Rollema H, Kuhr W G, Kranenborg G, De Vries J, Van den Berg C
Department of Medicinal Chemistry, State University Groningen, The Netherlands.
J Pharmacol Exp Ther. 1988 Jun;245(3):858-66.
Perfusion of rat striatum with 10 mM 1-methyl-4-phenylpyridinium (MPP+) during 1 min caused a rapid reversible increase in dopamine (DA) efflux (maximal after 4 min) that was similar to the effects of 1 or 15 min 10 mM amphetamine. A massive, prolonged, and irreversible release of DA occurred after 15 min 10 mM MPP+, showing a biphasic trend: the rapid amphetamine-like increase was followed by a slower and larger DA efflux, reaching its maximum after 25 min. One minute perfusions with 1-100 mM MPP+ caused a gradual increase in the overflow of striatal lactate, reaching a maximum effect after 20-30 min. The similarity between the time courses of the MPP+-induced efflux of DA and lactate suggests that both effects are probably consequences of inhibition of aerobic glycolysis by MPP+. A comparison with the courses of DA and lactate efflux after death of control rats showed a delay of several minutes before the toxic effects of MPP+ become apparent. These in vivo data are consistent with the hypothesis that MPP+ accumulates and then kills dopaminergic cells, possibly by the irreversible inhibition of mitochondrial respiration.
用10 mM 1-甲基-4-苯基吡啶鎓（MPP+）灌注大鼠纹状体1分钟会导致多巴胺（DA）流出迅速可逆增加（4分钟后达到最大值），这与10 mM苯丙胺1分钟或15分钟的作用相似。在10 mM MPP+灌注15分钟后，出现了大量、持久且不可逆的DA释放，呈现双相趋势：先是类似苯丙胺的快速增加，随后是较慢且更大的DA流出，在25分钟后达到最大值。用1 - 100 mM MPP+灌注1分钟会导致纹状体乳酸溢出逐渐增加，在20 - 30分钟后达到最大效应。MPP+诱导的DA和乳酸流出的时间进程相似，表明这两种效应可能都是MPP+抑制有氧糖酵解的结果。与对照大鼠死亡后DA和乳酸流出进程的比较显示，在MPP+的毒性作用显现之前有几分钟的延迟。这些体内数据与MPP+积累然后杀死多巴胺能细胞的假设一致，可能是通过对线粒体呼吸的不可逆抑制来实现的。
