We investigate the effect of rosiglitazone, a ligand for peroxisome proliferator-activated receptor-gamma (PPAR gamma) with anti-inflammatory and anti-oxidative actions, on hippocampal injury and its roles in mitochondrial uncoupling protein 2 (UCP2) expression caused by transient global ischemia (TGI) in rats. Increased UCP2 expression was observed in mitochondria of hippocampal CA1 2-24 h after TGI/reperfusion, with maximal expression levels at 6-18 h. Administration of rosiglitazone to hippocampus 30 min prior to the onset of TGI further enhanced mitochondrial UCP2 expression 2-6 h following TGI/reperfusion. Rats subjected to TGI/reperfusion displayed a significant increase in lipid peroxidation, based on increased malondialdehyde (MDA) levels, in hippocampal CA1 mitochondria 2-6 h after reperfusion. Rosiglitazone significantly attenuated TGI/reperfusion -induced lipid peroxidation and suppressed hippocampal CA1 neuronal death based on the surviving neuronal counts. In conclusion, our results provide correlative evidence for the "PPAR gamma -> UCP2 -> neuroprotection" cascade in ischemic brain injury. (c) 2006 Elsevier Inc. All rights reserved.