Toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes.
Toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes.
复制标题
DOI：
--
复制
发表时间：
1992-04
期刊：
影响因子：
--
通讯作者：
D. Monte;E. Wu;L. Delanney;I. Irwin;J. Langston
中科院分区：
文献类型：
--
作者：
D. Monte;E. Wu;L. Delanney;I. Irwin;J. Langston
B 型单胺氧化酶 (MAO) 催化下 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 转化为有毒的 1-甲基-4-苯基吡啶鎓 (MPP+) 代谢物很可能发生在中枢神经系统的胶质细胞内。在这项研究中，使用小鼠星形胶质细胞的原代培养物来评估暴露于 MPTP 的生化和毒性后果。 MPTP 导致细胞活力的浓度依赖性丧失。这种效应可能是由于细胞内 MPP+ 的产生，因为在 MAO 抑制剂存在的情况下预孵育星形胶质细胞可防止细胞毒性。添加 250 microM MPTP 后，细胞活力丧失之前，葡萄糖利用率和乳酸积累率增加，并且 ATP 耗尽。乳酸产生速率 (0.37 mM/hr) 和葡萄糖消耗速率 (0.2 mM/hr) 之间的比率为 1.85，表明培养基中存在的大部分葡萄糖通过糖酵解按化学计量转化为乳酸。我们发现 ATP 消耗和 MPTP 引起的细胞毒性之间存在显着相关性，并且当星形胶质细胞在无葡萄糖培养基中孵育时，ATP 消耗和活力丧失发生得更快。最后，即使在暴露数天后，通过从培养介质中清洗 MPTP 也可以防止星形胶质细胞死亡，这表明 MPP(+) 诱导的线粒体损伤可能是可逆的。我们得出的结论是，星形胶质细胞长时间暴露于 MPTP 可能会通过 MAO 依赖性 MPP+ 的产生而导致活力丧失，并且这种有毒代谢物会损害线粒体功能。（摘要截断为 250 字）
The conversion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to its toxic 1-methyl-4-phenylpyridinium (MPP+) metabolite catalyzed by monoamine oxidase (MAO) type B is likely to occur within glial cells in the central nervous system. In this study, primary cultures of mouse astrocytes were used to assess the biochemical and toxic consequences of exposure to MPTP. MPTP caused a concentration-dependent loss of cell viability. This effect was probably due to the intracellular generation of MPP+, because cytotoxicity was prevented by preincubation of astrocytes in the presence of MAO inhibitors. After addition of 250 microM MPTP, loss of cell viability was preceded by an increased rate of glucose utilization and lactate accumulation, and by depletion of ATP. The ratio between the rates of lactate production (0.37 mM/hr) and glucose consumption (0.2 mM/hr) was 1.85, indicating that most of the glucose present in the medium was stoichiometrically converted to lactate via glycolysis. A remarkable correlation was found between ATP depletion and cytotoxicity caused by MPTP, and, when astrocytes were incubated in glucose-free medium, both ATP depletion and loss of viability occurred more rapidly. Finally, even after exposure for several days, astrocyte death could be prevented by washing MPTP from the incubation medium, suggesting that MPP(+)-induced mitochondrial damage may be reversible. We conclude that prolonged exposure of astrocytes to MPTP may result in loss of viability via the MAO-dependent generation of MPP+ and the ability of this toxic metabolite to impair mitochondrial function.(ABSTRACT TRUNCATED AT 250 WORDS)