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The Journal of Neuroscience, November 4, 2009, 29(44):13823-13836; doi:10.1523/JNEUROSCI.3574-09.2009

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

Quan-Guang Zhang,^1 * Limor Raz,^1 * Ruimin Wang,^2 * Dong Han,¹ Liesl De Sevilla,¹ Fang Yang,² Ratna K. Vadlamudi,³ and Darrell W. Brann¹

¹Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, and Department of Neurology, Medical College of Georgia, Augusta, Georgia 30912, ²Research Center for Molecular Biology, North China Coal Medical University, Tangshan 063000, China, and ³Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229

Correspondence should be addressed to Dr. Darrell W. Brann, Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, 1120 Fifteenth Street, Medical College of Georgia, Augusta, GA 30912. Email: dbrann{at}mcg.edu

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. E₂ 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, 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 ER, but not ERβ, 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.

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Received July 23, 2009; revised Aug. 21, 2009; accepted Sept. 15, 2009.

Correspondence should be addressed to Dr. Darrell W. Brann, Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, 1120 Fifteenth Street, Medical College of Georgia, Augusta, GA 30912. Email: dbrann{at}mcg.edu

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