Curcumin protects neurons against oxygen‐glucose deprivation/reoxygenation‐induced injury through activation of peroxisome proliferator‐activated receptor‐γ function

The turmeric derivative curcumin protects against cerebral ischemic injury. We previously demonstrated that curcumin activates peroxisome proliferator‐activated receptor‐γ (PPARγ), 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 PPARγ. Curcumin (10 μM) potently enhanced PPARγ 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 PPARγ antagonist 2‐chloro‐5‐nitrobenzanilide (GW9662) and by prior transfection of a small‐interfering RNA (siRNA) targeting PPARγ, 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 PPARγ siRNA transfection mitigated the protective effects of curcumin on mitochondrial function. Curcumin suppressed IκB kinase phosphorylation and IκB degradation, thereby inhibiting nuclear factor‐κ B (NF‐κB) nuclear translocation, effects also blocked by GW9662 or PPARγ siRNA. Immunoprecipitation experiments revealed that PPARγ interacted with NF‐κB p65 and inhibited NF‐κB activation. The present study provides strong evidence that at least some of the neuroprotective effects of curcumin against OGD/R are mediated by PPARγ activation. © 2014 Wiley Periodicals, Inc.