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

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 4 H), 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 4 H, 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-a (TNF-a) and interleukin-6 (IL-6) were measured. Key results: Oral administration of JNJ 26993135 (5, 15 and 30 mg kg À1 , 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 dosedependently reduced the elevated colonic levels of LTB 4 , as well as the inflammatory biomarkers, MPO, IL-6 and TNF-a. 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 4 H for the treatment of inflammatory bowel diseases.

Effects of Magnetic Infrared Laser Irradiation on Formalin-Induced Chronic Paw Inflammation of Mice

“…TNF-α, a 17-kDa protein, which was first identified as a product of activated macrophages, is a well-known proinflammatory cytokine 25) and it is involved in various inflammations 11,26) . Recently, evidence has been provided of the widespread role of TNF-α in mediating hyperalgesia at different levels 8) , both facilitating neuronal excitability and triggering the release of other pro-inflammatory substances 9,10) .…”

Systematic review of animal models of post-infectious/post-inflammatory irritable bowel syndrome

“…The acute transmural damage became maximal from 3 days to 1 week after instillation, and resolved within 2 weeks [90][91][92]. The TNBS-induced colitis may be mediated by reactive oxygen metabolites and various inflammatory mediators, such as prostaglandin E 2 , interleukin and platelet-activating factor [93][94][95].…”

Targeting leukotriene B4in inflammation

“…Structurebased drug design also allowed Berlex to design a series of glutamic acid analogs as potent LTA 4 H inhibitors [112]. Johnson&Johnson also started a drug program culminating in the development of (1-[4-(benzothiazol-2-yloxy)benzyl]piperidine)-4-carboxylic acid (JNJ-26993135) ( Table 3), which showed beneficial effects for the treatment of inflammatory bowel disease, allergic airway inflammation, and pulmonary hypertension in preclinical studies [113][114][115][116]. Moreover, it is interesting to note that JNJ-26993135 was more efficacious than zileuton for blocking the influx of neutrophils into the peritoneum in a peritonitis mouse model [113].…”

“…Treatment of inflammatory bowel diseases and allergic airway inflammation in pre-clinical models [113,114,116] DG-051…”