Estrogen Attenuates Ischemic Oxidative Damage via an Estrogen Receptor α-Mediated Inhibition of NADPH Oxidase Activation

Abstract

The goal of this study was to elucidate the mechanisms of 17␤-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 ␣ (ER␣)-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␣, but not ER␤, 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.

Estrogen attenuates coupling factor 6-induced salt-sensitive hypertension and cardiac systolic dysfunction in mice

“…With regard to cardioprotection, estrogen was shown to increase the expression of superoxide dismutase and inhibit NADPH oxidase activity. 8,32,36 Estrogen increases protein S-nitrosylation, a common posttranslational protein modification, 37 and reduces inflammatory markers 32,38 and afterload-or agonist-induced cardiac hypertrophy via the inhibition of calcineurin hypertrophic transcription factor and mitogen-activated protein kinase signaling pathways. 39 Estrogen also improves endothelial and myocardial function after ischemia by an antiapoptotic and pro-survival effect on cardiomyocytes, 40,41 endothelial progenitor cell mobilization 42 and mesenchymal stem cell-mediated vascular endothelial growth factor release.…”

The Antioxidant Effect of Carnosol in Bovine Aortic Endothelial Cells Is Mainly Mediated <i>via</i> Estrogen Receptor α Pathway

“…23,27) ERα and ERβ show different effects during that procedure. 31) In several cases, ERα has been reported as the main factor in antioxidative process. As mentioned in the beginning, much more attention has been paid to phytoestrogens in recent years, especially some active components in Chinese medicine that show estrogenic effects.…”

A mechanism emerges for the critical period hypothesis for estrogen treatment

“…Estrogen exerts its cellular effects through binding to ERs, with ER-α and ER-β activating multiple signaling cascades through regulation of transcription in the nucleus and direct effects on synaptic structure and transmission (10). Brann's group demonstrated previously that long-term estrogen depletion (LTED) resulted in a failure of ET to provide neuroprotection against cerebral ischemia in CA1, which was accompanied by decreased levels of ER-α in CA1 (11). Following up on a previous study…”