Moon Younghye, Lee Kun Ho, Park June-Hee, Geum Dongho, Kim Kyungjin
Interdisciplinary Program in Neurosciences, Seoul National University, Seoul, Korea.
J Neurochem. 2005 Jun;93(5):1199-208. doi: 10.1111/j.1471-4159.2005.03112.x.
Chronic exposure to the pesticide rotenone induces a selective degeneration of nigrostriatal dopaminergic neurons and reproduces the features of Parkinson's disease in experimental animals. This action is thought to be relevant to its inhibition of the mitochondrial complex I, but the precise mechanism of this suppression in selective neuronal death is still elusive. Here we investigate the mechanism of dopaminergic neuronal death mediated by rotenone in primary rat mesencephalic neurons. Low concentrations of rotenone (5-10 nM) induce the selective death of dopaminergic neurons without significant toxic effects on other mesencephalic cells. This cell death was coincident with apoptotic events including capsase-3 activation, DNA fragmentation, and mitochondrial membrane depolarization. Pretreatment with coenzyme Q10, the electron transporter in the mitochondrial respiratory chain, remarkably reduced apoptosis as well as the mitochondrial depolarization induced by rotenone, but other free radical scavengers such as N-acetylcysteine, glutathione, and vitamin C did not. Furthermore, the selective neurotoxicity of rotenone was mimicked by the mitochondrial protonophore carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), a cyanide analog that effectively collapses a mitochondrial membrane potential. These data suggest that mitochondrial depolarization may play a crucial role in rotenone-induced selective apoptosis in rat primary dopaminergic neurons.
长期接触农药鱼藤酮会导致黑质纹状体多巴胺能神经元选择性退化，并在实验动物中重现帕金森病的特征。这种作用被认为与其对线粒体复合体I的抑制有关，但这种抑制在选择性神经元死亡中的精确机制仍不清楚。在这里，我们研究了鱼藤酮介导的原代大鼠中脑神经元多巴胺能神经元死亡的机制。低浓度的鱼藤酮（5-10 nM）可诱导多巴胺能神经元选择性死亡，而对其他中脑细胞无明显毒性作用。这种细胞死亡与凋亡事件同时发生，包括半胱天冬酶-3激活、DNA片段化和线粒体膜去极化。用线粒体呼吸链中的电子转运体辅酶Q10预处理，可显著减少鱼藤酮诱导的凋亡以及线粒体去极化，但其他自由基清除剂如N-乙酰半胱氨酸、谷胱甘肽和维生素C则不能。此外，线粒体质子载体羰基氰化物4-（三氟甲氧基）苯腙（FCCP）模拟了鱼藤酮的选择性神经毒性，FCCP是一种氰化物类似物，可有效破坏线粒体膜电位。这些数据表明，线粒体去极化可能在鱼藤酮诱导的大鼠原代多巴胺能神经元选择性凋亡中起关键作用。
