A novel adenosine A(1) and A(2A) receptor antagonist ASP5854 ameliorates motor impairment in MPTP-treated marmosets: comparison with existing anti-Parkinson's disease drugs.
Recent evidence indicates that adenosine A(2A) receptor antagonists hold therapeutic potential for the treatment of Parkinson's disease (PD). A study on the novel adenosine A(1) and A(2A) 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 7h at doses higher than 1mg/kg, and significantly increased total locomotor activity at doses higher than 0.1mg/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 10mg/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.
Mihara
Takuma
T
Department of Neuroscience, Pharmacology Research Labs, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. takuma.mihara@jp.astellas.com
Iwashita
Akinori
A
Matsuoka
Nobuya
N
D000631:Aminopyridines / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D002144:Callithrix; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020267:MPTP Poisoning / Q000139:chemically induced / Q000150:complications*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009069:Movement Disorders / Q000188:drug therapy* / Q000209:etiology*; D010879:Piperazines / Q000627:therapeutic use*; D058914:Purinergic Antagonists; D013997:Time Factors
C524699:5-(5-amino-3-(4-fluorophenyl)pyrazin-2-yl)-1-isopropylprydine-2(1H)-one; D000631:Aminopyridines; D000978:Antiparkinson Agents; D010879:Piperazines; D058914:Purinergic Antagonists