Ovarian cancer G-protein-coupled receptor 1 (OGR1, also known as GPR68) is a member of proton-sensing G-protein-coupled receptors, involved in cardiovascular physiology, tumor biology, and asthma, and exerts a neuroprotective effect against brain ischemia. The effects of GPR68 on anesthesia-induced nerve damage and myelination were investigated in this study. First, 2-day old postnatal rats were exposed to 4.9% sevoflurane for 2 h. Data from hematoxylin and eosin staining and Nissl staining showed that sevoflurane induced pathological changes in the hippocampus with a reduced number of neurons. GPR68 was downregulated in the hippocampus of sevoflurane-induced rats. Second, sevoflurane-induced rats were injected with adeno-associated virus (AAV)-mediated overexpression of GPR68, and overexpression of GPR68 ameliorated sevoflurane-induced pathological changes, enhanced the number of neurons, and improved the learning and memory function. Moreover, overexpression of GPR68 increased the number of BrdU-positive and Olig2-positive cells and enhanced protein expression of Olig2 in sevoflurane-induced rats. Third, the number of myelin basic protein (MBP) positive cells and protein expression of MBP in sevoflurane-induced rats were also enhanced by injection with AAV-GPR68. Overexpression of GPR68 attenuated sevoflurane-induced neuronal apoptosis and oxidative stress in rats. Lastly, overexpression of GPR68 upregulated protein expression of the brain-derived neurotrophic factor (BDNF) by increasing cAMP and phosphorylated cAMP response element-binding protein (CREB). In conclusion, GPR68 alleviated sevoflurane-induced nerve damage and myelination through BDNF-mediated activation of the cAMP/CREB pathway.
Keywords: BDNF; GPR68; activation of cAMP/CREB; myelination; nerve damage; preterm neonates; sevoflurane.