Sawada H, Shimohama S, Tamura Y, Kawamura T, Akaike A, Kimura J
Department of Neurology, Kyoto University, Japan.
J Neurosci Res. 1996 Jan 1;43(1):55-62. doi: 10.1002/jnr.490430107.
Parkinson's disease is characterized by chronic progression of dopaminergic neuronal death, the mechanism of which is still unknown. Although methyl-4-phenylpyridium ion (MPP+) or MPP(+)-like substance, that can reduce mitochondrial complex I activity, is supposed to be a causative agent for Parkinson's disease, it is difficult to explain the chronic neuronal degeneration for years. It is important to identify other putative agents capable of causing chronic cell death besides MPP+. We hypothesized that treatment with small doses of MPP+, not causing severe damage to dopaminergic neurons but merely reducing the activity of mitochondrial complex I, can be a model of Parkinson's disease, and that glutamate can be a putative agent causing chronic neuronal degeneration. Using primary culture of the rat mesencephalon, we investigated glutamate-induced cytotoxicity against dopaminergic and non-dopaminergic neurons with or without the pretreatment with MPP+. Brief exposure to glutamate showed similar cytotoxicity against both dopaminergic and non-dopaminergic neurons. An N-methyl-D-aspartate receptor antagonist completely blocked the glutamate-induced cytotoxicity against both dopaminergic and non-dopaminergic neurons. In the dopaminergic neurons, MPP+ caused cytotoxicity that was not blocked by co-administration of MK-801. After pretreatment with small doses of MPP+, sub-lethal doses of glutamate caused severe cell damage restricted to dopaminergic neurons, suggesting that MPP+ potentiates the glutamate-induced cytotoxicity only against dopaminergic neurons. As glutamate is putatively capable of causing cytotoxicity against dopaminergic neurons, the present findings might be important in considering the pathogenesis of dopaminergic neuronal degeneration and a possible therapeutic application of glutamate receptor antagonists in Parkinson's disease.
帕金森病的特征是多巴胺能神经元死亡的慢性进展，其机制尚不清楚。尽管甲基-4-苯基吡啶离子（MPP+）或类似MPP+的物质可降低线粒体复合物I的活性，被认为是帕金森病的致病因素，但很难解释多年来的慢性神经元变性。除了MPP+之外，确定其他可能导致慢性细胞死亡的因素很重要。我们假设，用小剂量MPP+进行治疗，不会对多巴胺能神经元造成严重损伤，而仅仅降低线粒体复合物I的活性，可以作为帕金森病的一种模型，并且谷氨酸可能是导致慢性神经元变性的一种因素。利用大鼠中脑原代培养物，我们研究了谷氨酸对多巴胺能和非多巴胺能神经元的细胞毒性，以及在有无MPP+预处理的情况下的情况。短暂暴露于谷氨酸对多巴胺能和非多巴胺能神经元均显示出类似的细胞毒性。一种N-甲基-D-天冬氨酸受体拮抗剂完全阻断了谷氨酸对多巴胺能和非多巴胺能神经元的细胞毒性。在多巴胺能神经元中，MPP+引起的细胞毒性不会因同时给予MK-801而被阻断。用小剂量MPP+预处理后，亚致死剂量的谷氨酸会导致仅限于多巴胺能神经元的严重细胞损伤，这表明MPP+仅增强谷氨酸对多巴胺能神经元的细胞毒性。由于谷氨酸可能对多巴胺能神经元具有细胞毒性，本研究结果对于考虑多巴胺能神经元变性的发病机制以及谷氨酸受体拮抗剂在帕金森病中的可能治疗应用可能具有重要意义。
