MPEP, an mGlu5 receptor antagonist, reduces the development of L-DOPA-induced motor complications in de novo parkinsonian monkeys: Biochemical correlates

作者：Morin Nicolas; Gregoire Laurent; Morissette Marc; Desrayaud Sandrine; Gomez Mancilla Baltazar; Gasparini Fabrizio; Di Paolo Therese^*

来源：Neuropharmacology, 2013, 66: 355-364.

DOI：10.1016/j.neuropharm.2012.07.036

• mGlu5 receptor
• Dyskinesia
• L-DOPA
• MPTP-lesioned monkey
• MPEP

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 nova 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 MPTP-lesioned 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. [H-3]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 [H-3]ABP688 specific binding in the putamen. This study showed a beneficial chronic antidyskinetic effect of MPEP in de novo L-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'.

• 出版日期2013-3