Effect of a selective glutamate antagonist on L-dopa-induced dyskinesias in drug-naive parkinsonian monkeys.
Alterations of striatal glutamate receptors are believed to be responsible, at least in part, for the pathogenesis of L-dopa-induced dyskinesias (LID). To evaluate whether co-administration of CI-1041, a novel NMDA receptor antagonist selective for the NR1A/NR2B subtype, with L-dopa might prevent the appearance of this side effect, eight de novo parkinsonian monkeys were treated chronically orally with either L-dopa alone or L-dopa plus CI-1041 (n= 4 for each group). After 4 weeks of treatment with L-dopa alone, all four animals developed moderate dyskinesias either choreic or dystonic in nature. CI-1041 co-treatment completely prevented the induction of dyskinesias in three animals and only one monkey developed mild dyskinesias at the end of the fourth week of treatment in the L-dopa + CI-1041 group. The magnitude and duration of the antiparkinsonian action of L-dopa was similar in both groups. These results suggest that selective NMDA receptor antagonism may be interesting for managing LID in Parkinson's disease patients.
Neuroscience Research Unit (RC 9800), CHUL, Laval University Research Center, Ste-Foy, Québec, Canada G1V 4G2.
Abdallah
A
Hadj Tahar
Laurent
L
Grégoire
Aurélie
A
Darré
Nancy
N
Bélanger
Leonard
L
Meltzer
Paul J
PJ
Bédard
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D008252:Macaca fascicularis; D010300:Parkinson Disease / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
D001583:Benzoxazoles; D018691:Excitatory Amino Acid Antagonists; C473649:NR1A NMDA receptor, rat; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D007980:Levodopa; C481484:besonprodil