Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model
Identifieur interne : 000261 ( Istex/Corpus ); précédent : 000260; suivant : 000262Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model
Auteurs : Donato A. Di Monte ; Alison Mccormack ; Giselle Petzinger ; Ann Marie Janson ; Maryka Quik ; William J. LangstonSource :
- Movement Disorders [ 0885-3185 ] ; 2000-05.
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- KwdEn :
Abstract
Presynaptic denervation is likely to play an important role in the pathophysiology of dyskinesias that develop after levodopa administration to patients with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa‐induced involuntary movements were compared in squirrel monkeys lesioned with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Animals treated with a regimen of MPTP that caused parkinsonism displayed ≥95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake sites, and 70% nigral neuronal loss. Levodopa administration ameliorated the parkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%–70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 40% loss of dopaminergic nigral neurons. While these monkeys displayed no behavioral signs of parkinsonism, they all became dyskinetic after levodopa administration. The priming effect of levodopa, that is, the recurrence of dyskinesias in animals previously exposed to the drug, was compared in severely versus mildly lesioned monkeys. When severely injured parkinsonian animals underwent a second cycle of levodopa treatment, they immediately and consistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa‐induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures.
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DOI: 10.1002/1531-8257(200005)15:3<459::AID-MDS1006>3.0.CO;2-3
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<titleGroup><title type="main" xml:lang="en">Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model</title>
<title type="short" xml:lang="en">Nigrostriatal Denervation and Dyskinesias</title>
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<creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Alison</givenNames>
<familyName>McCormack</familyName>
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<creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Giselle</givenNames>
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<creator xml:id="au4" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Ann Marie</givenNames>
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<familyName>Quik</familyName>
<degrees>PhD</degrees>
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<creator xml:id="au6" creatorRole="author" affiliationRef="#af1"><personName><givenNames>William J.</givenNames>
<familyName>Langston</familyName>
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<keyword xml:id="kwd2">Dyskinesias</keyword>
<keyword xml:id="kwd3">Levodopa</keyword>
<keyword xml:id="kwd4">Dopamine</keyword>
<keyword xml:id="kwd5">MPTP</keyword>
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<fundingInfo><fundingAgency>NINDS</fundingAgency>
<fundingNumber>NS34886‐01A2</fundingNumber>
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<fundingInfo><fundingAgency>Lookout Fund Foundation</fundingAgency>
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<fundingInfo><fundingAgency>Mylan Pharmaceuticals</fundingAgency>
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<fundingInfo><fundingAgency>Swedish Medical Research Council</fundingAgency>
<fundingNumber>10816</fundingNumber>
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<fundingInfo><fundingAgency>Karolinska Institute Foundation</fundingAgency>
</fundingInfo>
<fundingInfo><fundingAgency>Kapten Arthur Eriksson, King Gustaf V and Queen Victoria Foundation</fundingAgency>
</fundingInfo>
<fundingInfo><fundingAgency>Fredrik and Ingrid Thuring Foundation</fundingAgency>
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<abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title>
<p>Presynaptic denervation is likely to play an important role in the pathophysiology of dyskinesias that develop after levodopa administration to patients with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa‐induced involuntary movements were compared in squirrel monkeys lesioned with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Animals treated with a regimen of MPTP that caused parkinsonism displayed ≥95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake sites, and 70% nigral neuronal loss. Levodopa administration ameliorated the parkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%–70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 40% loss of dopaminergic nigral neurons. While these monkeys displayed no behavioral signs of parkinsonism, they all became dyskinetic after levodopa administration. The priming effect of levodopa, that is, the recurrence of dyskinesias in animals previously exposed to the drug, was compared in severely versus mildly lesioned monkeys. When severely injured parkinsonian animals underwent a second cycle of levodopa treatment, they immediately and consistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa‐induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures.</p>
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<name type="personal"><namePart type="given">Donato A.</namePart>
<namePart type="family">Di Monte</namePart>
<namePart type="termsOfAddress">MD</namePart>
<affiliation>The Parkinson's Institute, Sunnyvale, California, USA</affiliation>
<description>Correspondence: The Parkinson's Institute, 1170 Morse Avenue, Sunnyvale, CA 94089‐1605, U.S.A.</description>
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<name type="personal"><namePart type="given">Alison</namePart>
<namePart type="family">McCormack</namePart>
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<affiliation>Department of Neuroscience, Karolinska Institute, Stockholm, Sweden</affiliation>
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<name type="personal"><namePart type="given">Ann Marie</namePart>
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<affiliation>The Parkinson's Institute, Sunnyvale, California, USA</affiliation>
<affiliation>Department of Neuroscience, Karolinska Institute, Stockholm, Sweden</affiliation>
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<name type="personal"><namePart type="given">Maryka</namePart>
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<affiliation>The Parkinson's Institute, Sunnyvale, California, USA</affiliation>
<role><roleTerm type="text">author</roleTerm>
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<name type="personal"><namePart type="given">William J.</namePart>
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<abstract lang="en">Presynaptic denervation is likely to play an important role in the pathophysiology of dyskinesias that develop after levodopa administration to patients with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa‐induced involuntary movements were compared in squirrel monkeys lesioned with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Animals treated with a regimen of MPTP that caused parkinsonism displayed ≥95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake sites, and 70% nigral neuronal loss. Levodopa administration ameliorated the parkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%–70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 40% loss of dopaminergic nigral neurons. While these monkeys displayed no behavioral signs of parkinsonism, they all became dyskinetic after levodopa administration. The priming effect of levodopa, that is, the recurrence of dyskinesias in animals previously exposed to the drug, was compared in severely versus mildly lesioned monkeys. When severely injured parkinsonian animals underwent a second cycle of levodopa treatment, they immediately and consistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa‐induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures.</abstract>
<note type="funding">NINDS - No. NS34886‐01A2; </note>
<note type="funding">Retirement Research Foundation</note>
<note type="funding">Lookout Fund Foundation</note>
<note type="funding">Mylan Pharmaceuticals</note>
<note type="funding">Swedish Medical Research Council - No. 10816; </note>
<note type="funding">Karolinska Institute Foundation</note>
<note type="funding">Kapten Arthur Eriksson, King Gustaf V and Queen Victoria Foundation</note>
<note type="funding">Fredrik and Ingrid Thuring Foundation</note>
<subject lang="en"><genre>Keywords</genre>
<topic>Parkinson's disease</topic>
<topic>Dyskinesias</topic>
<topic>Levodopa</topic>
<topic>Dopamine</topic>
<topic>MPTP</topic>
<topic>Monkeys</topic>
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<relatedItem type="host"><titleInfo><title>Movement Disorders</title>
<subTitle>Official Journal of the Movement Disorder Society</subTitle>
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<identifier type="ISSN">0885-3185</identifier>
<identifier type="eISSN">1531-8257</identifier>
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<identifier type="PublisherID">MDS</identifier>
<part><date>2000</date>
<detail type="volume"><caption>vol.</caption>
<number>15</number>
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<accessCondition type="use and reproduction" contentType="copyright">Copyright © 2000 Movement Disorder Society</accessCondition>
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