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

Quanguang Zhang, Limor Raz, Ruimin Wang, Dong Han, Liesl De Sevilla, Fang Yang, Ratna K. Vadlamudi, Darrell W Brann

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)13823-13836
Number of pages14
JournalJournal of Neuroscience
Volume29
Issue number44
DOIs
StatePublished - Nov 4 2009

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NADPH Oxidase
Estrogen Receptors
Estrogens
Antioxidants
Stroke
Uterus
Hypersensitivity
Pyramidal Cells
Wounds and Injuries
Superoxides
Estradiol
Hippocampus
Phosphorylation
Neurons
Membranes
Neuroprotection

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Estrogen attenuates ischemic oxidative damage via an estrogen receptor α-mediated inhibition of NADPH oxidase activation. / Zhang, Quanguang; Raz, Limor; Wang, Ruimin; Han, Dong; De Sevilla, Liesl; Yang, Fang; Vadlamudi, Ratna K.; Brann, Darrell W.

In: Journal of Neuroscience, Vol. 29, No. 44, 04.11.2009, p. 13823-13836.

Research output: Contribution to journalArticle

Zhang, Quanguang ; Raz, Limor ; Wang, Ruimin ; Han, Dong ; De Sevilla, Liesl ; Yang, Fang ; Vadlamudi, Ratna K. ; Brann, Darrell W. / Estrogen attenuates ischemic oxidative damage via an estrogen receptor α-mediated inhibition of NADPH oxidase activation. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 44. pp. 13823-13836.
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