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 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 (PPARgamma), including the antidiabetic thiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and the prostanoid 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 PPARgamma 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 PPARgamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.
Heneka
M T
MT
Department of Neurology, University of Bonn, 53105 Bonn, Germany. m.heneka@uni-bonn.de
Klockgether
T
T
Feinstein
D L
DL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000008:administration & dosage / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D007052:Ibuprofen / Q000008:administration & dosage / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000008:administration & dosage; D008024:Ligands; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008845:Microinjections; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009578:Nitrobenzenes / Q000008:administration & dosage; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage / Q000378:metabolism; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*; D000077288:Troglitazone
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002839:Chromans; D016861:Cyclooxygenase Inhibitors; D008024:Ligands; D008070:Lipopolysaccharides; D009578:Nitrobenzenes; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D000077288:Troglitazone; D015230:Prostaglandin D2; D007052:Ibuprofen