Estradiol is a potent preventative against neurodegenerative disease, in part, by activating antioxidant defense systems scavenging reactive oxygen species, limiting mitochondrial protein damage, improving electron transport chain activity and reducing mitochondrial DNA damage. Estradiol also increases the activity of complex IV of the electron transport chain, improving mitochondrial respiration and ATP production under normal and stressful conditions. However, the high oxidative cellular environment present during neurodegeneration makes estradiol a poor agent for treatment of existing disease. Oxidative stress stimulates the production of the hydroperoxide-dependent hydroxylation of estradiol to the catecholestrogen metabolites, which can undergo reactive oxygen species producing redox cycling, setting up a self-generating toxic cascade offsetting any antioxidant/antiapoptotic effects generated by the parent estradiol. Additional disease-induced factors can further perpetuate this cycle. For example dysregulation of the catecholamine system could alter catechol-O-methyltransferase-catalyzed methylation, preventing removal of redox cycling catecholestrogens from the system enhancing pro-oxidant effects of estradiol.

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雌二醇和神经退行性氧化应激

雌二醇是一种有效的神经退行性疾病预防剂，部分原因是通过激活抗氧化防御系统清除活性氧、限制线粒体蛋白质损伤、改善电子传递链活性和减少线粒体 DNA 损伤。雌二醇还增加电子传递链复合体 IV 的活性，改善正常和压力条件下的线粒体呼吸和 ATP 产生。然而，神经变性过程中存在的高氧化细胞环境使雌二醇成为治疗现有疾病的不良药物。氧化应激刺激雌二醇的氢过氧化物依赖性羟基化作用生成儿茶酚雌激素代谢物，这些代谢物可以经历活性氧产生氧化还原循环，建立一个自我产生的毒性级联，抵消母体雌二醇产生的任何抗氧化/抗细胞凋亡作用。其他疾病诱发因素可以进一步延续这个循环。例如，儿茶酚胺系统失调可能会改变儿茶酚-O-甲基转移酶催化的甲基化，防止从系统中去除氧化还原循环儿茶酚雌激素，从而增强雌二醇的促氧化作用。