Abstract | BACKGROUND AND PURPOSE: 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.
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Authors | Brad R S Broughton, Vanessa H Brait, Hyun Ah Kim, Seyoung Lee, Hannah X Chu, Chantelle V Gardiner-Mann, Elizabeth Guida, Megan A Evans, Alyson A Miller, Thiruma V Arumugam, Grant R Drummond, Christopher G Sobey |
Journal | Stroke
(Stroke)
Vol. 45
Issue 3
Pg. 835-41
(Mar 2014)
ISSN: 1524-4628 [Electronic] United States |
PMID | 24457292
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Caspase Inhibitors
- Receptors, Estrogen
- Receptors, G-Protein-Coupled
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Topics |
- Aging
(physiology)
- Animals
- Apoptosis
(drug effects)
- Blotting, Western
- Brain
(pathology)
- Brain Ischemia
(drug therapy, pathology)
- Caspase Inhibitors
(pharmacology)
- Cerebral Infarction
(pathology)
- Female
- Immunohistochemistry
- Male
- Mice
- Nervous System Diseases
(pathology, physiopathology)
- Ovariectomy
- Receptors, Estrogen
(physiology)
- Receptors, G-Protein-Coupled
(agonists, antagonists & inhibitors, physiology)
- Reperfusion Injury
(pathology)
- Sex Characteristics
- Stroke
(drug therapy, pathology)
- Treatment Outcome
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