title: Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury.
abstract: OBJECTIVE
  Lactates accumulate in ischemic brains. G protein-coupled receptor 81 (GPR81) is an endogenous receptor for lactate. We aimed to explore whether lactate is involved in ischemic injury via activating GPR81.
  
  
  METHODS
  N2A cells were transfected with GFP-GPR81 plasmids 24 h previously, and then treated with GPR81 antagonist 3-hydroxy-butyrate (3-OBA) alone or cotreated with agonists lactate or 3, 5-dihydroxybenzoic acid (3, 5-DHBA) during 3 h of oxygen-glucose deprivation (OGD). Adult male C57BL/6J mice and primary cultured cortical neurons were treated with 3-OBA at the onset of middle cerebral artery occlusion (MCAO) or OGD, respectively.
  
  
  RESULTS
  The GPR81 overexpression increased the cell vulnerability to ischemic injury. And GPR81 antagonism by 3-OBA significantly prevented cell death and brain injury after OGD and MCAO, respectively. Furthermore, inhibition of GPR81 reversed ischemia-induced apoptosis and extracellular signal-regulated kinase (ERK) signaling may be involved in the neuroprotection.
  
  
  CONCLUSIONS
  G protein-coupled receptor 81 (GPR81) inhibition attenuated ischemic neuronal death. Lactate may aggravate ischemic brain injury by activating GPR81. GPR81 antagonism might be a novel therapeutic strategy for the treatment of cerebral ischemia.
authors.affiliation: Department of Pharmacology, Key Laboratory of Medical Neurobiology of The Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shen
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yuan
authors.forename: Tian
authors.initials: T
authors.lastname: Deng
authors.forename: Yan-Rong
authors.initials: YR
authors.lastname: Zheng
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zhao
authors.forename: Wen-Lu
authors.initials: WL
authors.lastname: Li
authors.forename: Jia-Ying
authors.initials: JY
authors.lastname: Wu
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Gao
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Hu
authors.forename: Xiang-Nan
authors.initials: XN
authors.lastname: Zhang
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D062385:Hydroxybenzoates / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery; D019344:Lactic Acid / Q000008:administration & dosage / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology
chemical_list: D002491:Central Nervous System Agents; C000603107:GPR81 protein, rat; C529424:Hcar1 protein, mouse; D062385:Hydroxybenzoates; D018696:Neuroprotective Agents; D043562:Receptors, G-Protein-Coupled; D012118:Resorcinols; C076950:alpha-resorcylic acid; D019344:Lactic Acid; D005947:Glucose; D020155:3-Hydroxybutyric Acid
keywords: Cerebral ischemia; G protein-coupled receptor 81; Lactates; Neuroprotection