title: GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke.
abstract: Stroke could lead to serious morbidity, of which ischemic stroke counts for majority of the cases. Inflammation plays an important role in the pathogenesis of ischemic stroke, thus drugs targeting inflammation could be potentially neuroprotective. Estradiol was shown to be neuroprotective as well as anti-inflammatory in animal models of ischemic stroke with unclear mechanism. We hypothesize that the anti-inflammatory and neuroprotective effect of estradiol is mediated by the estradiol receptor G protein-coupled estrogen receptor 1 (GPER) expressed on microglia.
  
  
  
  We have generated the rat global cerebral ischemic model and the primary microglia culture to study the neuroprotective and anti-inflammatory effect of estradiol. We have further used pharmacological methods and siRNA knockdown approach to study the underlying mechanism.
  
  
  
  We found that estradiol reduced the level of proinflammatory cytokines including IL-1β and TNF-α, both in vivo and in vitro. We also found that the specific GPER agonist G1 could reduce the level of IL-1β (P = 0 P = 0.0017, one-way ANOVA and post hoc test) and TNF-α (P < 0.0001) in the primary microglia culture. Moreover, the specific GPER antagonist G15 was able to abolish the anti-inflammatory effect of estradiol. Estradiol failed to reduce the level of IL-1β (P = 0.4973, unpaired Student's t-test) and TNF-α (P = 0.1627) when GPER was knocked down.
  
  
  
  Our studies have suggested that GPER expressed on microglia mediated the anti-inflammatory effect of estradiol after ischemic stroke. Our studies could potentially help to develop more specific drugs to manage inflammation postischemic stroke.
authors.affiliation: Department of Neurosurgery Wuhan General Hospital of Guangzhou Military Command of Chinese PLA Wuhan 430070 Hubei Province China; Department of Neurosurgery Tangdu Hospital Fourth Military Medical University No. 569 Xinsi Road Baqiao District Xi'an 710038 Shanxi Province China.
authors.forename: Tian-Zhi
authors.initials: TZ
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology Tangdu Hospital Fourth Military Medical University No. 569 Xinsi Road Baqiao District Xi'an 710038 Shanxi Province China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Neurology Chinese PLA No. 451 Hospital Xi'an 710054 Shanxi Province China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Neurosurgery Tangdu Hospital Fourth Military Medical University No. 569 Xinsi Road Baqiao District Xi'an 710038 Shanxi Province China.
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: He
authors.affiliation: Department of Aerospace Biodynamics Fourth Military Medical University Xi'an 710032 Shanxi Province China.
authors.forename: Fei
authors.initials: F
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery Wuhan General Hospital of Guangzhou Military Command of Chinese PLA Wuhan 430070 Hubei Province China.
authors.forename: Lian-Ting
authors.initials: LT
authors.lastname: Ma
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000276:immunology / Q000378:metabolism; D020521:Stroke / Q000276:immunology / Q000378:metabolism
chemical_list: C520305:Gper1 protein, rat; D018696:Neuroprotective Agents; D043562:Receptors, G-Protein-Coupled; D004958:Estradiol
keywords: GPER; estradiol; inflammation; ischemic stroke; microglia