Milusheva Elisaveta, Baranyi Mária, Kittel Agnes, Sperlágh Beáta, Vizi E Sylvester
Department of Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest.
Free Radic Biol Med. 2005 Jul 1;39(1):133-42. doi: 10.1016/j.freeradbiomed.2005.02.034. Epub 2005 Mar 25.
It is believed that both mitochondrial dysfunction and oxidative stress play important roles in the pathogenesis of Parkinson's disease (PD). We studied the effect of chronic systemic exposure to the mitochondrial inhibitor rotenone on the uptake, content, and release of striatal neurotransmitters upon neuronal activity and oxidative stress, the latter simulated by H(2)O(2) perfusion. The dopamine content in the rat striatum is decreased simultaneously with the progressive loss of tyrosine hydroxylase (TH) immunoreactivity in response to chronic intravenous rotenone infusion. However, surviving dopaminergic neurons take up and release only a slightly lower amount of dopamine (DA) in response to electrical stimulation. Striatal dopaminergic neurons showed increased susceptibility to oxidative stress by H(2)O(2), responding with enhanced release of DA and with formation of an unidentified metabolite, which is most likely the toxic dopamine quinone (DAQ). In contrast, the uptake of [(3)H]choline and the electrically induced release of acetylcholine increased, in coincidence with a decline in its D(2) receptor-mediated dopaminergic control. Thus, oxidative stress-induced dysregulation of DA release/uptake based on a mitochondrial deficit might underlie the selective vulnerability of dopaminergic transmission in PD, causing a self-amplifying production of reactive oxygen species, and thereby contributing to the progressive degeneration of dopaminergic neurons.
人们认为线粒体功能障碍和氧化应激在帕金森病（PD）的发病机制中都起着重要作用。我们研究了长期全身暴露于线粒体抑制剂鱼藤酮对神经元活动和氧化应激（后者通过H₂O₂灌注模拟）时纹状体神经递质摄取、含量和释放的影响。响应于慢性静脉内注入鱼藤酮，大鼠纹状体中的多巴胺含量随着酪氨酸羟化酶（TH）免疫反应性的逐渐丧失而同时降低。然而，存活的多巴胺能神经元在电刺激下摄取和释放的多巴胺（DA）量仅略有降低。纹状体多巴胺能神经元对H₂O₂诱导的氧化应激表现出更高的敏感性，表现为DA释放增加以及形成一种不明代谢产物，该产物很可能是有毒的多巴胺醌（DAQ）。相反，[³H]胆碱的摄取和电诱导的乙酰胆碱释放增加，同时其D₂受体介导的多巴胺能控制下降。因此，基于线粒体缺陷的氧化应激诱导的DA释放/摄取失调可能是PD中多巴胺能传递选择性易损性的基础，导致活性氧的自我放大产生，从而促进多巴胺能神经元的进行性变性。
