The turmeric derivative curcumin protects against cerebral ischemic injury. We previously demonstrated that curcumin activates peroxisome proliferator-activated receptor-gamma (PPAR gamma), a ligand-activated transcription factor involved in both neuroprotective and anti-inflammatory signaling pathways. This study tested whether the neuroprotective effects of curcumin against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury of rat cortical neurons are mediated (at least in part) by PPAR gamma. Curcumin (10 mu M) potently enhanced PPAR gamma expression and transcriptional activity following OGD/R. In addition, curcumin markedly increased neuronal viability, as evidenced by decreased lactate dehydrogenase release and reduced nitric oxide production, caspase-3 activity, and apoptosis. These protective effects were suppressed by coadministration of the PPAR gamma antagonist 2-chloro-5-nitrobenzanilide (GW9662) and by prior transfection of a small-interfering RNA (siRNA) targeting PPAR gamma, treatments that had no toxic effects on healthy neurons. Curcumin reduced OGD/R-induced accumulation of reactive oxygen species and inhibited the mitochondrial apoptosis pathway, as indicated by reduced release of cytochrome c and apoptosis-inducing factor and maintenance of both the mitochondrial membrane potential and the Bax/Bcl-2 ratio. Again, GW9662 or PPAR gamma siRNA transfection mitigated the protective effects of curcumin on mitochondrial function. Curcumin suppressed I kappa B kinase phosphorylation and I kappa B degradation, thereby inhibiting nuclear factor-kappa B (NF-kappa B) nuclear translocation, effects also blocked by GW9662 or PPAR gamma siRNA. Immunoprecipitation experiments revealed that PPAR gamma interacted with NF-kappa B p65 and inhibited NF-kappa B activation. The present study provides strong evidence that at least some of the neuroprotective effects of curcumin against OGD/R are mediated by PPAR gamma activation. (C) 2014 Wiley Periodicals, Inc.