Effect of the metabotropic glutamate receptor type 5 antagonists MPEP and MTEP in parkinsonian monkeys
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.
Section snippets
Animals
Six female ovariectomized cynomolgus monkeys (Macaca fascicularis) weighing between 2.8 and 4.4 kg were used for these experiments. Handling of the primates was performed in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. All procedures, including means to minimize discomfort, were reviewed and approved by the Institutional Animal Care Committee of Laval University. The animals were rendered parkinsonian by continuous infusion of MPTP
Results
l-Dopa administered alone to MPTP monkeys induced a decrease (improvement) of parkinsonian scores; this was maintained with the addition of MPEP at all doses tested (Fig. 1A). Similar decreases (improvement) of parkinsonian scores were obtained with l-Dopa + MTEP, but at the highest doses of 30 mg/kg of MTEP, the mean parkinsonian scores were not significantly reduced. l-Dopa administered alone to MPTP monkeys increased their locomotor activity and this was not changed with the addition of MPEP
Discussion
Involvement of an excessive glutamate transmission in the basal ganglia has been proposed in the pathophysiology of PD and l-Dopa-induced dyskinesias (Bezard et al., 2001, Chase and Oh, 2000). Beneficial effect with ionotropic glutamate receptors antagonists treatment confirmed the role of an excessive glutamatergic transmission in the pathology of parkinsonian symptoms and dyskinesias (Blanchet et al., 2003, Brown et al., 2002), however psychiatric and cognitive impairments limit their
Acknowledgements
This work was supported by a grant from the Canadian Institutes of Health Research to TDP. N.M. holds a studentship from the Fonds de l'Enseignement et de la Recherche (FER) of the Faculty of Pharmacy, Laval University.
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