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

The goal of this study was to elucidate the mechanisms of 17β-estradiol (E₂) antioxidant and neuroprotective actions in stroke. The results reveal a novel extranuclear receptor-mediated antioxidant mechanism for E₂ 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 α (ERα)-mediated nongenomic signaling, involving Akt activation and subsequent phosphorylation/ inactivation of Rac1, a factor critical for activation of NOX2 NADPH oxidase. Intriguingly, E₂ nongenomic signaling, antioxidant action, and neuroprotection in the CA1 region were lost after long-term E₂ deprivation, and this loss was tissue specific because the uterus remained responsive to E₂. Correspondingly, a remarkable loss of ERα, but not ERα, was observed in the CA1 after long-term E₂ deprivation, with no change observed in the uterus. As a whole, the study reveals a novel, membrane-mediated antioxidant mechanism in neurons by E₂ provides support and mechanistic insights for a "critical period" of E₂ replacement in the hippocampus and demonstrates a heretofore unknown hypersensitivity of the CA3/CA4 to ischemic injury after prolonged hypoestrogenicity.