Inhibition of G Protein-Coupled Receptor 81 (GPR81) Protects Against Ischemic Brain Injury

Abstract

Summary: Aim: 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.