Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury.

Abstract

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.

• Authors: Zhe Shen, Lei Jiang, Yang Yuan, Tian Deng, Yan-Rong Zheng, Yan-Yan Zhao, Wen-Lu Li, Jia-Ying Wu, Jian-Qing Gao, Wei-Wei Hu, Xiang-Nan Zhang, Zhong Chen
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 21 Issue 3 Pg. 271-9 (Mar 2015) ISSN: 1755-5949 [Electronic] England
• PMID: 25495836 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons Ltd.

Chemical References

• Central Nervous System Agents
• GPR81 protein, rat
• Hcar1 protein, mouse
• Hydroxybenzoates
• Neuroprotective Agents
• Receptors, G-Protein-Coupled
• Resorcinols
• alpha-resorcylic acid
• Lactic Acid
• Glucose
• 3-Hydroxybutyric Acid

Topics

• 3-Hydroxybutyric Acid (pharmacology)
• Animals
• Brain Ischemia (drug therapy, physiopathology)
• Cell Death (drug effects, physiology)
• Cell Hypoxia (drug effects, physiology)
• Cell Line, Tumor
• Cells, Cultured
• Central Nervous System Agents (pharmacology)
• Cerebral Cortex (drug effects, physiopathology)
• Disease Models, Animal
• Glucose (deficiency)
• Hydroxybenzoates (pharmacology)
• Infarction, Middle Cerebral Artery
• Lactic Acid (administration & dosage, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Neurons (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Rats, Sprague-Dawley
• Receptors, G-Protein-Coupled (agonists, antagonists & inhibitors, metabolism)
• Resorcinols (pharmacology)