Journal
CNS NEUROSCIENCE & THERAPEUTICS
Volume 21, Issue 3, Pages 271-279Publisher
WILEY-BLACKWELL
DOI: 10.1111/cns.12362
Keywords
Cerebral ischemia; G protein-coupled receptor 81; Lactates; Neuroprotection
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Funding
- National Natural Science Foundation of China [81030061, 81273506, 81373393]
- Zhejiang Provincial Natural Science Foundation [LZ14H300001, LQ14H310002]
- Program for Zhejiang Leading Team of S&T Innovation Team [2011R50014]
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AimLactates 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. MethodsN2A cells were transfected with GFP-GPR81 plasmids 24h 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 3h 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. ResultsThe 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. ConclusionsG 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.
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