Activation of type 4 metabotropic glutamate receptor attenuates oxygen and glucose deprivation-induced apoptosis in human neural stem cells via inhibition of ASK1-p38 signaling pathway.

Hypoxic ischemic brain injury (HIBI) has been one of the most severe central nervous system (CNS) diseases with high fatality and disability rate. Neural stem cells (NSCs) persist in the mammalian brain throughout life and NSCs-associated therapies might be a promising strategy for the HIBI treatment. In this study, we identified that type 4 metabotropic glutamate receptor (mGluR4) was expressed in cultured human NSCs (hNSCs) isolated from the human fetus cortex and further established the oxygen and glucose deprivation (OGD) model in hNSCs to study the role of mGluR4 in hypoxic and ischemic injury. The results indicated that mGluR4 activation by using VU0155041 (mGluR4-specific agonist) markedly attenuated the OGD-induced alterations in TUNEL staining, apoptosis rate, cleavages of pro-caspase-8, -9, -3, and Bcl-2/Bax expression balance. Furthermore, mGluR4 activation inhibited the ASK1/p38 signaling pathway. Asiatic acid, as a p38 MAPK activator, is capable of abolishing the neuroprotective effect of mGluR4, while both NQDI-1 (ASK-1 inhibitor) and SB203580 (p38 MAPK inhibitor) exerted similar effects to VU0155041 in the OGD-induced hNSC damage. In conclusion, this study indicates that mGluR4 activation protects hNSCs against the OGD-induced cell death via inhibiting the ASK1-p38 pathway. Activation of mGluR4 might be a promising strategy for enhancing NSCs survival in hypoxic and ischemic injury.