A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys.
L-DOPA remains the gold-standard treatment for Parkinson's disease but causes motor fluctuations and dyskinesia. Metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for antidyskinetic therapies. Here, we evaluate the effects of fenobam, a noncompetitive mGluR5 antagonist already tested in humans, using rodent and nonhuman primate models of Parkinson's disease. In both animal models, acute administration of fenobam attenuated the L-DOPA-induced abnormal involuntary movements (50-70% reduction at the doses of 30mg/kg in rats and 10mg/kg in monkeys). The effect consisted in a reduction of peak-dose dyskinesia, whereas the end-dose phase was not affected. Chronic administration of fenobam to previously drug-naïve animals (de novo treatment) attenuated the development of peak-dose dyskinesia without compromising the anti-parkinsonian effect of L-DOPA. In addition, fenobam prolonged the motor stimulant effect of L-DOPA. We conclude that fenobam acts similarly in rat and primate models of L-DOPA-induced dyskinesia and represents a good candidate for antidyskinetic treatment in Parkinson's disease.
Rylander
Daniella
D
Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Science, Lund University, BMC F11, Lund, Sweden.
Iderberg
Hanna
H
Li
Qin
Q
Dekundy
Andrzej
A
Zhang
Jinlan
J
Li
Hao
H
Baishen
Ren
R
Danysz
Wojciech
W
Bezard
Erwan
E
Cenci
M Angela
MA
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D007980:Levodopa / Q000009:adverse effects*; D008253:Macaca mulatta; D008297:Male; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D018094:Receptors, Metabotropic Glutamate; C032794:fenobam; D007980:Levodopa; D016627:Oxidopamine