Sex-dependent effects of g protein-coupled estrogen receptor activity on outcome after ischemic stroke

Broughton, Brad R.S., Brait, Vanessa H., Ah Kim, Hyun, Lee, Seyoung, Chu, Hannah X., Gardiner-Mann, Chantelle V., Guida, Elizabeth, Evans, Megan A., Miller, Alyson A., Arumugam, Thiruma V., Drummond, Grant R. and Sobey, Christopher G. (2014) Sex-dependent effects of g protein-coupled estrogen receptor activity on outcome after ischemic stroke. Stroke, 45 3: 835-841. doi:10.1161/STROKEAHA.113.001499

Author Broughton, Brad R.S.
Brait, Vanessa H.
Ah Kim, Hyun
Lee, Seyoung
Chu, Hannah X.
Gardiner-Mann, Chantelle V.
Guida, Elizabeth
Evans, Megan A.
Miller, Alyson A.
Arumugam, Thiruma V.
Drummond, Grant R.
Sobey, Christopher G.
Title Sex-dependent effects of g protein-coupled estrogen receptor activity on outcome after ischemic stroke
Journal name Stroke   Check publisher's open access policy
ISSN 0039-2499
Publication date 2014-01-23
Year available 2014
Sub-type Article (original research)
DOI 10.1161/STROKEAHA.113.001499
Open Access Status DOI
Volume 45
Issue 3
Start page 835
End page 841
Total pages 7
Place of publication Philadelphia, PA United States
Publisher Lippincott Williams and Wilkins
Language eng
Subject 2902 Advanced and Specialised Nursing
2728 Clinical Neurology
2705 Cardiology and Cardiovascular Medicine
Formatted abstract
 BACKGROUND AND PURPOSE: Experimental studies indicate that estrogen typically, but not universally, has a neuroprotective effect in stroke. Ischemic stroke increases membrane-bound G protein-coupled estrogen receptor (GPER) distribution and expression in the brain of male but not female mice. We hypothesized that GPER activation may have a greater neuroprotective effect in males than in females after stroke.

METHODS: Vehicle (dimethyl sulfoxide), a GPER agonist (G-1, 30 μg/kg), or a GPER antagonist (G-15, 300 μg/kg) were administered alone or in combination to young or aged male mice, or young intact or ovariectomized female mice, 1 hour before or 3 hours after cerebral ischemia-reperfusion. Some mice were treated with a combination of G-1 and the pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh), 1 hour before stroke. We evaluated functional and histological end points of stroke outcome up to 72 hours after ischemia-reperfusion. In addition, apoptosis was examined using cleaved caspase-3 immunohistochemistry.

RESULTS: Surprisingly, G-1 worsened functional outcomes and increased infarct volume in males poststroke, in association with an increased expression of cleaved caspase-3 in peri-infarct neurons. These effects were blocked by G-15 or Q-VD-OPh. Conversely, G-15 improved functional outcomes and reduced infarct volume after stroke in males, whether given before or after stroke. In contrast to findings in males, G-1 reduced neurological deficit, apoptosis, and infarct volume in ovariectomized females, but had no significant effect in intact females.

CONCLUSIONS: Future therapies for acute stroke could exploit the modulation of GPER activity in a sex-specific manner.
Keyword Apoptosis
Cerebral Ischemia
Middle cerebral artery strok
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
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