title: 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.affiliation: Molecular Endocrinology and Genomic Research Center, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, 2705 Laurier Blvd., Quebec, QC, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Grégoire
authors.forename: Nicolas
authors.initials: N
authors.lastname: Morin
authors.forename: Bazoumana
authors.initials: B
authors.lastname: Ouattara
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.forename: Graeme
authors.initials: G
authors.lastname: Bilbe
authors.forename: Donald
authors.initials: D
authors.lastname: Johns
authors.forename: Ivo
authors.initials: I
authors.lastname: Vranesic
authors.forename: Srikumar
authors.initials: S
authors.lastname: Sahasranaman
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000517:prevention & control*; D005260:Female; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
chemical_list: D000978:Antiparkinson Agents; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D007980:Levodopa