Effect of kynurenine 3‐hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in parkinsonian monkeys
Identifieur interne : 000934 ( Istex/Corpus ); précédent : 000933; suivant : 000935Effect of kynurenine 3‐hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in parkinsonian monkeys
Auteurs : Pershia Samadi ; Laurent Grégoire ; Arash Rassoulpour ; Paolo Guidetti ; Emanuela Izzo ; Robert Schwarcz ; Paul J. BédardSource :
- Movement Disorders [ 0885-3185 ] ; 2005-07.
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- KwdEn :
Abstract
Homeostatic interactions between dopamine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa‐induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID. To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3‐hydroxylase inhibitor Ro 61‐8048, which raises KYNA levels acutely. Ro 61‐8048 was tested in MPTP cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias after each dose of levodopa. Serum and CSF concentrations of KYNA and its precursor kynurenine increased dose‐dependently after Ro 61‐8048 administration, alone or in combination with levodopa. Coadministration of Ro 61‐8048 with levodopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. These results suggest that elevation of KYNA levels through inhibition of kynurenine 3‐hydroxylase constitutes a promising novel approach for managing LID in Parkinson's disease. © 2005 Movement Disorder Society
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DOI: 10.1002/mds.20596
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This relationship is altered in Parkinsonism and in levodopa‐induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID. To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3‐hydroxylase inhibitor Ro 61‐8048, which raises KYNA levels acutely. Ro 61‐8048 was tested in MPTP cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias after each dose of levodopa. Serum and CSF concentrations of KYNA and its precursor kynurenine increased dose‐dependently after Ro 61‐8048 administration, alone or in combination with levodopa. Coadministration of Ro 61‐8048 with levodopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. 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PhD</degrees></personName><contactDetails><email>paul.bedard@crchul.ulaval.ca</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="CA" type="organization"><unparsedAffiliation>Centre de Recherche en Neurosciences, Centre Hospitalier Universitaire de Québec, Québec, Canada</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="CA" type="organization"><unparsedAffiliation>Département de Medicine, Université Laval, Québec, Canada</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="US" type="organization"><unparsedAffiliation>Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="IT" type="organization"><unparsedAffiliation>Newron Pharmaceuticals, Bresso, Italy</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">dyskinesia</keyword><keyword xml:id="kwd2">glutamate</keyword><keyword xml:id="kwd3">kynurenic acid</keyword><keyword xml:id="kwd4">MPTP</keyword><keyword xml:id="kwd5">Parkinson's disease</keyword></keywordGroup><fundingInfo><fundingAgency>Newron Pharmaceuticals</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Canadian Institute of Health Research</fundingAgency></fundingInfo><fundingInfo><fundingAgency>le Fonds de la Recherche en Santé du Québec</fundingAgency></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Homeostatic interactions between dopamine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa‐induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID. To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3‐hydroxylase inhibitor Ro 61‐8048, which raises KYNA levels acutely. Ro 61‐8048 was tested in MPTP cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias after each dose of levodopa. Serum and CSF concentrations of KYNA and its precursor kynurenine increased dose‐dependently after Ro 61‐8048 administration, alone or in combination with levodopa. Coadministration of Ro 61‐8048 with levodopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. These results suggest that elevation of KYNA levels through inhibition of kynurenine 3‐hydroxylase constitutes a promising novel approach for managing LID in Parkinson's disease. © 2005 Movement Disorder Society</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><!--Version 0.6 générée le 4-12-2015--><mods version="3.6"><titleInfo lang="en"><title>Effect of kynurenine 3‐hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in parkinsonian monkeys</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Kynurenine 3‐Hydroxylase Inhibition</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Effect of kynurenine 3‐hydroxylase inhibition on the dyskinetic and antiparkinsonian responses to levodopa in parkinsonian monkeys</title></titleInfo><name type="personal"><namePart type="given">Pershia</namePart><namePart type="family">Samadi</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Centre de Recherche en Neurosciences, Centre Hospitalier Universitaire de Québec, Québec, Canada</affiliation><affiliation>Département de Medicine, Université Laval, Québec, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Laurent</namePart><namePart type="family">Grégoire</namePart><namePart type="termsOfAddress">BSc</namePart><affiliation>Centre de Recherche en Neurosciences, Centre Hospitalier Universitaire de Québec, Québec, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Arash</namePart><namePart type="family">Rassoulpour</namePart><namePart type="termsOfAddress">BSc</namePart><affiliation>Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paolo</namePart><namePart type="family">Guidetti</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Emanuela</namePart><namePart type="family">Izzo</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Newron Pharmaceuticals, Bresso, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert</namePart><namePart type="family">Schwarcz</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul J.</namePart><namePart type="family">Bédard</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Centre de Recherche en Neurosciences, Centre Hospitalier Universitaire de Québec, Québec, Canada</affiliation><affiliation>Département de Medicine, Université Laval, Québec, Canada</affiliation><description>Correspondence: Centre de Recherche en Neurosciences, Le Centre Hospitalier Universitaire de Québec, CHUL RC‐9800, 2705 Boulevard Laurier, Québec, Canada, G1V4G2</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre authority="originalCategForm">article</genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2005-07</dateIssued><dateCaptured encoding="w3cdtf">2004-08-20</dateCaptured><dateValid encoding="w3cdtf">2004-12-02</dateValid><copyrightDate encoding="w3cdtf">2005</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">7</extent><extent unit="tables">1</extent><extent unit="references">66</extent><extent unit="words">6783</extent></physicalDescription><abstract lang="en">Homeostatic interactions between dopamine and glutamate are central to the normal physiology of the basal ganglia. This relationship is altered in Parkinsonism and in levodopa‐induced dyskinesias (LID), resulting in an upregulation of corticostriatal glutamatergic function. Kynurenic acid (KYNA), a tryptophan metabolite with antagonist activity at ionotropic glutamate receptors and the capability to inhibit glutamate release presynaptically, might therefore be of therapeutic value in LID. To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3‐hydroxylase inhibitor Ro 61‐8048, which raises KYNA levels acutely. Ro 61‐8048 was tested in MPTP cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias after each dose of levodopa. Serum and CSF concentrations of KYNA and its precursor kynurenine increased dose‐dependently after Ro 61‐8048 administration, alone or in combination with levodopa. Coadministration of Ro 61‐8048 with levodopa produced a moderate but significant reduction in the severity of dyskinesias while maintaining the motor benefit. These results suggest that elevation of KYNA levels through inhibition of kynurenine 3‐hydroxylase constitutes a promising novel approach for managing LID in Parkinson's disease. © 2005 Movement Disorder Society</abstract><note type="funding">Newron Pharmaceuticals</note><note type="funding">Canadian Institute of Health Research</note><note type="funding">le Fonds de la Recherche en Santé du Québec</note><subject lang="en"><genre>Keywords</genre><topic>dyskinesia</topic><topic>glutamate</topic><topic>kynurenic acid</topic><topic>MPTP</topic><topic>Parkinson's disease</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. Disord.</title></titleInfo><subject><genre>article category</genre><topic>Research Article</topic></subject><identifier type="ISSN">0885-3185</identifier><identifier type="eISSN">1531-8257</identifier><identifier type="DOI">10.1002/(ISSN)1531-8257</identifier><identifier type="PublisherID">MDS</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>20</number></detail><detail type="issue"><caption>no.</caption><number>7</number></detail><extent unit="pages"><start>792</start><end>802</end><total>11</total></extent></part></relatedItem><identifier type="istex">256B7C33FBCE6776065D822ED459000FF7F568DA</identifier><identifier type="DOI">10.1002/mds.20596</identifier><identifier type="ArticleID">MDS20596</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2005 Movement Disorder Society</accessCondition><recordInfo><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin><recordContentSource>WILEY</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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