Inhibition of G Protein‐Coupled Receptor 81 ( GPR 81) Protects Against Ischemic Brain Injury

摘要

Summary Aim Lactates accumulate in ischemic brains. G protein‐coupled receptor 81 ( GPR 81) is an endogenous receptor for lactate. We aimed to explore whether lactate is involved in ischemic injury via activating GPR 81. Methods N2A cells were transfected with GFP ‐ GPR 81 plasmids 24 h previously, and then treated with GPR 81 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 C57 BL /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 GPR 81 overexpression increased the cell vulnerability to ischemic injury. And GPR 81 antagonism by 3‐ OBA significantly prevented cell death and brain injury after OGD and MCAO , respectively. Furthermore, inhibition of GPR 81 reversed ischemia‐induced apoptosis and extracellular signal‐regulated kinase ( ERK ) signaling may be involved in the neuroprotection. Conclusions G protein‐coupled receptor 81 ( GPR 81) inhibition attenuated ischemic neuronal death. Lactate may aggravate ischemic brain injury by activating GPR 81. GPR 81 antagonism might be a novel therapeutic strategy for the treatment of cerebral ischemia.