We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rapidly induced cytopathological changes in the brain, involving some neurons selectively, as well as astrocytes and blood vessels. Dopaminergic neurons in the midbrain, as identified by immunostaining for tyrosine hydroxylase, were damaged as early as 2.5 hr after MPTP administration. Ultrastructurally, there was disruption of the endoplasmic reticulum and cytoplasmic condensation and vacuolation of the tyrosine hydroxylase reactive neurons in the substantia nigra as well as their axon terminals in the striatum. Perivascular edema was associated with vacuolation and swelling of astrocytic cytoplasm and rupture of perivascular foot processes. There was also capillary and arteriolar endothelial damage. Surprisingly, there was no clear correlation of MPTP-induced pathology with mitochondrial damage in any cell type. Biochemically, dopamine was depleted in the substantia nigra and the striatum within a few hours following MPTP administration. However, in the substantia nigra, homovanillic acid (HVA), one of the metabolites of dopamine, showed relatively less depletion than did dopamine by MPTP. These results may indicate that the turnover of dopamine was stimulated in the brain as a homeostatic mechanism.

译文

:我们发现1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)迅速诱导大脑的细胞病理变化,选择性地涉及一些神经元以及星形胶质细胞和血管。通过对酪氨酸羟化酶进行免疫染色鉴定,中脑中的多巴胺能神经元最早于MPTP给药后2.5小时被破坏。在超微结构中,黑质及其纹状体中轴突末端的内质网破裂和胞浆缩合,酪氨酸羟化酶反应性神经元空泡化。血管周围水肿与星形胶质细胞质的空泡化和肿胀以及血管周围足突的破裂有关。还存在毛细血管和小动脉内皮损伤。出人意料的是,在任何细胞类型中,MPTP诱导的病理学与线粒体损伤均无明显关联。生化方面,在MPTP给药后数小时内,黑质和纹状体中的多巴胺被消耗掉。但是,在黑质中,多巴胺的代谢产物之一高香草酸(HVA)的耗竭量比MPTP的多巴胺要少。这些结果可能表明,多巴胺的更新是作为稳态机制在大脑中被刺激的。

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