Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A4 hydrolase

Abstract

Background and purpose: Leukotriene B4 (LTB4), formed by the sequential actions of the 5-lipoxygenase (5-LO) and leukotriene A 4 hydrolase (LTA4H), is a pro-inflammatory mediator implicated in the pathogenesis of inflammatory bowel disease. However, inhibitors of 5-LO have not proved to be consistent in their therapeutic efficacy in colitis. Another approach to inhibiting LTB4 synthesis is through the use of inhibitors of LTA4H, such as the novel, potent and selective compound, JNJ 26993135. Experimental approach: The effect of oral administration of JNJ 26993135 has been evaluated in a rat model of colitis provoked by colonic instillation of trinitrobenzenesulphonic acid (TNBS). The extent and severity of the macroscopic inflammatory response, the colonic levels of myeloperoxidase (MPO) and LTB4 and of the pro-inflammatory cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured. Key results: Oral administration of JNJ 26993135 (5, 15 and 30 mg kg-1, twice a day) dose-dependently reduced both the extent and intensity of the colonic inflammatory damage observed 3 days after TNBS challenge. JNJ 26993135 also dose-dependently reduced the elevated colonic levels of LTB4, as well as the inflammatory biomarkers, MPO, IL-6 and TNF-α. This dosing regimen was supported by the pharmacokinetic profile of JNJ 26993135, along with the demonstration of the inhibition of ex vivo production of LTB4 in whole blood following oral administration. Conclusions and implications: These results with JNJ 26993135 in the rat TNBS model support the role of LTB4 in colitis and the potential value of targeting LTA4H for the treatment of inflammatory bowel diseases. © 2008 Nature Publishing Group All rights reserved.