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 17 beta-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 (ER alpha)-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 ER alpha, but not ER beta, 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.