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-infl ammatory cytokines results in cell death that was potentiated by excess L-a rginine and inhibited by the selective iNOS inhibitor, 2-amino-dihydro-6-me thyl-4N-1,3-thiazine. The NO-mediated cell death was accompanied by increas ed caspase-3-like activity, DNA fragmentation and positive terminal transfe rase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory dr ugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-Delta(12,14) pros taglandin J(2) (PGJ(2)) downregulates iNOS expression and reduces subsequen t cell death. Since in other cell types, both NSAIDs and PGJ(2) can activat e the peroxisome proliferator-activated receptor-gamma (PPAR gamma) and dow nregulate cytokine levels and iNOS expression, and since CGCs express PPAR gamma in vivo and in vitro, our data suggest that activation of CGC PPAR ga mma mediates iNOS suppression and reduced cell death. Because PPAR gamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neurona l iNOS expression and apoptotic cell death have been described, these resul ts may help explain the basis for the beneficial effects of NSAIDs in PLD. (C) 1999 Elsevier Science B.V. All rights reserved.