DOPAMINE NEUROTOXICITY - INHIBITION OF MITOCHONDRIAL RESPIRATION
DOPAMINE NEUROTOXICITY - INHIBITION OF MITOCHONDRIAL RESPIRATION
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DOI：
10.1046/j.1471-4159.1995.64020718.x
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发表时间：
1995-02-01
影响因子：
4.7
通讯作者：
GLINKA, Y
中科院分区：
文献类型：
--
作者：
BENSHACHAR, D;ZUK, R;GLINKA, Y
多巴胺通过单胺氧化酶代谢或自氧化作用产生过氧化氢、氧自由基、半醌、醌等有毒产物，发挥神经毒性作用。脑室内注射多巴胺到用单胺氧化酶非选择性抑制剂帕吉林预处理的大鼠中以剂量依赖性方式引起死亡，LD（50）= 90 μ g。LD（50）= 141 μ g时，去甲肾上腺素效果较差。铁螯合剂去铁胺完全防止多巴胺诱导的死亡。在没有帕吉林的情况下，更多的大鼠存活，表明多巴胺酶代谢产物不是多巴胺诱导毒性的主要贡献者。接受致死剂量多巴胺的大鼠额叶皮质和纹状体的生化分析显示，在脂质和蛋白质过氧化以及谷胱甘肽还原酶和过氧化物酶活性方面与对照组大鼠没有任何差异。此外，多巴胺显着减少铁诱导的丙二醛在体外的形成，从而表明，在细胞损伤的早期事件参与多巴胺毒性。事实上，多巴胺抑制线粒体NADH脱氢酶活性的IC 50 = 8 μ M，去甲肾上腺素是两倍（IC 50 = 15 μ M）。多巴胺诱导的抑制NADH脱氢酶活性仅部分逆转去铁胺，这对去甲肾上腺素诱导的抑制没有影响。这些结果表明，儿茶酚胺不仅可以通过诱导氧化应激状态，而且可能通过与线粒体电子传递系统的直接相互作用引起毒性。ADP以剂量依赖性方式逆转多巴胺诱导的NADH脱氢酶活性抑制的能力进一步支持了后者。
Dopamine, due to metabolism by monoamine oxidase or autoxidation, can generate toxic products such as hydrogen peroxide, oxygen-derived radicals, semiquinones, and quinones and thus exert its neurotoxic effects. Intracerebroventricular injection of dopamine into rats pretreated with the monoamine oxidase nonselective inhibitor pargyline caused mortality in a dose-dependent manner with LD(50) = 90 mu g. Norepinephrine was less effective with LD(50) = 141 mu g. The iron chelator desferrioxamine completely protected against dopamine-induced mortality. In the absence of pargyline more rats survived, indicating that the products of dopamine enzymatic metabolism are not the main contributors to dopamine-induced toxicity. Biochemical analysis of frontal cortex and striatum from rats that received a lethal dose of dopamine did not show any difference from control rats in lipid and protein peroxidation and glutathione reductase and peroxidase activities. Moreover, dopamine significantly reduced the formation of iron-induced malondialdehyde in vitro, thus suggesting that earlier events in cell damage are involved in dopamine toxicity. Indeed, dopamine inhibited mitochondrial NADH dehydrogenase activity with IC50 = 8 mu M, and that of norepinephrine was twice as much (IC50 = 15 mu M). Dopamine-induced inhibition of NADH dehydrogenase activity was only partially reversed by desferrioxamine, which had no effect on norepinephrine-induced inhibition. These results suggest that catecholamines can cause toxicity not only by inducing an oxidative stress state but also possibly through direct interaction with the mitochondrial electron transport system. The latter was further supported by the ability of ADP to reverse dopamine-induced inhibition of NADH dehydrogenase activity in a dose-dependent manner.