Journal
STROKE
Volume 31, Issue 3, Pages 738-743Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.STR.31.3.738
Keywords
estrogen; cerebral ischemia; gender; menopause; stroke
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Funding
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS033668, P01NS020020] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NURSING RESEARCH [R01NR003521] Funding Source: NIH RePORTER
- NINDS NIH HHS [NS33668, NS20020] Funding Source: Medline
- NINR NIH HHS [NR03521] Funding Source: Medline
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Background and Purpose-Recent evidence suggests that endogenous estrogens or hormone replacement therapy can ameliorate brain damage from experimental stroke. Protective mechanisms involve enhanced cerebral vasodilation during 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 exaggerated cerebral infarction damage after middle cerebral artery occlusion, Methods-The histopathology of cresyl violet-stained tissues was evaluated after reversible middle cerebral artery occlusion (2 hours, followed by 22 hours of reperfusion) in ER alpha KO transgenic and wild-type (WT) mice (C57BL/6J background strain), End-ischemic cerebral blood flow mapping was obtained from additional female murine cohorts by using [C-14]iodoantipyrine autoradiography, Results-Total hemispheric tissue damage was not altered by ER alpha deficiency 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 KO and 13.4+/-1.0 mm(3) in WT mice, but cortical infarction was paradoxically smaller relative to that of the WT (20.7+/-4.5 mm(3) in ER alpha KO versus 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 reduced infarction in this anatomic area. There were no differences in stroke outcomes by region or genotype in male animals. Conclusions-Loss of ER alpha does not enhance tissue damage in the female animal, suggesting that estrogen inhibits brain injury by mechanisms that do not depend on activation of this receptor subtype.
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