Pai K S, Ravindranath V
Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
Brain Res. 1991 Aug 2;555(2):239-44. doi: 10.1016/0006-8993(91)90347-x.
Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes loss of dopaminergic neurons in humans, primates and mice. Exposure of sagittal slices of mouse brain to MPTP (100 pM) caused inhibition of mitochondrial NADH-dehydrogenase activity. Leakage of lactate dehydrogenase from the slice into the medium was observed following incubation of slices with 1 nM MPTP. Neurotoxicity induced by MPTP was prevented by prior exposure of the slices to the dopamine uptake inhibitor GBR 12935. Deprenyl and pargyline (inhibitors of monoamine oxidase), also protected the slices from MPTP-induced toxicity. However, both pargyline and deprenyl also inhibited cytochrome P-450 mediated aminopyrine N-demethylase activity in brain slices. Pargyline, when administered in vivo to mice, decreased brain cytochrome P-450 levels significantly. Other cytochrome P-450 inhibitors, namely, piperonyl butoxide and SKF 525A were found to offer protection against MPTP induced neurotoxicity in slices without affecting monoamine oxidase activity. MPTP toxicity was potentiated significantly in brain slices prepared from mice pretreated with phenobarbital, an inducer of cytochrome P-450. The present study suggests the possible involvement of cytochrome P-450 in MPTP-induced neurotoxicity, in vitro, in brain slices.
接触1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）会导致人类、灵长类动物和小鼠体内多巴胺能神经元的丧失。将小鼠脑矢状切片暴露于MPTP（100 pM）会导致线粒体NADH脱氢酶活性受到抑制。在用1 nM MPTP孵育切片后，观察到乳酸脱氢酶从切片泄漏到培养基中。切片预先暴露于多巴胺摄取抑制剂GBR 12935可预防MPTP诱导的神经毒性。司来吉兰和帕吉林（单胺氧化酶抑制剂）也可保护切片免受MPTP诱导的毒性。然而，帕吉林和司来吉兰也会抑制脑切片中细胞色素P-450介导的氨基比林N-脱甲基酶活性。当在体内给小鼠施用帕吉林时，会显著降低脑内细胞色素P-450水平。发现其他细胞色素P-450抑制剂，即胡椒基丁醚和SKF 525A可在不影响单胺氧化酶活性的情况下，保护切片免受MPTP诱导的神经毒性。在用细胞色素P-450诱导剂苯巴比妥预处理的小鼠制备的脑切片中，MPTP毒性显著增强。本研究表明，在体外脑切片中，细胞色素P-450可能参与MPTP诱导的神经毒性。
