Stroke in estrogen receptor-alpha-deficient mice.
OBJECTIVE
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 (ERalpha) is important to estrogen's signaling in the ischemic brain, then ERalpha-deficient (knockout) (ERalphaKO) 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 ERalphaKO 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 [(14)C]iodoantipyrine autoradiography.


RESULTS
Total hemispheric tissue damage was not altered by ERalpha deficiency in female mice: 51.9+/-10.6 mm(3) in ERalphaKO versus 60.5+/-5.0 mm(3) in WT. Striatal infarction was equivalent, 12.2+/-1.7 mm(3) in ERalphaKO 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 ERalphaKO versus 30.6+/-4.1 mm(3) in WT). Intraocclusion blood flow to the parietal cortex was higher in ERalphaKO 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 ERalpha 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.
Sampei
K
K
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Goto
S
S
Alkayed
N J
NJ
Crain
B J
BJ
Korach
K S
KS
Traystman
R J
RJ
Demas
G E
GE
Nelson
R J
RJ
Hurn
P D
PD
D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology; D002540:Cerebral Cortex / Q000098:blood supply / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation; D003342:Corpus Striatum / Q000098:blood supply / Q000473:pathology; D047628:Estrogen Receptor alpha; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010296:Parietal Lobe / Q000098:blood supply / Q000473:pathology; D011960:Receptors, Estrogen / Q000172:deficiency* / Q000235:genetics; D020521:Stroke / Q000209:etiology* / Q000473:pathology
D047628:Estrogen Receptor alpha; D011960:Receptors, Estrogen