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. CONCLUSIONS: Future therapies for acute stroke could exploit the modulation of GPER activity in a sex-specific manner.
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. CONCLUSIONS: Future therapies for acute stroke could exploit the modulation of GPER activity in a sex-specific manner.
Authors: Maria Shvedova; Maxim M Litvak; Jesse D Roberts; Dai Fukumura; Tomoaki Suzuki; İkbal Şencan; Ge Li; Paula Reventun; Emmanuel S Buys; Hyung-Hwan Kim; Sava Sakadžić; Cenk Ayata; Paul L Huang; Robert Feil; Dmitriy N Atochin Journal: J Cereb Blood Flow Metab Date: 2019-08-18 Impact factor: 6.200
Authors: Jennifer M Colón; Pablo A González; Ámbar Cajigas; Wanda I Maldonado; Aranza I Torrado; José M Santiago; Iris K Salgado; Jorge D Miranda Journal: Exp Neurol Date: 2017-10-13 Impact factor: 5.330
Authors: Megan A Evans; Hyun Ah Kim; T Michael De Silva; Thiruma V Arumugam; Andrew N Clarkson; Grant R Drummond; Graeme R Zosky; Brad Rs Broughton; Christopher G Sobey Journal: J Cereb Blood Flow Metab Date: 2017-08-23 Impact factor: 6.200