Estrogen attenuates ischemic oxidative damage via an estrogen receptor alpha-mediated inhibition of NADPH oxidase activation.
The goal of this study was to elucidate the mechanisms of 17beta-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 (ERalpha)-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 ERalpha, but not ERbeta, 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.
Zhang
Quan-Guang
QG
Developmental Neurobiology Program, Institute of Molecular Medicine and Genetics, and Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.
Raz
Limor
L
Wang
Ruimin
R
Han
Dong
D
De Sevilla
Liesl
L
Yang
Fang
F
Vadlamudi
Ratna K
RK
Brann
Darrell W
DW
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D002545:Brain Ischemia / Q000201:enzymology* / Q000517:prevention & control; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics
D000975:Antioxidants; D047628:Estrogen Receptor alpha; D004967:Estrogens; D019255:NADPH Oxidases