Evaluation of the ability of carprofen and flunixin meglumine to inhibit activation of nuclear factor kappa B

Clare E. Bryant Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Rd, Cambridge, UK CB3 OES.

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Belinda A. Farnfield Department of Clinical Veterinary Medicine, University of Cambridge, Madingley Rd, Cambridge, UK CB3 OES.

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Heidi J. Janicke Department of Large Animal Clinical Studies, Division of Veterinary Clinical Science, University College Dublin, Lyons Estate, Celbridge, County Kildare, Ireland.

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 DVM, PhD

Abstract

Objective—To determine whether the nonsteroidal anti-inflammatory drugs (NSAIDs) carprofen, flunixin meglumine, and phenylbutazone have cyclooxygenase (COX)-independent effects that specifically inhibit activation of the proinflammatory transcription factor nuclear factor kappa B (NfκB).

Study Population—Purified ovine COX-1 and -2 and cultures of RAW 264.7 murine macrophages.

Procedure—The COX-1 and -2 inhibitory effects of the NSAIDs were tested in assays that used purified ovine COX-1 and -2. Prostaglandin production was analyzed by use of a radioimmunoassay. Inhibitory effects of these drugs on lipopolysaccharide (LPS)- induction of inducible nitric oxide synthase (iNOS) and LPS-stimulated translocation of NfκB were determined by use of RAW 264.7 murine macrophages.

Results—Flunixin meglumine and phenylbutazone were selective inhibitors of COX-1. Carprofen and flunixin meglumine, but not phenylbutazone, inhibited LPS-induction of iNOS. Carprofen and, to a lesser degree, flunixin meglumine had inhibitory effects on NFκB activation.

Conclusions and Clinical Relevance—The ability of drugs such as carprofen and flunixin meglumine to inhibit activation of NfκB-dependent genes such as iNOS, in addition to their effects on COX, suggests an additional mechanism for their anti-inflammatory effects and may explain the ability of flunixin meglumine to be an effective inhibitor of the effects of endotoxin in horses with endotoxemia. (Am J Vet Res 2003;64:211–215)

Abstract

Objective—To determine whether the nonsteroidal anti-inflammatory drugs (NSAIDs) carprofen, flunixin meglumine, and phenylbutazone have cyclooxygenase (COX)-independent effects that specifically inhibit activation of the proinflammatory transcription factor nuclear factor kappa B (NfκB).

Study Population—Purified ovine COX-1 and -2 and cultures of RAW 264.7 murine macrophages.

Procedure—The COX-1 and -2 inhibitory effects of the NSAIDs were tested in assays that used purified ovine COX-1 and -2. Prostaglandin production was analyzed by use of a radioimmunoassay. Inhibitory effects of these drugs on lipopolysaccharide (LPS)- induction of inducible nitric oxide synthase (iNOS) and LPS-stimulated translocation of NfκB were determined by use of RAW 264.7 murine macrophages.

Results—Flunixin meglumine and phenylbutazone were selective inhibitors of COX-1. Carprofen and flunixin meglumine, but not phenylbutazone, inhibited LPS-induction of iNOS. Carprofen and, to a lesser degree, flunixin meglumine had inhibitory effects on NFκB activation.

Conclusions and Clinical Relevance—The ability of drugs such as carprofen and flunixin meglumine to inhibit activation of NfκB-dependent genes such as iNOS, in addition to their effects on COX, suggests an additional mechanism for their anti-inflammatory effects and may explain the ability of flunixin meglumine to be an effective inhibitor of the effects of endotoxin in horses with endotoxemia. (Am J Vet Res 2003;64:211–215)

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