Glutamate Provides Cytoprotective Effect for Astrocytes Against Ischemic Insult and Promotes Astrogliosis

Glutamate-mediated excitotoxicity has been extensively explored as a therapeutic target for the development of potential treatments of neurological disorders including stroke. However, the effect of glutamate on astrocytes under pathological conditions has been less studied. Using primary astrocyte culture, we determined the effect of glutamate on astrocytes against ischemic insult. Glutamate provided a cytoprotective effect and acted as an alternative substrate for ATP production in primary astrocytes against oxygen glucose deprivation reoxygenation insult, which was blocked by glutamate uptake inhibition. The cytoprotective effect of glutamate appears to be astrocyte-specific, as glutamate dose-dependently induces cytotoxic action in murine hippocampal HT-22 cell line. Interestingly, the cytoprotective effect of glutamate against glucose deprivation was short-last, as no protection was observed after 3-day glucose deprivation. We determined the metabolic phenotype of primary astrocyte cultured in glucose or glutamate. Primary astrocytes cultured in glutamate displayed a different metabolic phenotype when compared to those cultured in glucose, evidenced by higher basal and maximal oxygen consumption rate (OCR), higher ATP production and proton leak-coupled OCR, as well as lower glycolysis. Furthermore, glutamate exposure resulted in astrocyte activation, evidenced by an increase in astrocyte size and GFAP expression. Our study demonstrated that glutamate exerts a dual effect on astrocytes under ischemic condition. Glutamate provides an alternative substrate for energy metabolism in the absence of glucose, thereby protecting astrocytes against ischemic insults. On the other hand, glutamate exposure induces astrogliosis. Modulation of glutamate uptake and metabolism in astrocytes may provide novel targets for alleviating ischemic injury and improving function recovery after ischemic stroke.