Effects of zileuton, a new 5-lipoxygenase inhibitor, in experimentally induced colitis in rats.
The efficacy of zileuton, a new 5-lipoxygenase inhibitor, was investigated in comparison with sulphasalazine in an experimental model of rat colitis. Under light anaesthesia with ether, male rats were subjected to intracolonic administration of trinitrobenzene sulfonic acid (TNB) in 50% ethanol and were then sacrificed 2, 4 and 7 days after colitis induction. Untreated rats exhibited elevated colonic levels of leukotriene B4 (LTB4) and 6-keto-PGF1 alpha, and an increase in colonic myeloperoxidase (MPO) activity (investigated as an index of leukocyte adhesion and accumulation). Moreover, ulceration and inflammation of the distal colon with formation of granuloma and pathologic connections were observed. Treated rats received zileuton or sulphasalazine (50 mg/kg per os twice a day) 24 h before the induction of colitis until they were sacrificed. Treatment with the specific 5-lipoxygenase inhibitor, zileuton, resulted in significant reductions of colonic leukotriene B4 and 6-keto-PGF1 alpha synthesis, macroscopic and histological colonic damage and colonic inflammation as assessed by the measurement of MPO activity. In contrast, sulphasalazine had a lower effect than zileuton on LTB4 and MPO levels (p < 0.05), while it was able to reduce colonic damage and 6-keto-PGF1 alpha levels as well as zileuton. This study shows, therefore, that zileuton is effective in attenuating the lesions in an experimental model of colitis. Furthermore, the results are consistent with the hypothesis that leukotrienes play an important role in the pathogenesis of intestinal bowel diseases (IBD).
Zingarelli
B
B
Institute of Pharmacology, School of Medicine, University of Messina, Italy.
Squadrito
F
F
Graziani
P
P
Camerini
R
R
Caputi
A P
AP
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015777:Eicosanoids / Q000096:biosynthesis; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects; D016859:Lipoxygenase Inhibitors / Q000627:therapeutic use*; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012460:Sulfasalazine / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid
D015777:Eicosanoids; D016859:Lipoxygenase Inhibitors; D012460:Sulfasalazine; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; C063449:zileuton; D006918:Hydroxyurea