The acute antiparkinsonian and antidyskinetic effect of AFQ056, a novel metabotropic glutamate receptor type 5 antagonist, in L-Dopa-treated parkinsonian monkeys.

Abstract

Overactivity of glutamatergic transmission has been implicated in Parkinson's disease (PD) and levodopa (L-Dopa)-induced dyskinesias. Striatal metabotropic glutamate receptors type 5 (mGluR5) are abundant and provide specific targets to modulate glutamatergic activity. This study investigated the acute effects of the novel mGluR5 antagonist AFQ056 on motor behavior in L-Dopa-treated monkeys with a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion to model PD. Six Macaca fascicularis MPTP monkeys were treated repeatedly with L-Dopa; this treatment increased their locomotion and reduced their parkinsonian scores, but also induced dyskinesias. When AFQ056 (doses of 5, 25, 125 or 250mg/kg) was administered one hour prior to a high dose of L-Dopa, the antiparkinsonian activity of L-Dopa was maintained as measured with locomotion and antiparkinsonian scores, whereas dyskinesias were significantly reduced at 25, 125 and 250mg/kg AFQ056 for peak dyskinesia score and at 125 and 250mg/kg for the 1h peak period of dyskinesia score. Administration of AFQ056 one hour before L-Dopa led to peak or elevated plasma AFQ056 concentrations occurring close to L-Dopa peak-dose dyskinesias. We next investigated AFQ056 25mg/kg combined with a low dose of L-Dopa. The antiparkinsonian activity of L-Dopa was increased as measured with locomotion, while dyskinesias remained low at these doses. Our results show a beneficial motor effect of AFQ056 with L-Dopa in MPTP monkeys. This supports the therapeutic use of an mGluR5 antagonist to restore normal glutamatergic neurotransmission in PD and decrease dyskinesias.

• Authors: Laurent Grégoire, Nicolas Morin, Bazoumana Ouattara, Fabrizio Gasparini, Graeme Bilbe, Donald Johns, Ivo Vranesic, Srikumar Sahasranaman, Baltazar Gomez-Mancilla, Thérèse Di Paolo
• Journal: Parkinsonism & related disorders (Parkinsonism Relat Disord) Vol. 17 Issue 4 Pg. 270-6 (May 2011) ISSN: 1873-5126 [Electronic] England
• PMID: 21315648 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Antiparkinson Agents
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate
• Levodopa

Topics

• Animals
• Antiparkinson Agents (adverse effects)
• Disease Models, Animal
• Dyskinesia, Drug-Induced (prevention & control)
• Female
• Levodopa (adverse effects)
• Macaca fascicularis
• Parkinsonian Disorders (drug therapy)
• Receptor, Metabotropic Glutamate 5
• Receptors, Metabotropic Glutamate (antagonists & inhibitors)