Antiparkinsonian actions of CP-101,606, an antagonist of NR2B subunit-containing N-methyl-d-aspartate receptors.
In the setting of nigrostriatal dopamine depletion, glutamatergic pathways to the striatum and basal ganglia output nuclei become overactive. Systemically administered glutamate receptor antagonists may have direct antiparkinsonian actions in rodents, but there is little evidence for this in primates. Glutamate antagonists may also potentiate conventional dopaminergic therapies; however, there is concern that broad spectrum, nonselective antagonists may have unwanted side-effects. Because subunit-selective antagonists may avoid these liabilities, we have examined the antiparkinsonian effects of a selective antagonist of the NR2B subunit of the NMDA receptor. In rats, CP-101,606 decreased haloperidol-induced catalepsy with an ED(50) of about 0.5 mg/kg. In MPTP-treated monkeys, CP-101,606 (1 mg/kg) reduced parkinsonian motor symptoms by 20%. At a dose of 0.05 mg/kg, CP-101,606 markedly potentiated the effect of a submaximal dose of levodopa, reducing motor symptoms by about 50% compared to vehicle and by about 30% compared to levodopa alone. No side-effects were apparent at any dose of CP-101,606. We conclude that CP-101,606 has direct antiparkinsonian actions in both rodents and monkeys and it synergistically potentiates levodopa in MPTP-treated monkeys. Clinical evaluation of selective NR2B antagonists may be warranted in Parkinson's disease.
Steece-Collier
K
K
Department of Neuroscience, Finch University of Health Sciences, North Chicago, Illinois 60064, USA.
Chambers
L K
LK
Jaw-Tsai
S S
SS
Menniti
F S
FS
Greenamyre
J T
JT
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D006220:Haloperidol; D007980:Levodopa / Q000627:therapeutic use; D008253:Macaca mulatta; D008297:Male; D010302:Parkinson Disease, Secondary / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C095106:traxoprodil mesylate; D006220:Haloperidol