Neuroprotection by rosiglitazone in transient focal cerebral ischemia might not be mediated by glutamate transporter-1.

Glutamate transport represents a key mechanism for maintaining low level of glutamate in the extracellular milieu to restrict the excitotoxic action of glutamate released during ischemia/reperfusion (I/R) injury. Recently, it has been reported that glutamate transporter-1 (GLT-1) is a novel target for peroxisome proliferator-activated receptor-γ (PPARγ) agonist, which shows neuroprotection following oxygen glucose deprivation (OGD) in neuronal-astrocytic cocultures. Hence, the present study was undertaken to investigate the role of rosiglitazone in neuroprotection mediated by GLT-1 following focal cerebral I/R injury in rat. We found that rosiglitazone (2 mg/kg i.p) administered pre- or post-I/R injury significantly improved behavioral outcome and decreased cerebral infarct volume. However, no significant changes were observed in GLT-1 mRNA and protein expression in rosiglitazone-treated rats following 1 hr of ischemia/24 hr of reperfusion (1/24 hr I/R) injury. Interestingly, bioinformatics analysis also does not reveal any PPAR response element on the GLT-1/EAAT2 promoter region. Further rosiglitazone neither increased [(3) H]glutamate uptake in glia-enriched preparations nor caused any change in glutamine synthetase activity. On the other hand, there was a significant (P < 0.05) downregulation in tumor necrosis factor-α and interleukin-1β gene expression, which were more pronounced in the posttreatment group. The posttreatment with rosiglitazone also significantly reduced the increase in prostaglandin E2 level in the ischemic brain. Therefore, the present findings suggest that the neuroprotective effect of rosiglitazone does not seem to be mediated by modulation of GLT-1 protein expression/activity in a focal cerebral ischemia model. However, the results do provide increasing evidence that the neuroprotective effect may be mediated by its antiinflammatory action.