Effect of the metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys

Abstract

Brain glutamate overactivity is well documented in Parkinson's disease (PD) and antiglutamatergic drugs have been proposed to relieve PD symptoms and decrease dyskinesias. Metabotropic glutamate receptors are topics of recent interest in PD. This study investigated the effects of the metabotropic glutamate receptors type 5 (mGluR5) antagonists MPEP and MTEP on motor behavior in monkeys with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion to model PD and treated with l-Dopa the gold standard therapy. Six Macaca fascicularis MPTP monkeys were initially treated repeatedly with l-Dopa; this treatment increased their locomotion and reduced their parkinsonian scores but also induced dyskinesias. Then, a dose–response of MPEP and MTEP (1.5–30 mg/kg) administered 15 and 30 min respectively prior to l-Dopa, showed that the antiparkinsonian activity of l-Dopa was generally maintained as measured with locomotion and antiparkinsonian scores as well as the onset and duration of the l-Dopa response. Interestingly the mean dyskinesia score during all the duration of the l-Dopa motor effect, the 1 h peak period dyskinesias scores as well as the maximal dyskinesias scores were dose-dependently reduced with both drugs reaching statistical significance at 10 and 30 mg/kg. Our results showed a beneficial antidyskinetic effect of blocking mGluR5 in l-Dopa-treated MPTP monkeys. This supports the therapeutic use of an mGluR5 antagonist to restore normal brain glutamate neurotransmission in PD and decrease dyskinesias.

Introduction

The most effective and commonly used treatment for Parkinson disease (PD) is to restore the dopamine (DA) loss with its precursor levodopa (l-Dopa). However, in the long term approximately 80% of l-Dopa treated patients will develop abnormal involuntary movements including l-Dopa-induced dyskinesias (LID) (Stacy et al., 2006, Van Gerpen et al., 2006). Excessive glutamate activity in the basal ganglia plays a critical role in expression of PD symptoms and l-Dopa-induced motor complications (Calon et al., 2003, Gubellini et al., 2006) and the inhibition of its action can alleviate dyskinesias (Chase and Oh, 2000). Antagonists of the ionotropic glutamate receptors have shown antidyskinetic activity in PD patients (Verhagen Metman et al., 1998) and animal models such as the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey (Hadj Tahar et al., 2004). However, these drugs have significant adverse effects such as cognitive impairment in many patients (Stocchi et al., 2008) which significantly limit their use.

The action of glutamate is also mediated through metabotropic glutamate receptors (Meldrum, 2000) a family of G-protein coupled receptors comprising eight subtypes. One subtype, the metabotropic glutamate type 5 (mGluR5) is highly expressed in the striatum. An antagonistic interaction between mGluR5 and D2 DA receptors (Fuxe et al., 2008) as well as a mGlu5 receptor mediated positive modulatory action on the NMDA receptor responses (Pisani et al., 2001) has been described making this receptor an interesting pharmacological target (Conn et al., 2005). Over the past three years, pharmacological antagonism of mGluR5 with the selective antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) was shown to inhibit expression of dyskinesias in the 6-hydroxydopamine (6-OHDA) lesioned rat model of PD (Gravius et al., 2008, Levandis et al., 2008, Mela et al., 2007, Rylander et al., 2009, Yamamoto and Soghomonian, 2009). However, no article is yet published in other PD models including in primate PD models to support the relevance of these interesting rat findings for humans although one group has recently reported in an abstract form the effect of MTEP in monkeys (Johnston et al., 2009a, Johnston et al., 2009b). In addition, mGluR5 specific binding was shown to be increased in the basal ganglia of parkinsonian monkeys that developed dyskinesias following chronic l-Dopa treatment (Samadi et al., 2008). Taken together, these studies suggested that antagonism of mGlu5 receptor may be useful in the treatment of l-Dopa-induced dyskinesias in PD. Therefore, the present study investigated the effect of the pharmacological blockade of mGluR5 with MPEP and MTEP on l-Dopa-induced dyskinesia in MPTP monkeys.