Stroke in estrogen receptor-alpha-deficient mice

Background and Purpose-Recent evidence suggests that endogenous estrogens o r hormone replacement therapy can ameliorate brain damage from experimental stroke. Protective mechanisms involve enhanced cerebral vasodilation durin g ischemic stress as well as direct preservation of neuronal viability. We hypothesized that if the intracellular estrogen receptor subtype-alpha (ER alpha) is important to estrogen's signaling in the ischemic brain, then ER alpha-deficient (knockout) (ER alpha KO) female mice would sustain exaggera ted cerebral infarction damage after middle cerebral artery occlusion, Methods-The histopathology of cresyl violet-stained tissues was evaluated a fter reversible middle cerebral artery occlusion (2 hours, followed by 22 h ours of reperfusion) in ER alpha KO transgenic and wild-type (WT) mice (C57 BL/6J background strain), End-ischemic cerebral blood flow mapping was obta ined from additional female murine cohorts by using [C-14]iodoantipyrine au toradiography, Results-Total hemispheric tissue damage was not altered by ER alpha deficie ncy in female mice: 51.9+/-10.6 mm(3) in ER alpha KO versus 60.5+/-5.0 mm(3 ) in WT. Striatal infarction was equivalent, 12.2+/-1.7 mm(3) in ER alpha K O and 13.4+/-1.0 mm(3) in WT mice, but cortical infarction was paradoxicall y smaller relative to that of the WT (20.7+/-4.5 mm(3) in ER alpha KO versu s 30.6+/-1.1 mm(3) in WT), Intraocclusion blood flow to the parietal cortex was higher in ER alpha KO than in WT mice, likely accounting for the reduc ed infarction in this anatomic area. There were no differences in stroke ou tcomes by region or genotype in male animals. Conclusions-Loss of ER alpha does not enhance tissue damage in the female a nimal, suggesting that estrogen inhibits brain injury by mechanisms that do not depend on activation of this receptor subtype.