Peroxisome proliferator-activated receptor-γ ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo

Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD). Expression of iNOS can be induced in cerebellar granule cells (CGCs) in vivo as well as in vitro, allowing these cells to be used to study regulation of neuronal iNOS expression. We report here that microinjection of bacterial lipopolysaccharide and interferon gamma into rat cerebellum induced iNOS expression in CGCs and subsequent cell death assessed by staining for DNA fragmentation. Co-injection of three structurally distinct agonists of the peroxisome proliferator-activated receptor gamma (PPAR gamma), including the antidiabetic thiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and the pro-stanoid 15-deoxy-Delta 12,14 prostaglandin J(2), reduced both iNOS expression and cell death, whereas co-injection of the selective cyclo-oxygenase inhibitor NS-398 had no effect. These data demonstrate that PPAR gamma agonists can modulate inflammatory responses in brain. Because sustained medication with NSAIDs reduces the risk and delays the onset of AD, these results further suggest that NSAIDs provide therapeutic value by binding to PPAR gamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.