Cyclooxygenase-independent mechanism of ibuprofen-induced antipyresis: the role of central vasopressin V1 receptors

Abstract

This study compared the antipyretic effects of ibuprofen and indomethacin regarding the efficacy in blocking fevers induced by lipopolysaccharide (LPS from E. coli) or pyrogenic mediators that act on prostaglandin (PG)-dependent and PG-independent pathways. The content of PGE₂ in the cerebrospinal fluid (CSF) and the dependence on central arginine vasopressin (AVP) release by both antipyretics were also compared during the reduction of LPS-induced fever. Finally, we investigated the effect of ibuprofen on hypothalamic cytokine content during LPS-induced fever. Ibuprofen (intraperitoneally, i.p.) dose-dependently inhibited the fever induced by LPS (intravenously, i.v.). Indomethacin (2 mg/kg) and ibuprofen (10 mg/kg) reduced the fever induced by i.c.v. injection of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, or arachidonic acid (AA). Ibuprofen, but not indomethacin, inhibited i.c.v. endothelin-1- and pre-formed pyrogenic factor (PFPF)-induced fever. Neither ibuprofen nor indomethacin affected fever by PGE₂ , PGF(2α) , or corticotrophin-releasing factor (CRF); however, both reduced the CSF PGE₂ content after LPS. Bilateral injection of the AVP V(1) receptor antagonist d(CH2)₅ Tyr(Me)AVP into the ventral septal area blocked both ibuprofen- and indomethacin-induced antipyresis. Ibuprofen did not modify the hypothalamic increase in either IL-1β or IL-6 induced by LPS. In conclusion, although the antipyretic effect of ibuprofen involves the blockage of central production of PGE₂ and the endogenous release of AVP, differently from low dose of indomethacin, ibuprofen not only reduced the fever induced by PGE₂ -dependent, but also, that induced by PGE₂ -independent endogenous pyrogens. Moreover, ibuprofen does not affect the hypothalamic synthesis/release of IL-1β and IL-6.

Central mediators involved in the febrile response: effects of antipyretic drugs

“…Additionally, similar to indomethacin, antipyresis that was promoted by ibuprofen was antagonized by a V 1 receptor antagonist. 101 Thus, one possibility is that the effectiveness of ibuprofen in reducing fever that is induced by PFPF, ET-1, 101 and CCL3, 123 all known PG-independent pyrogens, could be related to arginine vasopressin release.…”

Efeito da dipirona, 4-MAA e 4-AA sobre a resposta febril induzida pelo LPS e seus mediadores em ratos

“…Foi demonstrado que a aspirina, o salicilato de sódio, a indometacina e o ibuprofeno inibem a expressão gênica da forma induzida da enzima óxido sintase (iNOS) (AEBERHARD et al, 1995;AMIN et al, 1995;DI GIROLAMO et al, 2003); que a aspirina e o salicilato de sódio inibem a ativação do fator de transcrição NF-κB (KOPP;GHOSH, 1994;TAKADA et al, 2004) e de um fator nuclear à região promotora de TNF-α (TAKASHIBA et al, 1995); que a indometacina e etoricoxibe diminuem os níveis da subunidade p65 do NF-κB em ratos com câncer de pulmão (SETIA; SANYAL, 2012). Ainda, existem evidências de que o efeito antipirético da indometacina, salicilato e ibuprofeno seja inibido pelo antagonista de receptores V 1 da arginina-vasopressina (AVP) (ALEXANDER et al, 1989;WILKINSON;KASTING, 1985;De SOUZA et al, 2002;SOARES et al, 2011).…”