The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson's disease
Identifieur interne : 002C97 ( Main/Exploration ); précédent : 002C96; suivant : 002C98The NR2B-selective NMDA receptor antagonist CP-101,606 exacerbates L-DOPA-induced dyskinesia and provides mild potentiation of anti-parkinsonian effects of L-DOPA in the MPTP-lesioned marmoset model of Parkinson's disease
Auteurs : J. E. Nash [Canada] ; P. Ravenscroft [Royaume-Uni] ; S. Mcguire [Royaume-Uni] ; A. R. Crossman [Royaume-Uni] ; F. S. Menniti [États-Unis] ; J. M. Brotchie [Canada]Source :
- Experimental neurology : (Print) [ 0014-4886 ] ; 2004.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
In Parkinson's disease (PD), degeneration of the dopaminergic nigrostriatal pathway leads to enhanced transmission at NMDA receptors containing NR2B subunits. Previous studies have shown that some, but not all, NR2B-containing NMDA receptor antagonists alleviate parkinsonian symptoms in animal models of PD. Furthermore, enhanced NMDA receptor-mediated transmission underlies the generation of L-DOPA-induced dyskinesia (LID). The subunit content of NMDA receptors responsible for LID is not clear. Here, we assess the actions of the NMDA antagonist CP-101,606 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease. CP-101,606 is selective for NMDA receptors containing NR2B subunits, with higher affinity for NR1/NR2B complexes compared to ternary NR1/NR2A/NR2B complexes. CP-101,606 had no significant effect on parkinsonian symptoms when administered as monotherapy over a range of doses (0.1 - 10 mg/kg). CP-101,606 provided a modest potentiation of the anti-parkinsonian actions of L-DOPA (8 mg/kg), although, at doses of 1 and 3 mg/kg, CP-101,606 exacerbated LID. Results of this study provide further evidence of differences in the anti-parkinsonian activity and effects on LID of the NR2B subunit selective NMDA receptor antagonists. These distinctions may reflect disparities in action on NR1/NR2B as opposed to NR1/NR2A/NR2B receptors.
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E." last="Nash">J. E. Nash</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Toronto Western Research Institute</s1><s2>Toronto, ON, M5T 2S8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto Western Research Institute</wicri:noRegion></affiliation></author><author><name sortKey="Ravenscroft, P" sort="Ravenscroft, P" uniqKey="Ravenscroft P" first="P." last="Ravenscroft">P. Ravenscroft</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Motac Neuroscience Ltd</s1><s2>Manchester, M15 6SE</s2><s3>GBR</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Motac Neuroscience Ltd</wicri:noRegion></affiliation></author><author><name sortKey="Mcguire, S" sort="Mcguire, S" uniqKey="Mcguire S" first="S." last="Mcguire">S. Mcguire</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Motac Neuroscience Ltd</s1><s2>Manchester, M15 6SE</s2><s3>GBR</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Motac Neuroscience Ltd</wicri:noRegion></affiliation></author><author><name sortKey="Crossman, A R" sort="Crossman, A R" uniqKey="Crossman A" first="A. R." last="Crossman">A. R. Crossman</name><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Motac Neuroscience Ltd</s1><s2>Manchester, M15 6SE</s2><s3>GBR</s3><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Motac Neuroscience Ltd</wicri:noRegion></affiliation><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>School of Biological Sciences, University of Manchester</s1><s2>Manchester, M13 9PT</s2><s3>GBR</s3><sZ>4 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Manchester</settlement><region type="nation">Angleterre</region><region nuts="2" type="region">Grand Manchester</region></placeName><orgName type="university">Université de Manchester</orgName></affiliation></author><author><name sortKey="Menniti, F S" sort="Menniti, F S" uniqKey="Menniti F" first="F. S." last="Menniti">F. S. Menniti</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>CNS Discovery, Pfizer Global Research and Development</s1><s2>Groton, CT 06340</s2><s3>USA</s3><sZ>5 aut.</sZ></inist:fA14><country>États-Unis</country><wicri:noRegion>Groton, CT 06340</wicri:noRegion></affiliation></author><author><name sortKey="Brotchie, J M" sort="Brotchie, J M" uniqKey="Brotchie J" first="J. M." last="Brotchie">J. M. Brotchie</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Toronto Western Research Institute</s1><s2>Toronto, ON, M5T 2S8</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>6 aut.</sZ></inist:fA14><country>Canada</country><wicri:noRegion>Toronto Western Research Institute</wicri:noRegion></affiliation></author></analytic><series><title level="j" type="main">Experimental neurology : (Print)</title><title level="j" type="abbreviated">Exp. neurol. : (Print)</title><idno type="ISSN">0014-4886</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Experimental neurology : (Print)</title><title level="j" type="abbreviated">Exp. neurol. : (Print)</title><idno type="ISSN">0014-4886</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animal model</term><term>Biological receptor</term><term>Degeneration</term><term>Dopaminergic pathway</term><term>Dyskinesia</term><term>Levodopa</term><term>Motor control</term><term>NMDA</term><term>NMDA receptor</term><term>Nigrostriatal pathway</term><term>Parkinson disease</term><term>Potentiation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Dyskinésie</term><term>Récepteur NMDA</term><term>Lévodopa</term><term>Parkinson maladie</term><term>Potentialisation</term><term>Modèle animal</term><term>Dégénérescence</term><term>Voie dopaminergique</term><term>Voie nigrostriatale</term><term>NMDA</term><term>Récepteur biologique</term><term>Contrôle moteur</term><term>Sousunité NR2B</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">In Parkinson's disease (PD), degeneration of the dopaminergic nigrostriatal pathway leads to enhanced transmission at NMDA receptors containing NR2B subunits. Previous studies have shown that some, but not all, NR2B-containing NMDA receptor antagonists alleviate parkinsonian symptoms in animal models of PD. Furthermore, enhanced NMDA receptor-mediated transmission underlies the generation of L-DOPA-induced dyskinesia (LID). The subunit content of NMDA receptors responsible for LID is not clear. Here, we assess the actions of the NMDA antagonist CP-101,606 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease. CP-101,606 is selective for NMDA receptors containing NR2B subunits, with higher affinity for NR1/NR2B complexes compared to ternary NR1/NR2A/NR2B complexes. CP-101,606 had no significant effect on parkinsonian symptoms when administered as monotherapy over a range of doses (0.1 - 10 mg/kg). CP-101,606 provided a modest potentiation of the anti-parkinsonian actions of L-DOPA (8 mg/kg), although, at doses of 1 and 3 mg/kg, CP-101,606 exacerbated LID. Results of this study provide further evidence of differences in the anti-parkinsonian activity and effects on LID of the NR2B subunit selective NMDA receptor antagonists. These distinctions may reflect disparities in action on NR1/NR2B as opposed to NR1/NR2A/NR2B receptors.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Grand Manchester</li></region><settlement><li>Manchester</li></settlement><orgName><li>Université de Manchester</li></orgName></list><tree><country name="Canada"><noRegion><name sortKey="Nash, J E" sort="Nash, J E" uniqKey="Nash J" first="J. E." last="Nash">J. E. Nash</name></noRegion><name sortKey="Brotchie, J M" sort="Brotchie, J M" uniqKey="Brotchie J" first="J. M." last="Brotchie">J. M. Brotchie</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Ravenscroft, P" sort="Ravenscroft, P" uniqKey="Ravenscroft P" first="P." last="Ravenscroft">P. Ravenscroft</name></noRegion><name sortKey="Crossman, A R" sort="Crossman, A R" uniqKey="Crossman A" first="A. R." last="Crossman">A. R. Crossman</name><name sortKey="Crossman, A R" sort="Crossman, A R" uniqKey="Crossman A" first="A. R." last="Crossman">A. R. Crossman</name><name sortKey="Mcguire, S" sort="Mcguire, S" uniqKey="Mcguire S" first="S." last="Mcguire">S. Mcguire</name></country><country name="États-Unis"><noRegion><name sortKey="Menniti, F S" sort="Menniti, F S" uniqKey="Menniti F" first="F. S." last="Menniti">F. S. Menniti</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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