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Highlights • Global brain ischemia caused delayed neuronal death(DND) in CA1 hippocampus in rats. • The ischemia led to GLT-1 down-regulation and p-p38 MAPK up-regulation in rats. • Lethal OGD decreased GLT-1 and increased p-p38 MAPK expression in astrocytes. • SB203580 or p38 MAPK siRNA reduced neuronal death and GLT-1 decreasing after OGD. • SB203580 alleviated the DND and GLT-1 down-regulation after brain ischemia in rats. Abstract The previous studies have shown that glial glutamate transporter-1 (GLT-1) participates in cerebral ischemic injury in rats. However, the mechanism involved remains to be elucidated. This study was undertaken to investigate whether p38 MAPK was involved in regulating GLT-1 in the process. At first, it was observed that global brain ischemia for 8 min led to obvious delayed neuronal death, GLT-1 down-regulation and p-p38 MAPK up-regulation in CA1 hippocampus in rats. Then, whether p-p38 MAPK was involved in regulating GLT-1 during cerebral ischemic injury was studied in vitro. Astrocyte-neuron co-cultures exposed to oxygen and glucose deprivation (OGD) were used to mimic brain ischemia. It was observed that lethal OGD (4-h OGD) decreased GLT-1 expression and increased p-p38 MAPK expression in astrocytes. The p-p38 MAPK protein rised from 0 min to 48 h that is the end time of the observation, and the peak value was at 12 h, which was 12.45 times of the control group. Moreover, pre-administration of p38 MAPK inhibitor SB203580 or its siRNA dose-dependently increased GLT-1 expression, and meanwhile alleviated the neuronal death induced by lethal OGD. The above results indicated that p38 MAPK signaling pathway participated in regulating GLT-1 during OGD injury in vitro. Finally, back to in vivo experiment, it was found that pre-administration of SB203580 by intracerebroventricular injection dose-dependently reversed the down-regulation of GLT-1 expression and attenuated the delayed neuronal death normally induced by global brain ischemia in CA1 hippocampus in rats. Taken together, it can be concluded that the mechanism of GLT-1 mediating cerebral ischemic injury depends on the activation of p38 MAPK. [ABSTRACT FROM AUTHOR]

Our previous study showed that 3-min cerebral ischemic preconditioning (CIP) up-regulated the expression of glial glutamate transporter-1 (GLT-1) protein, which protects pyramidal neurons, allowing them to survive an 8-min ischemic insult that usually induces severe delayed neuronal death in the hippocampal CA1 subfield. In the present study, in situ hybridization and immunohistochemistry were used to observe whether GLT-1 mRNA is modulated and whether actrocytes and/or neurons express GLT-1 mRNA during the induction of brain ischemic tolerance. We observed that GLT-1 mRNA is expressed in neurons and astrocytes in the hippocampal CA1 subfield. The expression of GLT-1 mRNA was significantly down-regulated in both neurons and astrocytes after the 8-min lethal ischemic insult. CIP for 3 min increased the expression of GLT-1 mRNA in neurons and astrocytes, and induced the elongation of the astrocytic processes around pyramidal neurons. It may be concluded that CIP performed 2 days before lethal ischemic insult activated astrocytes, which resulted in an increased number of lengthened processes expressing high levels of GLT-1, which protected the neurons and allowed them to survive 8-min ischemic insult that is usually lethal to neurons in the hippocampal CA1 subfield.