Antiparkinsonian Actions of CP-101,606, an Antagonist of NR2B Subunit-Containing N-Methyl-d-Aspartate Receptors
Autor: | Sarah S. Jaw-Tsai, Kathy Steece-Collier, Frank S. Menniti, J. Timothy Greenamyre, Leslie K. Chambers |
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Rok vydání: | 2000 |
Předmět: |
Male
medicine.medical_specialty Levodopa Dopamine Agents Striatum Catalepsy Receptors N-Methyl-D-Aspartate Antiparkinson Agents chemistry.chemical_compound Piperidines Developmental Neuroscience Internal medicine Reaction Time medicine Animals Parkinson Disease Secondary Behavior Animal Dose-Response Relationship Drug business.industry MPTP Dopaminergic Antagonist Glutamate receptor Drug Synergism medicine.disease Macaca mulatta Rats Inbred F344 Rats Endocrinology Neurology chemistry 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine Dopamine Antagonists Haloperidol NMDA receptor Drug Therapy Combination Female business Excitatory Amino Acid Antagonists medicine.drug |
Zdroj: | Experimental Neurology. 163:239-243 |
ISSN: | 0014-4886 |
DOI: | 10.1006/exnr.2000.7374 |
Popis: | 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. |
Databáze: | OpenAIRE |
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