Peroxisome proliferator-activated receptor-gamma 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 m ay contribute to neurotoxicity in Alzheimer's disease (AD). Expression of i NOS 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 iNO S expression. We report here that microinjection of bacterial lipopolysacch aride and interferon gamma into rat cerebellum induced iNOS expression in C GCs and subsequent cell death assessed by staining for DNA fragmentation. C o-injection of three structurally distinct agonists of the peroxisome proli ferator-activated receptor gamma (PPAR gamma), including the antidiabetic t hiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSA ID) 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 s elective cyclo-oxygenase inhibitor NS-398 had no effect. These data demonst rate that PPAR gamma agonists can modulate inflammatory responses in brain. Because sustained medication with NSAIDs reduces the risk and delays the o nset of AD, these results further suggest that NSAIDs provide therapeutic v alue by binding to PPAR gamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.