Pramipexole inhibits MPTP toxicity in mice by dopamine D3 receptor dependent and independent mechanisms

被引:55
作者
Ramirez, AD [1 ]
Wong, SKF [1 ]
Menniti, FS [1 ]
机构
[1] CNS Discovery, Pfizer Global Res & Dev, Groton, CT 06340 USA
关键词
Parkinson's disease; MPTP; pramipcxole; dopamine D-3 receptor;
D O I
10.1016/s0014-2999(03)02087-9
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The role of dopamine D3 receptors was investigated in mediating the neuroprotective effect of the dopamine D2/D3 receptor agonist (S)-2-amino-4,5,6,7-tetrahydro-6-propylamine-benzothiazole (pramipexole) in vivo. Pramipexole retained the ability to inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in mice in which the dopamine D3 receptor had been deleted. However, the neuroprotective efficacy was reduced in the dopamine D3 receptor-deleted mice compared to that in littermates expressing the wildtype receptor. Furthermore, the dopamine D3 receptor selective antagonist 2-{3-[4-(2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl]propylthio}-4-pyrimidinol (A-437203) partially inhibited the neuroprotective effect of pramipexole in dopamine D3 receptor expressing mice but not in receptor-deleted mice. These results indicate that pramipexole protects dopamine neurons from MPTP-induced toxicity by mechanisms that are both dependent and independent of an interaction with dopamine D3 receptors. (C) 2003 Elsevier B.V All rights reserved.
引用
收藏
页码:29 / 35
页数:7
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