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

Broughton, B. R.S. et al. (2014) Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke. Stroke, 45(3), pp. 835-841. (doi: 10.1161/STROKEAHA.113.001499) (PMID:24457292)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Miller, Dr Alyson
• Authors: Broughton, B. R.S., Brait, V. H., Kim, H. A., Lee, S., Chu, H. X., Gardiner-Mann, C. V., Guida, E., Evans, M. A., Miller, A. A., Arumugam, T. V., Drummond, G. R., and Sobey, C. G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Stroke
• Publisher: American Heart Association
• ISSN: 0039-2499
• ISSN (Online): 1524-4628
• Published Online: 23 January 2014