Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 835 - 841 |
| Number of pages | 7 |
| Journal | Stroke |
| Volume | 45 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2014 |
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Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke. / Broughton, Bradley Randal Scott; Brait, Vanessa H; Kim, Helena H A; Lee, Seyoung Sandy; Chu, Hannah X; Gardiner-Mann, Chantelle V; Guida, Elizabeth; Evans, Megan A; Miller, Alyson Anne; Arumugam, Thiruma; Drummond, Grant R; Sobey, Christopher G.
In: Stroke, Vol. 45, No. 3, 2014, p. 835 - 841.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke
AU - Broughton, Bradley Randal Scott
AU - Brait, Vanessa H
AU - Kim, Helena H A
AU - Lee, Seyoung Sandy
AU - Chu, Hannah X
AU - Gardiner-Mann, Chantelle V
AU - Guida, Elizabeth
AU - Evans, Megan A
AU - Miller, Alyson Anne
AU - Arumugam, Thiruma
AU - Drummond, Grant R
AU - Sobey, Christopher G
PY - 2014
Y1 - 2014
N2 - 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 mug/kg), or a GPER antagonist (G-15, 300 mug/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.
AB - 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 mug/kg), or a GPER antagonist (G-15, 300 mug/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.
UR - http://stroke.ahajournals.org/content/45/3/835.full.pdf+html
U2 - 10.1161/STROKEAHA.113.001499
DO - 10.1161/STROKEAHA.113.001499
M3 - Article
VL - 45
SP - 835
EP - 841
JO - Stroke
JF - Stroke
SN - 0039-2499
IS - 3
ER -