Weak Inhibitors of Cyclooxygenases May Exert Their Antinociceptive Effect by Modulation of Transcription Factors

Scheuren, Nicole; Bang, Holger; Münster, Tino; Brune, Kay; Pahl, Andreas

doi:10.1007/978-1-4899-1810-9_9

Cited by 3 publications

(1 citation statement)

References 15 publications

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“…This observation seems to support the notion that the antipyretic effects of such drugs are produced by COX-independent mechanisms [15,16]. Thus, it has been shown that ibuprofen, aspirin, and salicylate at higher concentrations than those required to block COX can inhibit the activation and translocation of transcription factors such as nuclear factor-jB (NF-jB) and consequently induce downregulation of pro-inflammatory cytokines [17][18][19]. Ibuprofen attenuated (i) the recruitment/activation of myeloperoxidase-expressing cells in the liver, (ii) the increase in hepatic COX-2 protein, and (ii) the increase in serum TNF-a in mice challenged with the agonistic, anti-Fas antibody, Jo2 [20].…”

Section: Fundamental and Clinicalsupporting

confidence: 61%

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

Soares

Cristofoletti

Júnior

et al. 2010

Fundamental &Amp; Clinical Pharmacology

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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.

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Section: Fundamental and Clinicalsupporting

confidence: 61%

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

Soares

Cristofoletti

Júnior

et al. 2010

Fundamental &Amp; Clinical Pharmacology

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CCL3/Macrophage inflammatory protein-1α induces fever and increases prostaglandin E2 in cerebrospinal fluid of rats: Effect of antipyretic drugs

et al. 2006

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

2015

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Fever is a complex signal of inflammatory and infectious diseases. It is generally initiated when peripherally produced endogenous pyrogens reach areas that surround the hypothalamus. These peripheral endogenous pyrogens are cytokines that are produced by leukocytes and other cells, the most known of which are interleukin-1β, tumor necrosis factor-α, and interleukin-6. Because of the capacity of these molecules to induce their own synthesis and the synthesis of other cytokines, they can also be synthesized in the central nervous system. However, these pyrogens are not the final mediators of the febrile response. These cytokines can induce the synthesis of cyclooxygenase-2, which produces prostaglandins. These prostanoids alter hypothalamic temperature control, leading to an increase in heat production, the conservation of heat, and ultimately fever. The effect of antipyretics is based on blocking prostaglandin synthesis. In this review, we discuss recent data on the importance of prostaglandins in the febrile response, and we show that some endogenous mediators can still induce the febrile response even when known antipyretics reduce the levels of prostaglandins in the central nervous system. These studies suggest that centrally produced mediators other than prostaglandins participate in the genesis of fever. Among the most studied central mediators of fever are corticotropin-releasing factor, endothelins, chemokines, endogenous opioids, and substance P, which are discussed herein. Additionally, recent evidence suggests that these different pathways of fever induction may be activated during different pathological conditions.

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Weak Inhibitors of Cyclooxygenases May Exert Their Antinociceptive Effect by Modulation of Transcription Factors

Cited by 3 publications

References 15 publications

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

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

CCL3/Macrophage inflammatory protein-1α induces fever and increases prostaglandin E2 in cerebrospinal fluid of rats: Effect of antipyretic drugs

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

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