Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo.
Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo.
复制标题
线粒体酶的辅因子可在体外和体内减轻铜诱导的死亡。
DOI：
10.1002/ana.10276
复制
发表时间：
2002
影响因子：
11.2
通讯作者：
Choi,DennisW
中科院分区：
文献类型：
--
作者：
Sheline,ChristianT;Choi,EricH;Kim-Han,Jeong-Sook;Dugan,LauraL;Choi,DennisW
铜毒性导致威尔逊病中的神经元死亡，并推测与阿尔茨海默病和朊病毒疾病的发病机制有关。我们研究了铜诱导的神经元死亡，目的是开发神经保护策略。铜催化溶液中羟基自由基生成的增加，向小鼠新皮层细胞培养物中加入20μM铜22小时，诱导ATP水平降低和神经元死亡，而无神经胶质细胞死亡。这种选择性神经元死亡与caspase-3的激活相关，并被自由基清除剂和Z-瓦尔-Ala-Asp氟甲基酮降低，与导致细胞凋亡的自由基介导的损伤一致。丙酮酸脱氢酶特别容易受到氧自由基的抑制，并且在毒性暴露于铜后，皮质细胞中的上游代谢物丙酮酸、磷酸烯醇丙酮酸和2-磷酸甘油酸升高。保护丙酮酸脱氢酶免受氧化攻击的一种方法可能是增强与辅因子的结合。添加硫胺素、二氢硫辛酸或丙酮酸盐可减少铜诱导的神经元死亡。为了测试体内的功效，我们将1%的硫胺素添加到Long Evans Cinnamon大鼠的饮用水中，Long Evans Cinnamon大鼠是威尔逊病的动物模型。这种硫胺素治疗显著延长了寿命，从6.0 ± 1.6个月延长到16个月以上。
Copper toxicity contributes to neuronal death in Wilson's disease and has been speculatively linked to the pathogenesis of Alzheimer's and prion diseases. We examined copper‐induced neuronal death with the goal of developing neuroprotective strategies. Copper catalyzed an increase in hydroxyl radical generation in solution, and the addition of 20μM copper for 22 hours to murine neocortical cell cultures induced a decrease in ATP levels and neuronal death without glial death. This selective neuronal death was associated with activation of caspase‐3 and was reduced by free radical scavengers and Z‐Val‐Ala‐Asp fluoromethylketone, consistent with free radical–mediated injury leading to apoptosis. Pyruvate dehydrogenase is especially vulnerable to inhibition by oxygen free radicals, and the upstream metabolites, pyruvate, phosphoenolpyruvate, and 2‐phosphoglycerate were elevated in cortical cells after toxic exposure to copper. One approach to protecting pyruvate dehydrogenase from oxidative attack might be to enhance binding to cofactors. Addition of thiamine, dihydrolipoic acid, or pyruvate reduced copper‐induced neuronal death. To test efficacy in vivo, we added 1% thiamine to the drinking water of Long Evans Cinnamon rats, an animal model of Wilson's disease. This thiamine therapy markedly extended life span from 6.0 ± 1.6 months to greater than 16 months.