title: Combined fenobam and amantadine treatment promotes robust antidyskinetic effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate model of Parkinson's disease.
abstract: Amantadine, an N-methyl-D-aspartate glutamate receptor antagonist, is currently the only pharmacological treatment for levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but causes adverse effects on the central nervous system at therapeutic doses. Fenobam, a negative modulator of metabotropic glutamate receptor subtype 5, has recently been reported to attenuate LID in MPTP-treated macaques. The aim of the current study was to investigate the treatment interactions of fenobam and amantadine on LID in the MPTP-treated macaque model of PD. The antidyskinetic and -parkinsonian effects were measured after administration of fenobam (10-30 mg/kg) and amantadine (10-30 mg/kg) alone and in combination. Fenobam (30 mg/kg) and amantadine (30 mg/kg) alone reduced LID, whereas lower doses of either drug did not cause any significant effects. A combined treatment of fenobam and amantadine at subthreshold doses (10 and 20 mg/kg) significantly reduced LID without worsening PD disability. These data suggest that a low-dose combination of fenobam and amantadine can be used for alleviating dyskinesia without causing adverse motor effects. Such combined therapies may offer a new therapeutic strategy for treatment of LID in PD patients.
authors.affiliation: Motac Neuroscience Ltd, Manchester, United Kingdom; Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
authors.forename: Wai Kin D
authors.initials: WK
authors.lastname: Ko
authors.forename: Elsa
authors.initials: E
authors.lastname: Pioli
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.forename: Steve
authors.initials: S
authors.lastname: McGuire
authors.forename: Audrey
authors.initials: A
authors.lastname: Dufour
authors.forename: Todd B
authors.initials: TB
authors.lastname: Sherer
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
authors.forename: Maurizio F
authors.initials: MF
authors.lastname: Facheris
mesh_terms: D000547:Amantadine / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects; D020267:MPTP Poisoning / Q000188:drug therapy; D008252:Macaca fascicularis
chemical_list: D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; C032794:fenobam; D007980:Levodopa; D000547:Amantadine
keywords: Parkinson; dyskinesia; mGluR5 antagonist; macaque