Traumatic brain injury (TBI) is often caused by accidents that damage the brain. 
TBI can induce glutamate excitotoxicity and lead to neuronal and glial cell 
death. In this study, we investigated the mechanism of cell death during the 
secondary damage caused by TBI in vivo and in vitro, as well as the protective 
effect of resveratrol (RV). Here we report that glycogen synthase kinase-3β 
(GSK-3β) activation and microtubule-associated protein light chain 3 processing 
were induced in rat brains exposed to TBI. In the in vitro TBI model, apoptotic 
and autophagic cell death were induced through glutamate-mediated GSK-3β 
activation in normal CTX TNA2 astrocytes. The GSK-3β inhibitor SB216763 or 
transfection of GSK-3β small-interfering RNA increases cell survival. By 
contrast, overexpression of GSK-3β enhanced glutamate excitotoxicity. 
Administration of RV reduced cell death in CTX TNA2 astrocytes by suppressing 
reactive oxygen species (ROS)-mediated GSK-3β activation, the mechanism by which 
RV also exerted protective effects in vivo. Mitochondrial damages, including the 
opening of mitochondrial permeability transition pore (MPTP) and mitochondrial 
depolarization, were induced by glutamate through the ROS/GSK-3β pathway. 
Moreover, cyclosporine A, an MPTP inhibitor, suppressed mitochondrial damage and 
the percentages of cells undergoing autophagy and apoptosis and thereby 
increased cell survival. Taken together, our results demonstrated that cell 
death occurring after TBI is induced through the ROS/GSK-3β/mitochondria 
signaling pathway and that administration of RV can increase cell survival by 
suppressing GSK-3β-mediated autophagy and apoptosis. Therefore, the results 
indicated that resveratrol may serve as a potential therapeutic agent in the 
treatment of TBI.