MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates.
Identifieur interne : 000D42 ( Main/Exploration ); précédent : 000D41; suivant : 000D43MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates.
Auteurs : Nicolas Morin [Canada] ; Laurent Grégoire ; Marc Morissette ; Sandrine Desrayaud ; Baltazar Gomez-Mancilla ; Fabrizio Gasparini ; Thérèse Di PaoloSource :
- Neuropharmacology [ 1873-7064 ] ; 2013.
English descriptors
- KwdEn :
- Animals, Antiparkinson Agents (pharmacology), Antiparkinson Agents (therapeutic use), Disease Models, Animal, Dopamine (metabolism), Dopamine Plasma Membrane Transport Proteins (metabolism), Drug Administration Schedule, Dyskinesia, Drug-Induced (drug therapy), Dyskinesia, Drug-Induced (metabolism), Dyskinesia, Drug-Induced (prevention & control), Excitatory Amino Acid Antagonists (pharmacology), Excitatory Amino Acid Antagonists (therapeutic use), Female, Levodopa (antagonists & inhibitors), Macaca fascicularis, Oximes (pharmacology), Parkinsonian Disorders (drug therapy), Parkinsonian Disorders (metabolism), Putamen (drug effects), Putamen (metabolism), Pyridines (administration & dosage), Pyridines (pharmacokinetics), Pyridines (pharmacology), Pyridines (therapeutic use), Radioligand Assay (methods), Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate (antagonists & inhibitors), Receptors, Metabotropic Glutamate (metabolism).
- MESH :
- chemical , administration & dosage : Pyridines.
- chemical , antagonists & inhibitors : Levodopa, Receptors, Metabotropic Glutamate.
- chemical , metabolism : Dopamine, Dopamine Plasma Membrane Transport Proteins, Receptors, Metabotropic Glutamate.
- chemical , pharmacokinetics : Pyridines.
- chemical , pharmacology : Antiparkinson Agents, Excitatory Amino Acid Antagonists, Oximes, Pyridines.
- chemical , therapeutic use : Antiparkinson Agents, Excitatory Amino Acid Antagonists, Pyridines.
- drug effects : Putamen.
- drug therapy : Dyskinesia, Drug-Induced, Parkinsonian Disorders.
- metabolism : Dyskinesia, Drug-Induced, Parkinsonian Disorders, Putamen.
- methods : Radioligand Assay.
- prevention & control : Dyskinesia, Drug-Induced.
- Animals, Disease Models, Animal, Drug Administration Schedule, Female, Macaca fascicularis, Receptor, Metabotropic Glutamate 5.
Abstract
L-3,4-Dihydroxyphenylalanine (l-DOPA), the gold standard therapy for Parkinson disease (PD), is associated with motor fluctuations and dyskinesias. This study sought to prevent the development of l-DOPA-induced dyskinesias (LID) with the metabotropic glutamate receptor type 5 (mGlu5 receptor) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in the de novo treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a PD model. MPTP-lesioned monkeys were treated once daily for one month with either l-DOPA or l-DOPA + MPEP (10 mg/kg). MPEP (administered 15 min before l-DOPA) plasma concentrations were elevated during all the l-DOPA motor activation and did not accumulate during a month. The antiparkinsonian effect was maintained throughout the treatment period in MPTP-lesioned monkeys treated with l-DOPA + MPEP, while the duration of this effect decreased over time in MPTP-lesioned monkeys treated with l-DOPA alone, suggesting wearing-off. Over the month-long treatment, the mean dyskinesia score increased in l-DOPA-treated monkeys; interestingly, this increase was reduced by overall 72% in the l-DOPA + MPEP group. Mean dyskinesia scores of monkeys correlated inversely with plasma MPEP concentrations. Normal control and saline-treated MPTP-lesioned monkeys were also included for biochemical analyses. All MPTP-lesioned monkeys were extensively and similarly denervated. [(3)H]ABP688 specific binding to mGlu5 receptors increased in the putamen of l-DOPA-treated monkeys compared to control, saline or l-DOPA + MPEP-treated monkeys. Mean dyskinesia scores of MPTP-lesioned monkeys correlated positively with [(3)H]ABP688 specific binding in the putamen. This study showed a beneficial chronic antidyskinetic effect of MPEP in de novol-DOPA-treated MPTP-lesioned monkeys, supporting the therapeutic use of mGlu5 receptor antagonists in PD to prevent LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.
DOI: 10.1016/j.neuropharm.2012.07.036
PubMed: 22884464
Affiliations:
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Le document en format XML
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5</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">L-3,4-Dihydroxyphenylalanine (l-DOPA), the gold standard therapy for Parkinson disease (PD), is associated with motor fluctuations and dyskinesias. This study sought to prevent the development of l-DOPA-induced dyskinesias (LID) with the metabotropic glutamate receptor type 5 (mGlu5 receptor) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in the de novo treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as a PD model. MPTP-lesioned monkeys were treated once daily for one month with either l-DOPA or l-DOPA + MPEP (10 mg/kg). MPEP (administered 15 min before l-DOPA) plasma concentrations were elevated during all the l-DOPA motor activation and did not accumulate during a month. The antiparkinsonian effect was maintained throughout the treatment period in MPTP-lesioned monkeys treated with l-DOPA + MPEP, while the duration of this effect decreased over time in MPTP-lesioned monkeys treated with l-DOPA alone, suggesting wearing-off. Over the month-long treatment, the mean dyskinesia score increased in l-DOPA-treated monkeys; interestingly, this increase was reduced by overall 72% in the l-DOPA + MPEP group. Mean dyskinesia scores of monkeys correlated inversely with plasma MPEP concentrations. Normal control and saline-treated MPTP-lesioned monkeys were also included for biochemical analyses. All MPTP-lesioned monkeys were extensively and similarly denervated. [(3)H]ABP688 specific binding to mGlu5 receptors increased in the putamen of l-DOPA-treated monkeys compared to control, saline or l-DOPA + MPEP-treated monkeys. Mean dyskinesia scores of MPTP-lesioned monkeys correlated positively with [(3)H]ABP688 specific binding in the putamen. This study showed a beneficial chronic antidyskinetic effect of MPEP in de novol-DOPA-treated MPTP-lesioned monkeys, supporting the therapeutic use of mGlu5 receptor antagonists in PD to prevent LID. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Desrayaud, Sandrine" sort="Desrayaud, Sandrine" uniqKey="Desrayaud S" first="Sandrine" last="Desrayaud">Sandrine Desrayaud</name><name sortKey="Di Paolo, Therese" sort="Di Paolo, Therese" uniqKey="Di Paolo T" first="Thérèse" last="Di Paolo">Thérèse Di Paolo</name><name sortKey="Gasparini, Fabrizio" sort="Gasparini, Fabrizio" uniqKey="Gasparini F" first="Fabrizio" last="Gasparini">Fabrizio Gasparini</name><name sortKey="Gomez Mancilla, Baltazar" sort="Gomez Mancilla, Baltazar" uniqKey="Gomez Mancilla B" first="Baltazar" last="Gomez-Mancilla">Baltazar Gomez-Mancilla</name><name sortKey="Gregoire, Laurent" sort="Gregoire, Laurent" uniqKey="Gregoire L" first="Laurent" last="Grégoire">Laurent Grégoire</name><name sortKey="Morissette, Marc" sort="Morissette, Marc" uniqKey="Morissette M" first="Marc" last="Morissette">Marc Morissette</name></noCountry><country name="Canada"><noRegion><name sortKey="Morin, Nicolas" sort="Morin, Nicolas" uniqKey="Morin N" first="Nicolas" last="Morin">Nicolas Morin</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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