The effect of leukotriene-B4 receptor antagonist, SC-41930, on acetic acid-induced colonic inflammation

Abstract

SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-p ropyl- 2H-1-benzopyran-2-carboxylic acid, is a potent in vitro leukotriene-B4 (LTB4) receptor antagonist. LTB4 levels are elevated in colonic tissue of inflammatory bowel disease (IBD) patients which may account for the high degree of neutrophil (PMN) infiltration. The guinea pig acetic acid-induced colonic inflammation model has characteristics of IBD including PMN infiltration, edema, ulceration and necrosis. The model was used to evaluate the effect of SC-41930. SC-41930 was given orally, 30 min before and after intrarectal administration of 3% acetic acid. The PMN marker enzyme, myeloperoxidase, was measured along with histological evaluation to assess inflammation. Both parameters showed significantly less inflammation in SC-41930 treated animals with an oral ED50 of 20 mg/kg. These study results with an LTB4 receptor antagonist indicate a role for LTB4 in colonic inflammation and that an LTB4 receptor antagonist may be beneficial for treatment of IBD.

Effects of Morin on an Experimental Model of Acute Colitis in Rats

“…The results obtained revealed that all the doses of morin which reduced macroscopic colonic damage significantly inhibited LTB 4 synthesis, and this inhibition was maximal at the highest dose of morin assayed (200 mg/kg). Since LTB 4 has been shown to potently promote neutrophil chemotaxis, adherence and degranulation in the TNBS-treated colon [27], this mechanim may account for the aforementioned decrease in MPO colonic activity. Furthermore, the diminished number of neutrophils in the colonic tissue in the morin-treated groups (10 and 25 mg/kg) may, at least partially, contribute to the reduction in LTB 4 production by the colonic tissue.…”

“…Ocete/Gá lvez/Crespo/Cruz/Gonzá lez/ Torres/Zarzuelo LTB 4 is considered as an important proinflammatory mediator in colonic inflammation [23,25], and inhibition of LTB 4 synthesis [25,26] or blockade of the LTB 4 receptor [27] is beneficial in experimental colitis, whereas administration of exogenous LTB 4 exacerbates inflammation [28]. Because morin is an inhibitor of 5-lipoxygenase [29], we tested whether its intestinal anti-inflammatory activity could be ascribed to a reduction in colonic LTB 4 synthesis.…”

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…Nevertheless, the exact role of these ligands and the two BLTR subtypes in IBD remains to be established. Whereas different BLTR antagonists inhibit colonic inflammation and neutrophil infiltration in animal models of IBD (Fretland et al, 1990(Fretland et al, , 1991, BLT 2 R-deficient mice exhibit exacerbated colonic inflammation (Iizuka et al, 2010).…”

Blockade of LTB4/BLT1 pathway improves CD8+ T-cell-mediated colitis

“…57 Fretland et al 57 investigated in several animal species (rat, guinea pig, and rabbit) the influence of locally administration of the BLT 1 antagonist SC-411930 on acetic acid-induced colitis. 58 They found that LTB 4 receptor antagonist substantially ameliorates colonic inflammation. However, it is not likely that protection in these models was due to blockade of the LTB 4 /BLT 1 pathway mediating chemotaxis of neutrophils and possibly monocytes, rather than T cells.…”