Inhibition of brain cyclooxygenase-2 activity and the antipyretic action of nimesulide

• Published in: European journal of pharmacology 1997-07, Vol.330 (2), p.221-229
• Main Authors: Taniguchi, Yasuaki, Yokoyama, Kazuyuki, Inui, Keiichiro, Deguchi, Yoshiki, Furukawa, Koji, Noda, Kanji
• Format: Article
• Language: English
• Subjects: Analgesics; Analgesics, Non-Narcotic - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antipyretic action; Biological and medical sciences; Body Temperature; Brain - enzymology; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Female; Fever - drug therapy; Fever - enzymology; Fever - metabolism; Hypothalamus; Hypothalamus - metabolism; Isoenzymes - biosynthesis; Isoenzymes - metabolism; Male; Medical sciences; Membrane Proteins; Neuropharmacology; Nimesulide; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - biosynthesis; Prostaglandin-Endoperoxide Synthases - metabolism; Rats; Rats, Wistar; RNA, Messenger - metabolism; RT-PCR (reverse transcription and polymerase chain reaction); Sulfonamides - pharmacology; Yeast-induced hyperthermia
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(97)00183-0

The antipyretic action and the mechanism of action of 4-nitro-2-phenoxymethanesulfonanilide (nimesulide), a new nonsteroidal antiinflammatory drug, were investigated in yeast-induced febrile rats. Yeast-injected rats developed marked fever and exhibited an approximately 7-fold increase in brain levels of prostaglandin E 2 and an approximately 2-fold increase in the expression of cyclooxygenase-2 mRNA despite an almost unchanged expression of cyclooxygenase-1 mRNA. Nimesulide produced a dose dependent antipyretic action, which was stronger than that of indomethacin and ibuprofen, and decreased dose dependently the increased brain prostaglandin E 2 levels, whereas it did not influence the expression of cyclooxygenase-2 mRNA. It inhibited markedly the enhanced brain cyclooxygenase activity, primarily cyclooxygenase-2, in vivo and dose dependently increased brain cyclooxygenase activity in vitro. These results suggest that the marked antipyretic action of nimesulide is primarily mediated through the selective inhibition of the activity of brain cyclooxygenase-2 induced under febrile conditions.