Reduction of L-DOPA-induced dyskinesia by the selective metabotropic glutamate receptor 5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.
Identifieur interne : 001996 ( Main/Exploration ); précédent : 001995; suivant : 001997Reduction of L-DOPA-induced dyskinesia by the selective metabotropic glutamate receptor 5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease.
Auteurs : Tom H. Johnston [Canada] ; Susan H. Fox ; Matthew J. Mcildowie ; Matthew J. Piggott ; Jonathan M. BrotchieSource :
- The Journal of pharmacology and experimental therapeutics [ 1521-0103 ] ; 2010.
English descriptors
- KwdEn :
- Animals, Antiparkinson Agents (toxicity), Behavior, Animal (drug effects), Dyskinesia, Drug-Induced (physiopathology), Dyskinesia, Drug-Induced (prevention & control), Female, Levodopa (antagonists & inhibitors), Levodopa (toxicity), MPTP Poisoning (prevention & control), Macaca fascicularis, Male, Motor Activity (drug effects), Parkinson Disease, Secondary (chemically induced), Parkinson Disease, Secondary (physiopathology), Parkinson Disease, Secondary (prevention & control), Piperidines (pharmacokinetics), Piperidines (therapeutic use), Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate (antagonists & inhibitors), Thiazoles (pharmacokinetics), Thiazoles (therapeutic use).
- MESH :
- chemical , antagonists & inhibitors : Levodopa, Receptors, Metabotropic Glutamate.
- chemical , pharmacokinetics : Piperidines, Thiazoles.
- chemical , therapeutic use : Piperidines, Thiazoles.
- chemical , toxicity : Antiparkinson Agents, Levodopa.
- chemically induced : Parkinson Disease, Secondary.
- drug effects : Behavior, Animal, Motor Activity.
- physiopathology : Dyskinesia, Drug-Induced, Parkinson Disease, Secondary.
- prevention & control : Dyskinesia, Drug-Induced, MPTP Poisoning, Parkinson Disease, Secondary.
- Animals, Female, Macaca fascicularis, Male, Receptor, Metabotropic Glutamate 5.
Abstract
Long-term motor complications of dopamine replacement, such as L-DOPA-induced dyskinesia (LID) and reduced quality of L-DOPA action, remain obstacles in the treatment of Parkinson's disease. Dysfunctional glutamatergic neurotransmitter systems have been observed in both the untreated parkinsonian and dyskinetic states and represent novel targets for treatment. Here, we assess the pharmacokinetic profile and corresponding pharmacodynamic effects on behavior of the orally active, selective metabotropic glutamate receptor type 5 (mGlu5) antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (as the hydrochloride salt) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. Six parkinsonian, MPTP-lesioned cynomolgus monkeys, with established LID, were administered acute challenges with MTEP (4.5-36 mg/kg p.o.) or vehicle, either alone or in combination with L-DOPA (33 +/- 1 mg/kg p.o.). Motor activity, parkinsonian disability, and dyskinesia were assessed for a 6-h period. Plasma drug levels were assessed by liquid chromatography-tandem mass spectrometry. MTEP had no antiparkinsonian action as monotherapy. However, administration of L-DOPA in combination with MTEP (36 mg/kg) reduced peak dose LID by 96%. Moreover, although total on-time (duration for which L-DOPA exerted an antiparkinsonian effect) was not significantly reduced, MTEP (36 mg/kg) reduced the duration of on-time with disabling LID by 70% compared with that for L-DOPA alone. These effects were associated with a peak plasma concentration of 20.9 microM and an area under the curve from 0 to 24 h of 136.1 h x microM (36 mg/kg). Although total on-time was not reduced, the peak antiparkinsonian benefit of l-DOPA/MTEP (36 mg/kg) was less than that with L-DOPA alone. Selective mGlu5 inhibitors may have significant potential to ameliorate dyskinesia, but care should be taken to ensure that such effects do not come at the expense of the peak antiparkinsonian benefit of L-DOPA.
DOI: 10.1124/jpet.110.166629
PubMed: 20231306
Affiliations:
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Le document en format XML
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Fox</name></author><author><name sortKey="Mcildowie, Matthew J" sort="Mcildowie, Matthew J" uniqKey="Mcildowie M" first="Matthew J" last="Mcildowie">Matthew J. Mcildowie</name></author><author><name sortKey="Piggott, Matthew J" sort="Piggott, Matthew J" uniqKey="Piggott M" first="Matthew J" last="Piggott">Matthew J. Piggott</name></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. 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Johnston</name><affiliation wicri:level="1"><nlm:affiliation>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Ontario, Canada. tom.johnston@uhnresearch.ca</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H" last="Fox">Susan H. Fox</name></author><author><name sortKey="Mcildowie, Matthew J" sort="Mcildowie, Matthew J" uniqKey="Mcildowie M" first="Matthew J" last="Mcildowie">Matthew J. Mcildowie</name></author><author><name sortKey="Piggott, Matthew J" sort="Piggott, Matthew J" uniqKey="Piggott M" first="Matthew J" last="Piggott">Matthew J. Piggott</name></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name></author></analytic><series><title level="j">The Journal of pharmacology and experimental therapeutics</title><idno type="eISSN">1521-0103</idno><imprint><date when="2010" type="published">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiparkinson Agents (toxicity)</term><term>Behavior, Animal (drug effects)</term><term>Dyskinesia, Drug-Induced (physiopathology)</term><term>Dyskinesia, Drug-Induced (prevention & control)</term><term>Female</term><term>Levodopa (antagonists & inhibitors)</term><term>Levodopa (toxicity)</term><term>MPTP Poisoning (prevention & control)</term><term>Macaca fascicularis</term><term>Male</term><term>Motor Activity (drug effects)</term><term>Parkinson Disease, Secondary (chemically induced)</term><term>Parkinson Disease, Secondary (physiopathology)</term><term>Parkinson Disease, Secondary (prevention & control)</term><term>Piperidines (pharmacokinetics)</term><term>Piperidines (therapeutic use)</term><term>Receptor, Metabotropic Glutamate 5</term><term>Receptors, Metabotropic Glutamate (antagonists & inhibitors)</term><term>Thiazoles (pharmacokinetics)</term><term>Thiazoles (therapeutic use)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Levodopa</term><term>Receptors, Metabotropic Glutamate</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Piperidines</term><term>Thiazoles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Piperidines</term><term>Thiazoles</term></keywords><keywords scheme="MESH" type="chemical" qualifier="toxicity" xml:lang="en"><term>Antiparkinson Agents</term><term>Levodopa</term></keywords><keywords scheme="MESH" qualifier="chemically induced" xml:lang="en"><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Behavior, Animal</term><term>Motor Activity</term></keywords><keywords scheme="MESH" qualifier="physiopathology" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Dyskinesia, Drug-Induced</term><term>MPTP Poisoning</term><term>Parkinson Disease, Secondary</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Female</term><term>Macaca fascicularis</term><term>Male</term><term>Receptor, Metabotropic Glutamate 5</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Long-term motor complications of dopamine replacement, such as L-DOPA-induced dyskinesia (LID) and reduced quality of L-DOPA action, remain obstacles in the treatment of Parkinson's disease. Dysfunctional glutamatergic neurotransmitter systems have been observed in both the untreated parkinsonian and dyskinetic states and represent novel targets for treatment. Here, we assess the pharmacokinetic profile and corresponding pharmacodynamic effects on behavior of the orally active, selective metabotropic glutamate receptor type 5 (mGlu5) antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (as the hydrochloride salt) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. Six parkinsonian, MPTP-lesioned cynomolgus monkeys, with established LID, were administered acute challenges with MTEP (4.5-36 mg/kg p.o.) or vehicle, either alone or in combination with L-DOPA (33 +/- 1 mg/kg p.o.). Motor activity, parkinsonian disability, and dyskinesia were assessed for a 6-h period. Plasma drug levels were assessed by liquid chromatography-tandem mass spectrometry. MTEP had no antiparkinsonian action as monotherapy. However, administration of L-DOPA in combination with MTEP (36 mg/kg) reduced peak dose LID by 96%. Moreover, although total on-time (duration for which L-DOPA exerted an antiparkinsonian effect) was not significantly reduced, MTEP (36 mg/kg) reduced the duration of on-time with disabling LID by 70% compared with that for L-DOPA alone. These effects were associated with a peak plasma concentration of 20.9 microM and an area under the curve from 0 to 24 h of 136.1 h x microM (36 mg/kg). Although total on-time was not reduced, the peak antiparkinsonian benefit of l-DOPA/MTEP (36 mg/kg) was less than that with L-DOPA alone. Selective mGlu5 inhibitors may have significant potential to ameliorate dyskinesia, but care should be taken to ensure that such effects do not come at the expense of the peak antiparkinsonian benefit of L-DOPA.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H" last="Fox">Susan H. Fox</name><name sortKey="Mcildowie, Matthew J" sort="Mcildowie, Matthew J" uniqKey="Mcildowie M" first="Matthew J" last="Mcildowie">Matthew J. Mcildowie</name><name sortKey="Piggott, Matthew J" sort="Piggott, Matthew J" uniqKey="Piggott M" first="Matthew J" last="Piggott">Matthew J. Piggott</name></noCountry><country name="Canada"><noRegion><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H" last="Johnston">Tom H. Johnston</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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