Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons
Effects of mitochondrial dysfunction on glutamate receptor-mediated neurotoxicity in cultured rat spinal motor neurons
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DOI：
10.1016/j.brainres.2004.04.044
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发表时间：
2004-07-23
期刊：
影响因子：
2.9
通讯作者：
Shimohama, S
中科院分区：
文献类型：
--
作者：
Kanki, R;Nakamizo, T;Shimohama, S
谷氨酸诱导的兴奋性毒性在肌萎缩侧索硬化症（ALS）的发病机制中起着关键作用，并且在ALS患者中也发现了线粒体功能障碍。我们研究了谷氨酸兴奋性毒性和线粒体功能障碍引起的鱼藤酮（复合物I抑制剂），丙二酸（复合物II抑制剂），或抗霉素（复合物III抑制剂），在原代培养的胚胎大鼠脊髓之间的关系。鱼藤酮和丙二酸诱导相对选择性毒性运动神经元相比，非运动神经元，而抗霉素引起非选择性毒性。非N-甲基-D-天冬氨酸（NMDA）受体拮抗剂6-氰基-7-硝基喹喔啉-2，3-二酮（CNQX）可阻止鱼藤酮的毒性，而NMDA受体拮抗剂5-甲基-10，11-二氢-5H-二苯并[a，d]环庚烯-5，10-亚胺马来酸氢盐（MK-801）则不能阻止鱼藤酮的毒性。CNQX和MK-801均可阻断丙二酸的毒性。CNQX和MK-801均不影响抗霉素的毒性。当线粒体复合物I被亚致死浓度的鱼藤酮轻度抑制时，AMPA诱导的运动神经元死亡显著加剧。亚致死浓度的丙二酸加重了NMDA和AMPA诱导的运动神经元死亡。这些数据表明，线粒体功能障碍倾向于运动神经元离子型谷氨酸受体介导的兴奋性毒性。(C)2004 Elsevier B. V.保留所有权利。
Glutamate-induced excitotoxicity is implicated as playing a key role in the pathogenesis of amyotrophic lateral sclerosis (ALS), and mitochondrial dysfunction is also found in ALS patients. We investigated the relationship between glutamate excitotoxicity and mitochondrial dysfunction elicited by rotenone (a complex I inhibitor), malonate (a complex II inhibitor), or antimycin (a complex III inhibitor), in primary cultures of the embryonic rat spinal cord. Rotenone and malonate induced relatively selective toxicity against motor neurons as compared to non-motor neurons, whereas antimycin caused non-selective toxicity. The toxicity of rotenone was prevented by a non-N-methyl-D-aspartate (NMDA) receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) but not by an NMDA receptor antagonist, 5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801). The toxicity of malonate was blocked by both CNQX and MK-801. The toxicity of antimycin was affected by neither CNQX nor MK-801. When mitochondrial complex I was mildly inhibited by a sub-lethal concentration of rotenone, AMPA-induced motor neuron death was significantly exacerbated. A sub-lethal concentration of malonate exacerbated both NMDA- and AMPA-induced motor neuron death. These data suggest that mitochondrial dysfunction predisposes motor neurons to ionotropic glutamate receptor-mediated excitotoxicity. (C) 2004 Elsevier B.V. All rights reserved.