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

Bradley Randal Scott Broughton, Vanessa H Brait, Helena H A Kim, Seyoung Sandy Lee, Hannah X Chu, Chantelle V Gardiner-Mann, Elizabeth Guida, Megan A Evans, Alyson Anne Miller, Thiruma Arumugam, Grant R Drummond, Christopher G Sobey

Research output: Contribution to journalArticleResearchpeer-review

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 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.
Original languageEnglish
Pages (from-to)835 - 841
Number of pages7
JournalStroke
Volume45
Issue number3
DOIs
Publication statusPublished - 2014

Cite this

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. / Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke. In: Stroke. 2014 ; Vol. 45, No. 3. pp. 835 - 841.
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title = "Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke",
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 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.",
author = "Broughton, {Bradley Randal Scott} and Brait, {Vanessa H} and Kim, {Helena H A} and Lee, {Seyoung Sandy} and Chu, {Hannah X} and Gardiner-Mann, {Chantelle V} and Elizabeth Guida and Evans, {Megan A} and Miller, {Alyson Anne} and Thiruma Arumugam and Drummond, {Grant R} and Sobey, {Christopher G}",
year = "2014",
doi = "10.1161/STROKEAHA.113.001499",
language = "English",
volume = "45",
pages = "835 -- 841",
journal = "Stroke",
issn = "0039-2499",
publisher = "American Heart Association",
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}

Broughton, BRS, Brait, VH, Kim, HHA, Lee, SS, Chu, HX, Gardiner-Mann, CV, Guida, E, Evans, MA, Miller, AA, Arumugam, T, Drummond, GR & Sobey, CG 2014, 'Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke', Stroke, vol. 45, no. 3, pp. 835 - 841. https://doi.org/10.1161/STROKEAHA.113.001499

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 journalArticleResearchpeer-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 -