HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

AbstractBACKGROUND 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.
AuthorsBrad 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
JournalStroke (Stroke) Vol. 45 Issue 3 Pg. 835-41 (Mar 2014) ISSN: 1524-4628 [Electronic] United States
PMID24457292 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Caspase Inhibitors
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: