Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A 4 hydrolase

B. J R Whittle, C. Varga, A. Berkó, K. Horvath, A. Pósa, J. P. Riley, K. A. Lundeen, A. M. Fourie, P. J. Dunford

Research output: Contribution to journalArticle

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Abstract

Background and purpose: Leukotriene B 4 (LTB 4), formed by the sequential actions of the 5-lipoxygenase (5-LO) and leukotriene A 4 hydrolase (LTA 4H), 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 LTB 4 synthesis is through the use of inhibitors of LTA 4H, 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 LTB 4 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 LTB 4, 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 LTB 4 in whole blood following oral administration. Conclusions and implications: These results with JNJ 26993135 in the rat TNBS model support the role of LTB 4 in colitis and the potential value of targeting LTA 4H for the treatment of inflammatory bowel diseases.

Original languageEnglish
Pages (from-to)983-991
Number of pages9
JournalBritish Journal of Pharmacology
Volume153
Issue number5
DOIs
Publication statusPublished - Mar 2008

Fingerprint

Leukotriene A4
Leukotriene B4
Hydrolases
Colitis
Trinitrobenzenesulfonic Acid
Cytokines
Inflammation
Oral Administration
Inflammatory Bowel Diseases
Peroxidase
Interleukin-6
Tumor Necrosis Factor-alpha
Arachidonate 5-Lipoxygenase
Lipoxygenase Inhibitors
1-(4-(benzothiazol-2-yloxy)benzyl)piperidine-4-carboxylic acid
Pharmacokinetics
Biomarkers
Therapeutics

Keywords

  • 5-lipoxygenase
  • Colitis
  • Inflammatory bowel disease
  • Interleukin-6
  • JNJ 26993135
  • Leukotriene A hydrolase
  • Leukotriene B
  • LTA H
  • Tumour necrosis factor-α
  • Zileuton

ASJC Scopus subject areas

  • Pharmacology

Cite this

Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A 4 hydrolase. / Whittle, B. J R; Varga, C.; Berkó, A.; Horvath, K.; Pósa, A.; Riley, J. P.; Lundeen, K. A.; Fourie, A. M.; Dunford, P. J.

In: British Journal of Pharmacology, Vol. 153, No. 5, 03.2008, p. 983-991.

Research output: Contribution to journalArticle

Whittle, B. J R ; Varga, C. ; Berkó, A. ; Horvath, K. ; Pósa, A. ; Riley, J. P. ; Lundeen, K. A. ; Fourie, A. M. ; Dunford, P. J. / Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A 4 hydrolase. In: British Journal of Pharmacology. 2008 ; Vol. 153, No. 5. pp. 983-991.
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AU - Pósa, A.

AU - Riley, J. P.

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