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J Neurosci. 2009 Nov 4;29(44):13823-36. doi: 10.1523/JNEUROSCI.3574-09.2009.

Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation.

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Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.


The goal of this study was to elucidate the mechanisms of 17beta-estradiol (E(2)) antioxidant and neuroprotective actions in stroke. The results reveal a novel extranuclear receptor-mediated antioxidant mechanism for E(2) during stroke, as well as a hypersensitivity of the CA3/CA4 region to ischemic injury after prolonged hypoestrogenicity. E(2) neuroprotection was shown to involve a profound attenuation of NADPH oxidase activation and superoxide production in hippocampal CA1 pyramidal neurons after stroke, an effect mediated by extranuclear estrogen receptor alpha (ERalpha)-mediated nongenomic signaling, involving Akt activation and subsequent phosphorylation/inactivation of Rac1, a factor critical for activation of NOX2 NADPH oxidase. Intriguingly, E(2) nongenomic signaling, antioxidant action, and neuroprotection in the CA1 region were lost after long-term E(2) deprivation, and this loss was tissue specific because the uterus remained responsive to E(2). Correspondingly, a remarkable loss of ERalpha, but not ERbeta, was observed in the CA1 after long-term E(2) deprivation, with no change observed in the uterus. As a whole, the study reveals a novel, membrane-mediated antioxidant mechanism in neurons by E(2) provides support and mechanistic insights for a "critical period" of E(2) replacement in the hippocampus and demonstrates a heretofore unknown hypersensitivity of the CA3/CA4 to ischemic injury after prolonged hypoestrogenicity.

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