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Estradiol and neurodegenerative oxidative stress
Authors:Nilsen Jon
Institution:aDepartment of Pharmacology and Pharmaceutical Sciences, University of Southern California, Pharmaceutical Sciences Center, Los Angeles, CA 90033, USA
Abstract: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.
Keywords:Estrogen  Oxidative stress  Neurodegeneration  Alzheimer’  s disease  Neuroprotection  Mitochondria  Calcium  Catecholestrogen  Aging  Reactive oxygen species
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