Differential effects of the nonsteroidal antiinflammatory drug flurbiprofen and its nitric oxide-releasing derivative, nitroflurbiprofen, on prostaglandin E(2), interleukin-1beta, and nitric oxide synthesis by activated microglia.
Increasing experimental, clinical, and epidemiological studies point to the pivotal role of inflammation in the pathogenesis of acute and chronic neurodegenerative diseases and to the protective effects of nonsteroidal antiinflammatory drug (NSAID) therapies. Nonetheless, NSAID long-term therapies are limited by their significant adverse effects on gastrointestinal tract and kidneys. Nitroflurbiprofen (NO-flurbiprofen) belongs to a novel class of antiinflammatory agents obtained by derivatization of conventional NSAIDs with a nitric oxide (NO)-releasing moiety, which strongly reduces their untoward side effects without altering the antiinflammatory effectiveness. The recent evidence of neuroprotective effects of NO-NSAIDs in animal models of chronic brain inflammation prompted us to investigate the activities of NO-flurbiprofen and its parent molecule flurbiprofen on activated rat microglia, the brain resident macrophages. We found that NO-flurbiprofen was as potent as flurbiprofen in preventing prostaglandin E(2) synthesis in lipopolysaccharide-activated microglial cultures. At variance with previous observations on peripheral macrophages is that NO-flurbiprofen did not show any additional capacity to inhibit interleukin-1beta synthesis compared with flurbiprofen. Moreover, NO enhanced the expression of the inducible NO synthase; this effect was most likely attributable to the NO released from the drug, as suggested by experiments performed in the presence of the NO donor Deta-NONOate, which similarly to NO-flurbiprofen is characterised by a slow and long-lasting release. Our findings indicate that NO-NSAIDs may differently affect peripheral and brain macrophages. Given their potential therapeutic role in brain inflammation, further in vivo and in vitro studies are required to understand fully their mechanism of action in the CNS.
Ajmone-Cat
M A
MA
Laboratory of Pathophysiology, Istituto Superiore di Sanità, Rome, Italy.
Nicolini
A
A
Minghetti
L
L
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D009573:Nitrites; D009603:Nitroso Compounds; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; C095631:nitroflurbiprofen; D009569:Nitric Oxide; D005480:Flurbiprofen; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone