Previous studies have shown that GSK-3 beta inhibitor could reduce infarct volume after ischemia brain injury. However, the underlying mechanisms of GSK-3 beta inhibitor involving neuroprotection remain poorly understood. In the present study, we demonstrated that GSK-3 beta inhibitor suppressed insult-induced neuroinflammation in rat cortex by increasing autophagy activation in ischemic injury. Male rats were subjected to pMCAO (permanent middle cerebral artery occlusion) followed by treating with SB216763, a GSK-3 beta inhibitor. We found that insult-induced inflammatory response was significantly decreased by intraperitoneal infusion of SB216763 in rat cortex. A higher level of autophagy was also detected after SB216763 treatment. In the cultured primary microglia, SB216763 activated autophagy and suppressed inflammatory response. Importantly, inhibition of autophagy by Beclin1-siRNA increased inflammatory response in the SB216763-treated microglia. These data suggest that GSK-3 beta inhibitor suppressed neuroinflammation by activating autophagy after ischemic brain injury, thus offering a new target for prevention of ischemic brain injury. (C) 2011 Elsevier Inc. All rights reserved.