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.