‐Saëns, BP, 59, 33076 Bordeaux Cedex, France.</affiliation><affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">François</forename><surname>Gonon</surname></persName><affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">Alain</forename><surname>Boireau</surname></persName><affiliation>CNS Programme, Rhône‐Poulenc Rorer, CRVA, 13 quai Jules Guesde, 94403 Vitry sur Seine Cedex, France</affiliation></author><author xml:id="author-5"><persName><forename type="first">Bertrand</forename><surname>Bloch</surname></persName><affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation></author><author xml:id="author-6"><persName><forename type="first">Christian E.</forename><surname>Gross</surname></persName><affiliation>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation></author></analytic><monogr><title level="j">European Journal of Neuroscience</title><idno type="pISSN">0953-816X</idno><idno type="eISSN">1460-9568</idno><idno type="DOI">10.1111/(ISSN)1460-9568</idno><imprint><publisher>Blackwell Science Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="2000-08"></date><biblScope unit="volume">12</biblScope><biblScope unit="issue">8</biblScope><biblScope unit="page" from="2892">2892</biblScope><biblScope unit="page" to="2900">2900</biblScope></imprint></monogr><idno type="istex">0767F6689204C21A242EBC8E6FC5D4CC9D81D477</idno><idno type="DOI">10.1046/j.1460-9568.2000.00180.x</idno><idno type="ArticleID">EJN180</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2000</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5‐day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH‐immunoreactive neurons (−70.2%) and striatal dopamine content (−38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>keywords</head><item><term>compensation</term></item><item><term>cytochrome oxidase</term></item><item><term>dopamine transporter</term></item><item><term>immunohistochemistry</term></item><item><term>Parkinson's disease</term></item><item><term>tyrosine hydroxylase</term></item><item><term>voltammetry</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2000-08">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/0767F6689204C21A242EBC8E6FC5D4CC9D81D477/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Science Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1460-9568</doi><issn type="print">0953-816X</issn><issn type="electronic">1460-9568</issn><idGroup><id type="product" value="EJN"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="EUROPEAN JOURNAL OF NEUROSCIENCE">European Journal of Neuroscience</title></titleGroup></publicationMeta><publicationMeta level="part" position="08008"><doi origin="wiley">10.1111/ejn.2000.12.issue-8</doi><numberingGroup><numbering type="journalVolume" number="12">12</numbering><numbering type="journalIssue" number="8">8</numbering></numberingGroup><coverDate startDate="2000-08">August 2000</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="0289200" status="forIssue"><doi origin="wiley">10.1046/j.1460-9568.2000.00180.x</doi><idGroup><id type="unit" value="EJN180"></id></idGroup><countGroup><count type="pageTotal" number="9"></count></countGroup><titleGroup><title type="tocHeading1">Original Articles</title></titleGroup><eventGroup><event type="firstOnline" date="2001-12-24"></event><event type="publishedOnlineFinalForm" date="2001-12-24"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.6 mode:FullText source:Header result:Header" date="2010-04-19"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:4.0.1" date="2014-03-12"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-16"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="2892">2892</numbering><numbering type="pageLast" number="2900">2900</numbering></numberingGroup><correspondenceTo> : Dr E. Bezard, as above.
E‐mail: <email normalForm="erwan.bezard@umr5543.u-bordeaux2.fr">erwan.bezard@umr5543.u‐bordeaux2.fr</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:EJN.EJN180.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received 11 November 1999, revised 4 May 2000, accepted 12 May 2000</unparsedEditorialHistory><countGroup><count type="figureTotal" number="4"></count><count type="tableTotal" number="0"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="55"></count><count type="wordTotal" number="8001"></count><count type="linksPubMed" number="0"></count><count type="linksCrossRef" number="0"></count></countGroup><titleGroup><title type="main">Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse</title><title type="shortAuthors">E. Bezard et al<i>.</i></title><title type="short">Adaptive mechanisms and level of nigral degeneration</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1"><personName><givenNames>Erwan</givenNames><familyName>Bezard</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a2" noteRef="#fn1"><personName><givenNames>Mohamed</givenNames><familyName>Jaber</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a2"><personName><givenNames>François</givenNames><familyName>Gonon</familyName></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a3"><personName><givenNames>Alain</givenNames><familyName>Boireau</familyName></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a2"><personName><givenNames>Bertrand</givenNames><familyName>Bloch</familyName></personName></creator><creator creatorRole="author" xml:id="cr6" affiliationRef="#a1"><personName><givenNames>Christian E.</givenNames><familyName>Gross</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="FR"><unparsedAffiliation>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="FR"><unparsedAffiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</unparsedAffiliation></affiliation><affiliation xml:id="a3" countryCode="FR"><unparsedAffiliation>CNS Programme, Rhône‐Poulenc Rorer, CRVA, 13 quai Jules Guesde, 94403 Vitry sur Seine Cedex, France</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">compensation</keyword><keyword xml:id="k2">cytochrome oxidase</keyword><keyword xml:id="k3">dopamine transporter</keyword><keyword xml:id="k4">immunohistochemistry</keyword><keyword xml:id="k5">Parkinson's disease</keyword><keyword xml:id="k6">tyrosine hydroxylase</keyword><keyword xml:id="k7">voltammetry</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5‐day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH‐immunoreactive neurons (−70.2%) and striatal dopamine content (−38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><label>*</label><p> Present address: INSERM 259, Université Victor Segalen, Rue Camille Saint‐Saëns, BP, 59, 33076 Bordeaux Cedex, France. </p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Adaptive mechanisms and level of nigral degeneration</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Adaptive changes in the nigrostriatal pathway in response to increased 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced neurodegeneration in the mouse</title></titleInfo><name type="personal"><namePart type="given">Erwan</namePart><namePart type="family">Bezard</namePart><affiliation>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mohamed</namePart><namePart type="family">Jaber</namePart><affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation><description>Present address: INSERM 259, Université Victor Segalen, Rue Camille Saint‐Saëns, BP, 59, 33076 Bordeaux Cedex, France.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">François</namePart><namePart type="family">Gonon</namePart><affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alain</namePart><namePart type="family">Boireau</namePart><affiliation>CNS Programme, Rhône‐Poulenc Rorer, CRVA, 13 quai Jules Guesde, 94403 Vitry sur Seine Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bertrand</namePart><namePart type="family">Bloch</namePart><affiliation>Laboratoire d'Histologie‐pathologie, CNRS UMR 5541, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian E.</namePart><namePart type="family">Gross</namePart><affiliation>Basal Gang, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université Victor Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Science Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2000-08</dateIssued><edition>Received 11 November 1999, revised 4 May 2000, accepted 12 May 2000</edition><copyrightDate encoding="w3cdtf">2000</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">4</extent><extent unit="references">55</extent><extent unit="words">8001</extent></physicalDescription><abstract lang="en">Although several adaptive mechanisms have been identified that mask the existence of Parkinson's disease and delay the onset and aggravation of motor symptoms, the timescale and implications of this compensatory process remain an enigma. In order to examine: (i) the nature of the dopaminergic adaptive mechanisms that come into action; (ii) their sequential activation in relation to the severity of degeneration; and (iii) their efficacy with regard to the maintenance of a normal level of basal ganglia activity, we analysed the brains of mice treated daily with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP, 4 mg/kg, i.p.) and killed at 5‐day intervals from day 0 (D0) to D20. Our results demonstrate the sequential activation of two compensatory mechanisms: (i) an increase in striatal tyrosine hydroxylase (TH) protein content attested by the persistence of TH immunolabelling up to D15, contrasting with the decrease observed in both the number of nigral TH‐immunoreactive neurons (−70.2%) and striatal dopamine content (−38.4%); (ii) a downregulation of DA uptake in surviving terminals at D20 (73.4% of nigral degeneration). At this point, the failure of adaptive mechanisms to maintain striatal dopaminergic homeostasis is also illustrated by an increase in the cytochrome oxidase activity of substantia nigra pars reticulata, a marker of neuronal function. It has been postulated that an increase in dopamine release per pulse could constitute an adaptive mechanism. The data we present from our MPTP mice model infirm this hypothesis. This study explores the link between the degree of nigral degeneration and the sequential activation of dopaminergic compensatory mechanisms in the nigrostriatal pathway and, in so doing, proposes a rethink of the paradigm applied to these mechanisms.</abstract><subject lang="en"><genre>keywords</genre><topic>compensation</topic><topic>cytochrome oxidase</topic><topic>dopamine transporter</topic><topic>immunohistochemistry</topic><topic>Parkinson's disease</topic><topic>tyrosine hydroxylase</topic><topic>voltammetry</topic></subject><relatedItem type="host"><titleInfo><title>European Journal of Neuroscience</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0953-816X</identifier><identifier type="eISSN">1460-9568</identifier><identifier type="DOI">10.1111/(ISSN)1460-9568</identifier><identifier type="PublisherID">EJN</identifier><part><date>2000</date><detail type="volume"><caption>vol.</caption><number>12</number></detail><detail type="issue"><caption>no.</caption><number>8</number></detail><extent unit="pages"><start>2892</start><end>2900</end><total>9</total></extent></part></relatedItem><identifier type="istex">0767F6689204C21A242EBC8E6FC5D4CC9D81D477</identifier><identifier type="DOI">10.1046/j.1460-9568.2000.00180.x</identifier><identifier type="ArticleID">EJN180</identifier><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Science Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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