Dynamic regulation of microglial functions by the non-steroidal anti-inflammatory drug NCX 2216: implications for chronic treatments of neurodegenerative diseases.
The nitric oxide-releasing derivative of flurbiprofen, NCX 2216, has a safer gastrointestinal profile than the parent drug flurbiprofen and a strong anti-amyloidogenic activity. Here, we show that in primary microglial cultures, in addition to the expected inhibition of prostaglandin synthesis, NCX 2216 specifically activated the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), a ligand-dependent transcription factor controlling several important microglial functions. Prolonged treatment (16 h) of microglial cultures with NCX 2216 induced PPAR-gamma nitration and prevented further activation of the receptor by specific agonists. At functional levels, NCX 2216 treatment of LPS-activated microglial cultures resulted in the transient reduction of TNF-alpha and NO production and in the protracted inhibition of IL-1beta and PGE2 synthesis. The dynamic regulation of the functional state of activated microglia by NCX 2216 helps explaining recent findings in Alzheimer's disease animal models and may offer new therapeutic opportunities for treating neurodegenerative diseases.
Bernardo
Antonietta
A
Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Gasparini
Laura
L
Ongini
Ennio
E
Minghetti
Luisa
L
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D015232:Dinoprostone / Q000096:biosynthesis; D004660:Encephalitis / Q000188:drug therapy* / Q000503:physiopathology; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005911:Gliosis / Q000188:drug therapy* / Q000503:physiopathology; D007375:Interleukin-1 / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000503:physiopathology; D009566:Nitrates / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C450321:(3-4-(2-fluoromethyl-(1,1'-biphenyl)-4-acetyloxy)-3-methoxyphenyl)-2-propenoic acid 4-nitrooxy butyl ester; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D009566:Nitrates; D047495:PPAR gamma; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D005480:Flurbiprofen; D015232:Dinoprostone