A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys.
Neurobiology of Disease. 2010-09-01; 39(3): 352-361
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1. Neurobiol Dis. 2010 Sep;39(3):352-61. doi: 10.1016/j.nbd.2010.05.001. Epub 2010
A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia
in parkinsonian rats and monkeys.
Rylander D(1), Iderberg H, Li Q, Dekundy A, Zhang J, Li H, Baishen R, Danysz W,
Bezard E, Cenci MA.
(1)Basal Ganglia Pathophysiology Unit, Department of Experimental Medical
Science, Lund University, BMC F11, Lund, Sweden.
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.
PMID: 20452425 [Indexed for MEDLINE]