Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke.
OBJECTIVE
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.
From the Vascular Biology and Immunopharmacology Group, Department of Pharmacology, Monash University, Clayton, Victoria, Australia (B.R.S.B., V.H.B., H.A.K., S.L., H.X.C., C.V.G.-M., E.G., M.A.E., A.A.M., G.R.D., C.G.S.); and School of Biomedical Sciences, University of Queensland, Brisbane, Queensland, Australia (T.V.A.).
Brad R S
BR
Broughton
Vanessa H
VH
Brait
Hyun Ah
HA
Kim
Seyoung
S
Lee
Hannah X
HX
Chu
Chantelle V
CV
Gardiner-Mann
Elizabeth
E
Guida
Megan A
MA
Evans
Alyson A
AA
Miller
Thiruma V
TV
Arumugam
Grant R
GR
Drummond
Christopher G
CG
Sobey
D000375:Aging / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D002544:Cerebral Infarction / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009422:Nervous System Diseases / Q000473:pathology / Q000503:physiopathology; D010052:Ovariectomy; D011960:Receptors, Estrogen / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology; D012727:Sex Characteristics; D020521:Stroke / Q000188:drug therapy / Q000473:pathology*; D016896:Treatment Outcome
D061945:Caspase Inhibitors; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled
GPER protein; GPR30 protein; apoptosis; cerebral ischemia; middle cerebral artery stroke