Antiparkinsonian effect of a new selective adenosine A(2A) receptor antagonist in MPTP-treated monkeys

Background: Chronic treatment with L-3,4-dihydroxyphenylalanine (L-dopa) is often associated with motor side effects in PD patients. The search for ne w therapeutic approaches has led to study the role of other neuromodulators including adenosine. Among the four adenosine receptors characterized so f ar, the A(2A) subtype is distinctively present on striatopallidal output ne urons containing enkephalin and mainly bearing dopamine (DA) D-2 receptors (indirect pathway). Studies in DA-denervated rats suggest that blockade of adenosine A(2A) receptors might be used in PD. Objective: To evaluate the a ntiparkinsonian effect of a new selective adenosine A(2A) receptor antagoni st, KW-6002, in 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treate d monkeys. Methods: In the present study, we used six MPTP-exposed cynomolg us monkeys already primed and exhibiting L-dopa-induced dyskinesias to eval uate both the antiparkinsonian and dyskinetic effect upon challenge with tw o oral doses (60 and 90 mg/kg) of KW-6002 administered alone or in combinat ion with L-dopa/benserazide (50/12.5 mg). Results: KW-6002 administered alo ne produced a dose-dependent antiparkinsonian response that reached the lev el of efficacy of L-dopa/benserazide but was less likely to reproduce dyski nesias in these animals. When co-administered, KW-6002 potentiated the effe cts of L-dopa/benserazide on motor activity (up to 30%) without affecting t he dyskinetic response. Conclusion: Adenosine A(2A) receptor antagonists ha ve antiparkinsonian effects of their own with a reduced propensity to elici t dyskinesias. They might therefore be useful agents in the treatment of PD .