title: MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates.
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'.
authors.affiliation: Molecular Endocrinology and Genomic Research Center, Laval University Medical Center (CHUQ), Quebec, QC, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Morin
authors.forename: Laurent
authors.initials: L
authors.lastname: Grégoire
authors.forename: Marc
authors.initials: M
authors.lastname: Morissette
authors.forename: Sandrine
authors.initials: S
authors.lastname: Desrayaud
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007980:Levodopa / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D010091:Oximes / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism*; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay / Q000379:methods; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D000978:Antiparkinson Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D018691:Excitatory Amino Acid Antagonists; D010091:Oximes; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D007980:Levodopa; C121465:6-methyl-2-(phenylethynyl)pyridine; D004298:Dopamine