title: Activation of G-protein coupled estrogen receptor 1 improves early-onset cognitive impairment via PI3K/Akt pathway in rats with traumatic brain injury.
abstract: Previous studies experimentally reveal that G-protein coupled estrogen receptor 1(GPER) has neuroprotection against ischemic injury. However, its effect on traumatic brain injury (TBI) is less well-established. Cognitive impairment following human TBI is a common clinical observation, and TBI is considered as a risk factor for Alzheimer's disease (AD). This study aimed to observe the possible protective effect of GPER on early-onset cognitive impairment after a single TBI and investigate the cellular mechanism underlying its actions. We found that selective GPER agonist G-1 significantly reduced hippocampal CA1 neuronal loss and improved cognitive impairment in TBI rats. Although previous studies have shown that AD-like tau pathology occurs many years after both repetitive and single TBI, accumulation of hyperphosphorylated tau was not observed within days (detected at 24 h and 7d) after TBI. Furthermore, tau phosphorylation was not altered by G-1 treatment. It was found that G-1 administration caused an increase in p-Akt level. However, the neuroprotective effects of G-1 on spatial cognition and neuronal death were attenuated by PI3K/Akt inhibitor LY294002. These findings indicate that GPER agonist G-1 had protection on cognitive function via activation of PI3K/Akt signaling. Early-onset cognitive impairment following a single TBI was closely associated with acute hippocampal neuronal loss rather than tau pathology. This study suggests that early activation of GPER might be a promising therapeutic strategy for improvement of TBI-induced cognitive outcomes.
authors.affiliation: Cerebral Vascular Diseases Center, Wuhan University School of Medicine, Wuhan, Hubei, China; Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, China.
authors.forename: Ze-Fen
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Pan
authors.affiliation: Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
authors.forename: Cheng-Shi
authors.initials: CS
authors.lastname: Xu
authors.affiliation: Cerebral Vascular Diseases Center, Wuhan University School of Medicine, Wuhan, Hubei, China; Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China. Electronic address: lizhiqiang@whu.edu.cn.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D000070642:Brain Injuries, Traumatic / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D043562:Receptors, G-Protein-Coupled; C520305:Gper1 protein, rat
keywords: Apoptosis; GPER; Hippocampus; Tau; Traumatic brain injury