Toward a primate model of l‐dopa‐unresponsive parkinsonism mimicking striatonigral degeneration
Identifieur interne : 000A38 ( Istex/Corpus ); précédent : 000A37; suivant : 000A39Toward a primate model of l‐dopa‐unresponsive parkinsonism mimicking striatonigral degeneration
Auteurs : Imad Ghorayeb ; Pierre O. Fernagut ; Incarnation Aubert ; Erwan Bezard ; Werner Poewe ; Gregor K. Wenning ; François TisonSource :
- Movement Disorders [ 0885-3185 ] ; 2000-05.
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Abstract
We developed a primate model of striatonigral degeneration (SND), the neuropathology underlying levodopa‐unresponsive parkinsonism associated with multiple systemic atrophy (MSA‐P), by sequential systemic administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and 3‐nitropropionic acid (3NP) in a Macaca fascicularis monkey. l‐Dopa‐responsive parkinsonian features emerged after MPTP injections. Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the l‐dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre‐pro‐enkephalin A‐ and substance P‐containing cells, whereas somatostatin (NADPH‐diaphorase)‐containing interneurons were relatively spared. Our model therefore reproduced levodopa‐unresponsive parkinsonism and SND‐like pathologic changes characteristic of MSA‐P. The double‐lesion primate model of SND may serve as a preclinical test‐bed for the evaluation of novel therapeutic strategies in MSA‐P.
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DOI: 10.1002/1531-8257(200005)15:3<531::AID-MDS1017>3.0.CO;2-C
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Fernagut</name><affiliation><mods:affiliation>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Aubert, Incarnation" sort="Aubert, Incarnation" uniqKey="Aubert I" first="Incarnation" last="Aubert">Incarnation Aubert</name><affiliation><mods:affiliation>CNRS‐UMR 5541, Université Victor Segalen Bordeaux 2, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Bezard, Erwan" sort="Bezard, Erwan" uniqKey="Bezard E" first="Erwan" last="Bezard">Erwan Bezard</name><affiliation><mods:affiliation>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Poewe, Werner" sort="Poewe, Werner" uniqKey="Poewe W" first="Werner" last="Poewe">Werner Poewe</name><affiliation><mods:affiliation>Neurological Research Laboratory, Innsbruck, Austria</mods:affiliation></affiliation></author><author><name sortKey="Wenning, Gregor K" sort="Wenning, Gregor K" uniqKey="Wenning G" first="Gregor K." last="Wenning">Gregor K. Wenning</name><affiliation><mods:affiliation>Neurological Research Laboratory, Innsbruck, Austria</mods:affiliation></affiliation></author><author><name sortKey="Tison, Francois" sort="Tison, Francois" uniqKey="Tison F" first="François" last="Tison">François Tison</name><affiliation><mods:affiliation>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratoire de Neurophysiologie, CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, 146, rue Léo‐Saignat, 33076 Bordeaux Cedex, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="sub">Official Journal of the Movement Disorder Society</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>John Wiley & Sons, Inc.</publisher><pubPlace>New York</pubPlace><date type="published" when="2000-05">2000-05</date><biblScope unit="volume">15</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="531">531</biblScope><biblScope unit="page" to="536">536</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">4D6E85DF3EC76EB51B1CC83F44AD782982A427DB</idno><idno type="DOI">10.1002/1531-8257(200005)15:3<531::AID-MDS1017>3.0.CO;2-C</idno><idno type="ArticleID">MDS1017</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>MPTP—3 nitropropionic acid</term><term>Multiple system atrophy</term><term>Parkinsonism</term><term>Primate model</term><term>Striatonigral degeneration</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">We developed a primate model of striatonigral degeneration (SND), the neuropathology underlying levodopa‐unresponsive parkinsonism associated with multiple systemic atrophy (MSA‐P), by sequential systemic administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and 3‐nitropropionic acid (3NP) in a Macaca fascicularis monkey. l‐Dopa‐responsive parkinsonian features emerged after MPTP injections. Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the l‐dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre‐pro‐enkephalin A‐ and substance P‐containing cells, whereas somatostatin (NADPH‐diaphorase)‐containing interneurons were relatively spared. Our model therefore reproduced levodopa‐unresponsive parkinsonism and SND‐like pathologic changes characteristic of MSA‐P. The double‐lesion primate model of SND may serve as a preclinical test‐bed for the evaluation of novel therapeutic strategies in MSA‐P.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Imad Ghorayeb MD</name><affiliations><json:string>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item><json:item><name>Pierre O. Fernagut BS</name><affiliations><json:string>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item><json:item><name>Incarnation Aubert PhD</name><affiliations><json:string>CNRS‐UMR 5541, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item><json:item><name>Erwan Bezard PhD</name><affiliations><json:string>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item><json:item><name>Werner Poewe MD</name><affiliations><json:string>Neurological Research Laboratory, Innsbruck, Austria</json:string></affiliations></json:item><json:item><name>Gregor K. Wenning MD, PhD</name><affiliations><json:string>Neurological Research Laboratory, Innsbruck, Austria</json:string></affiliations></json:item><json:item><name>François Tison MD, PhD</name><affiliations><json:string>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string><json:string>Laboratoire de Neurophysiologie, CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, 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>Striatonigral degeneration</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MPTP—3 nitropropionic acid</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Multiple system atrophy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinsonism</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Primate model</value></json:item></subject><articleId><json:string>MDS1017</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>We developed a primate model of striatonigral degeneration (SND), the neuropathology underlying levodopa‐unresponsive parkinsonism associated with multiple systemic atrophy (MSA‐P), by sequential systemic administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and 3‐nitropropionic acid (3NP) in a Macaca fascicularis monkey. l‐Dopa‐responsive parkinsonian features emerged after MPTP injections. Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the l‐dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre‐pro‐enkephalin A‐ and substance P‐containing cells, whereas somatostatin (NADPH‐diaphorase)‐containing interneurons were relatively spared. Our model therefore reproduced levodopa‐unresponsive parkinsonism and SND‐like pathologic changes characteristic of MSA‐P. The double‐lesion primate model of SND may serve as a preclinical test‐bed for the evaluation of novel therapeutic strategies in MSA‐P.</abstract><qualityIndicators><score>5.069</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>1433</abstractCharCount><pdfWordCount>3017</pdfWordCount><pdfCharCount>20525</pdfCharCount><pdfPageCount>6</pdfPageCount><abstractWordCount>171</abstractWordCount></qualityIndicators><title>Toward a primate model of l‐dopa‐unresponsive parkinsonism mimicking striatonigral degeneration</title><refBibs><json:item><author><json:item><name>PL Lantos</name></json:item></author><host><volume>57</volume><pages><last>1111</last><first>1099</first></pages><author></author><title>J Neuropathol Exp Neurol</title></host><title>The definition of multiple system atrophy: a review of recent developments</title></json:item><json:item><author><json:item><name>GK 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No. GZ 70038/2‐Pr/4/98);</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Toward a primate model of l‐dopa‐unresponsive parkinsonism mimicking striatonigral degeneration</title><author xml:id="author-1"><persName><forename type="first">Imad</forename><surname>Ghorayeb</surname></persName><roleName type="degree">MD</roleName><affiliation>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">Pierre O.</forename><surname>Fernagut</surname></persName><roleName type="degree">BS</roleName><affiliation>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation></author><author xml:id="author-3"><persName><forename type="first">Incarnation</forename><surname>Aubert</surname></persName><roleName type="degree">PhD</roleName><affiliation>CNRS‐UMR 5541, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation></author><author xml:id="author-4"><persName><forename type="first">Erwan</forename><surname>Bezard</surname></persName><roleName type="degree">PhD</roleName><affiliation>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation></author><author xml:id="author-5"><persName><forename type="first">Werner</forename><surname>Poewe</surname></persName><roleName type="degree">MD</roleName><affiliation>Neurological Research Laboratory, Innsbruck, Austria</affiliation></author><author xml:id="author-6"><persName><forename type="first">Gregor K.</forename><surname>Wenning</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Neurological Research Laboratory, Innsbruck, Austria</affiliation></author><author xml:id="author-7"><persName><forename type="first">François</forename><surname>Tison</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation><affiliation>Laboratoire de Neurophysiologie, CNRS‐UMR 5543, Université Victor Segalen Bordeaux 2, 146, rue Léo‐Saignat, 33076 Bordeaux Cedex, France</affiliation></author></analytic><monogr><title level="j">Movement Disorders</title><title level="j" type="sub">Official Journal of the Movement Disorder Society</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="pISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><idno type="DOI">10.1002/(ISSN)1531-8257</idno><imprint><publisher>John Wiley & Sons, Inc.</publisher><pubPlace>New York</pubPlace><date type="published" when="2000-05"></date><biblScope unit="volume">15</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="531">531</biblScope><biblScope unit="page" to="536">536</biblScope></imprint></monogr><idno type="istex">4D6E85DF3EC76EB51B1CC83F44AD782982A427DB</idno><idno type="DOI">10.1002/1531-8257(200005)15:3<531::AID-MDS1017>3.0.CO;2-C</idno><idno type="ArticleID">MDS1017</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2000</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>We developed a primate model of striatonigral degeneration (SND), the neuropathology underlying levodopa‐unresponsive parkinsonism associated with multiple systemic atrophy (MSA‐P), by sequential systemic administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and 3‐nitropropionic acid (3NP) in a Macaca fascicularis monkey. l‐Dopa‐responsive parkinsonian features emerged after MPTP injections. Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the l‐dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre‐pro‐enkephalin A‐ and substance P‐containing cells, whereas somatostatin (NADPH‐diaphorase)‐containing interneurons were relatively spared. Our model therefore reproduced levodopa‐unresponsive parkinsonism and SND‐like pathologic changes characteristic of MSA‐P. The double‐lesion primate model of SND may serve as a preclinical test‐bed for the evaluation of novel therapeutic strategies in MSA‐P.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>keywords</head><item><term>Striatonigral degeneration</term></item><item><term>MPTP—3 nitropropionic acid</term></item><item><term>Multiple system atrophy</term></item><item><term>Parkinsonism</term></item><item><term>Primate model</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article-category</head><item><term>Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2000-03-16">Received</change><change when="2000-04-05">Registration</change><change when="2000-05">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/4D6E85DF3EC76EB51B1CC83F44AD782982A427DB/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>John Wiley & Sons, Inc.</publisherName><publisherLoc>New York</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1531-8257</doi><issn type="print">0885-3185</issn><issn type="electronic">1531-8257</issn><idGroup><id type="product" value="MDS"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="subtitle">Official Journal of the Movement Disorder Society</title><title type="short">Mov. 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Vienna</fundingAgency><fundingNumber>GZ 70038/2‐Pr/4/98)</fundingNumber></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>We developed a primate model of striatonigral degeneration (SND), the neuropathology underlying levodopa‐unresponsive parkinsonism associated with multiple systemic atrophy (MSA‐P), by sequential systemic administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) and 3‐nitropropionic acid (3NP) in a <i>Macaca fascicularis</i> monkey. <sc>l</sc>‐Dopa‐responsive parkinsonian features emerged after MPTP injections. Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the <sc>l</sc>‐dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre‐pro‐enkephalin A‐ and substance P‐containing cells, whereas somatostatin (NADPH‐diaphorase)‐containing interneurons were relatively spared. Our model therefore reproduced levodopa‐unresponsive parkinsonism and SND‐like pathologic changes characteristic of MSA‐P. 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Subsequent chronic 3NP administration aggravated the motor symptoms and abolished the l‐dopa response. In vivo magnetic resonance imaging revealed bilateral striatal lesions. Histopathologically, there was severe dopaminergic cell loss in the substantia nigra pars compacta compared with the control monkey. Furthermore, we observed circumscribed areas of severe neuronal degeneration in the motor striatum. These changes were absent in the control monkey, and they were associated with diffuse metabolic failure as demonstrated by cytochrome oxidase histochemistry. The striatal pathology predominantly involved output pre‐pro‐enkephalin A‐ and substance P‐containing cells, whereas somatostatin (NADPH‐diaphorase)‐containing interneurons were relatively spared. Our model therefore reproduced levodopa‐unresponsive parkinsonism and SND‐like pathologic changes characteristic of MSA‐P. The double‐lesion primate model of SND may serve as a preclinical test‐bed for the evaluation of novel therapeutic strategies in MSA‐P.</abstract><note type="funding">Association France Parkinson, Institut Lilly, Conseil Général d'Aquitaine, Bundesministerium für Wissenschaft und Verkehr, Vienna - No. GZ 70038/2‐Pr/4/98); </note><subject lang="en"><genre>keywords</genre><topic>Striatonigral degeneration</topic><topic>MPTP—3 nitropropionic acid</topic><topic>Multiple system atrophy</topic><topic>Parkinsonism</topic><topic>Primate model</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title><subTitle>Official Journal of the Movement Disorder Society</subTitle></titleInfo><titleInfo type="abbreviated"><title>Mov. 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