Gastroprotective effect of zafirlukast against indomethacin induced gastric ulcer in rats via PGE2 and anti-inflammatory pathways

Document Type : Original Article


1 Department of Pharmacology, College of Pharmacy, University of Misan, Misan, Iraq

2 Department of Clinical Pharmacy, College of Pharmacy, University of Karbala, Karbala, Iraq

3 Al Rashad Hospital, Al-Rusafa Health Directorate, Baghdad, Iraq

4 Department of Biotechnology, College of Applied Sciences, University of Technology, Baghdad, Iraq


Objective(s): To evaluate the gastroprotective potential of zafirlukast against indomethacin-induced gastric ulcers in rats.
Materials and Methods: Thirty-two male Wistar rats were included in this study and randomly divided into 4 equal groups (n=8); control (normal) group, indomethacin group, Ranitidine group, and Zafirlukast group. Indomethacin was given as a single oral dose of (20 mg/kg) for the induction of ulcers. Both ranitidine (50 mg/kg) and zafirlukast (20 mg/ kg) were given orally for seven days after inducing the ulcer. All animals were sacrificed by an overdose of anesthesia at the end of the experimental period and their gastric tissues have been collected for histopathological and biological assay. Levels of prostaglandin E2 (PGE2), thiobarbituric acid reactive substances (TBARS), and interleukin 1β (IL-1β ) were measured as well as a histopathological study to evaluate the effect of zafirlukast on gastric tissues.
Results: Significant abnormalities were found in both the histological and biochemical parameters of the indomethacin group reflecting the changes seen with gastric ulcers. Significant improvement was found in the Zafirlukast group as reflected by the morphological improvement seen in the gastric tissues. An effect that was associated with an increase in the PGE2 levels along with reductions in IL-1β expression and TBARS concentrations.
Conclusion: As per the results of this study, zafirlukast shows promising gastroprotective properties possibly through enhancement of PGE2 levels as well as having anti-inflammatory and anti-oxidant properties.


Main Subjects

1. Vaananen PM, Keenan CM, Grisham MB, Wallace JL. Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy. Inflammation 1992; 16:227-240.
2. Gao H, Li L, Zhang C, Tu J, Geng X, Wang J, et al. Comparison of efficacy of pharmacological therapies for gastric endoscopic submucosal dissection-induced ulcers: A systematic review and network meta-analysis. Expert Rev Gastroenterol Hepatol 2020; 14:207-220.
3. Milivojevic V, Milosavljevic T. Burden of gastroduodenal diseases from the global perspective. Curr Treat Options Gastroenterol 2020, 18:148-157.
4. Sostek MB, Fort JG, Estborn L, Vikman K. Long-term safety of naproxen and esomeprazole magnesium fixed-dose combination: Phase III study in patients at risk for NSAID-associated gastric ulcers. Curr Med Res Opin 2011; 27:847-854.
5. García-Rayado G, Navarro M, Lanas A. NSAID induced gastrointestinal damage and designing GI-sparing NSAIDs. Expert Rev Clin Pharmacol 2018; 11:1031-1043.
6. Suleyman H, Albayrak A, Bilici M, Cadirci E, Halici Z. Different mechanisms in formation and prevention of indomethacin-induced gastric ulcers. Inflammation 2010; 33:224-234.
7. Ruiz-Hurtado PA, Garduño-Siciliano L. Propolis and its gastroprotective effects on NSAID-induced gastric ulcer disease: A systematic review.  Nutrients 2021; 13:1-33.
8. Dengiz GO, Odabasoglu F, Halici Z, Suleyman H, Cadirci E, Bayir Y. Gastroprotective and anti-oxidant effects of amiodarone on indomethacin-induced gastric ulcers in rats. Arch Pharm Res 2007; 30:1426-1434.
9. Damtew B, Marino JA, Fratianne RB, Spagnuolo PJ. Neutrophil lipoxygenase metabolism and adhesive function following acute thermal injury. J Lab Clin Med 1993; 121:328-336.
10. Hedi H, Norbert G. 5-Lipoxygenase pathway, dendritic cells, and adaptive immunity. J Biomed Biotechnol 2004; 2004:99-105.
11. Muthuraman A, Sood S. Antisecretory, anti-oxidative and antiapoptotic effects of montelukast on pyloric ligation and water immersion stress induced peptic ulcer in rat. Prostaglandins Leukot Essent Fat Acids 2010; 83:55-60.
12. Matsuyama M, Funao K, Chargui J, Touraine JL, Nakatani T, Yoshimura R. The role of cysteinyl-LT(1)receptor (CysLT(1)R) in renal ischemia-reperfusion injury. Transplant Proc 2009; 41:73-75.
13. Choi J, Azmat CE. Leukotriene receptor antagonists.  StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC.; 2023.
14. Dempsey OJ. Leukotriene receptor antagonist therapy. Postgrad Med J 2000; 76:767-773.
15. Rizk FH, Ibrahim MAA, Abd-Elsalam MM, Soliman NA, Abd-Elsalam SM. Gastroprotective effects of montelukast and Nigella sativa oil against corticosteroid-induced gastric damage: They are much more than antiasthmatic drugs. Can J Physiol Pharmacol 2017; 95:714-720.
16. Shahin NN, Abdelkader NF, Safar MM. A Novel role of irbesartan in gastroprotection against indomethacin-induced gastric injury in rats: Targeting DDAH/ADMA and EGFR/ERK signaling. Sci Rep 2018; 8:4280-4292.
17. Al-Zubaidy AA, Khalil AM. Gastroprotective effect of capparis spinosa on indomethacin-induced gastric ulcer in rats. Arch Razi Inst 2022; 77:1429-1437.
18. Odabasoglu F, Cakir A, Suleyman H, Aslan A, Bayir Y, Halici M, et al. Gastroprotective and anti-oxidant effects of usnic acid on indomethacin-induced gastric ulcer in rats. J Ethnopharmacol 2006; 103:59-65.
19. Ateufack G, Domgnim Mokam EC, Mbiantcha M, Dongmo Feudjio RB, David N, Kamanyi A. Gastroprotective and ulcer healing effects of piptadeniastrum africanum on experimentally induced gastric ulcers in rats. BMC Complement Altern Med 2015; 15:214-224.
20. Hagar HH, Abd El Tawab R. Cysteinyl leukotriene receptor antagonism alleviates renal injury induced by ischemia-reperfusion in rats. J Surg Res 2012; 178:25-34.
21. Zatroch KK, Knight CG, Reimer JN, Pang DSJ. Refinement of intraperitoneal injection of sodium pentobarbital for euthanasia in laboratory rats (rattus norvegicus). BMC Vet Res 2017; 13:60-67.
22. Wang WQ, Wang FH, Qin WX, Liu HY, Lu B, Chung C, et al. Joint antiangiogenic effect of ATN-161 and anti-VEGF antibody in a rat model of early wet age-related macular degeneration. Mol Pharm 2016; 13:2881-2890.
23. Bangun H, Arianto A, Rehngenana E. Anti-ulcer effect of gastroretentive drug delivery system of alginate beads containing turmeric extract solid dispersion. Open Access Maced J Med Sci 2021; 9:19-27.
24. AlKreathy HM, Alghamdi MK, Esmat A. Tetramethylpyrazine ameliorates indomethacin-induced gastric ulcer in rats: Impact on oxidative, inflammatory, and angiogenic machineries. Saudi Pharm J 2020; 28:916-926.
25. Tamura T, Yokoyama T, Ohmori K. Effects of diacerein on indomethacin-induced gastric ulceration. Pharmacology 2001; 63:228-233.
26. Suleyman H, Albayrak A, Bilici M, Cadirci E, Halici Z. Different mechanisms in formation and prevention of indomethacin-induced gastric ulcers. Inflammation 2010; 33:224-234.
27. El-Saka M, Abo Zeid A, Abou Fard G. Effect of L-citrulline and ranitidine on indomethacin-induced gastric ulcer in male albino wister rats. Bull Egypt Soc Physiol Sci 2014; 34:277-292.
28. Adkins JC, Brogden RN. Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma. Drugs 1998; 55:121-144.
29. Holma R, Salmenpera P, Riutta A, Virtanen I, Korpela R, Vapaatalo H. Acute effects of the cys-leukotriene-1 receptor antagonist, montelukast, on experimental colitis in rats. Eur J Pharmacol 2001; 429:309-318.
30. Bertrand V, Guessous F, Le Roy AL, Viossat B, Fessi H, El Abbouyi A, et al. Copper-indomethacinate associated with zwitterionic phospholipids prevents enteropathy in rats: Effect on inducible NO synthase. Dig Dis Sci 1999; 44:991-999.
31. Jaldani V, Dezfoulian O, Shahsavari G. Betaine improves gastroprotective effects of ranitidine and omeprazole against indomethacin-induced gastric ulcer in rats. Herb Med J 2017; 2:9-17.
32. Mahgoub AA, El-Medany AA, Hager HH, Mustafa AA, El-Sabah DM. Evaluating the prophylactic potential of zafirlukast against the toxic effects of acetic acid on the rat colon. Toxicol Lett 2003; 145:79-87.
33. Ugan RA, Un H. The protective roles of butein on indomethacin induced gastric ulcer in mice. Eurasian J Med 2020; 52:265-270.
34. Zhou X, Cai J, Liu W, Wu X, Gao C. Cysteinyl leukotriene receptor type 1 (CysLT1R) antagonist zafirlukast protects against TNF-alpha-induced endothelial inflammation. Biomed Pharmacother 2019; 111:452-459.
35. Tada N, Furukawa M, Ogura M, Arai S, Adachi Y, Ikehara S, et al. Experimental otitis media with effusion induced by leukotriene D4. Auris Nasus Larynx 2002; 29:127-132.