Article ID Journal Published Year Pages File Type
4315188 Behavioural Brain Research 2008 10 Pages PDF
Abstract

Recent evidence indicates that adenosine A2A receptor antagonists hold therapeutic potential for the treatment of Parkinson's disease (PD). A study on the novel adenosine A1 and A2A receptor dual antagonist 5-[5-amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854) showed it to be effective in various rodents models of PD and cognition. In the present study, we further investigated the potential of ASP5854 as an anti-PD drug using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, which is a highly predictive model of clinical efficacy in PD, and compared its effect with those of existing anti-PD drugs. ASP5854 significantly and dose-dependently improved the total motor disability score for 7 h at doses higher than 1 mg/kg, and significantly increased total locomotor activity at doses higher than 0.1 mg/kg without adverse effects. l-3,4-Dihydroxyphenylalanine + benserazide and bromocriptine also significantly improved the motor disability score and the hypolocomotion caused by MPTP treatment in a dose-dependent fashion. This amelioration was significant at 32 + 8 and 10–32 mg/kg, respectively, although bromocriptine induced severe emesis. Trihexiphenidyl also significantly improved the total motor disability score at doses of 10–32 mg/kg; however, while a significant increase in the total locomotor activity was observed at 10 mg/kg, the drug induced ataxia-like behavior at 32 mg/kg. On the other hand, neither selegiline nor amantadine improved the total motor disability and hypolocomotion. These data substantiate the evidence that the novel adenosine antagonist ASP5854 exerts comparable anti-PD activity with existing anti-PD drugs, which indicates that ASP5854 might have potential to ameliorate motor deficits in PD.

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