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)