Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase

Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-dihydro-6-methyl-4N-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-Delta(12,14) prostaglandin J(2) (PGJ(2)) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ(2) can activate the peroxisome proliferator-activated receptor-gamma (PPAR gamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPAR gamma in vivo and in vitro, our data suggest that activation of CGC PPAR gamma mediates iNOS suppression and reduced cell death. Because PPAR gamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in PLD. (C) 1999 Elsevier Science B.V. All rights reserved.