Amelioration of acetic acid-induced ulcerative colitis in rats by cetirizine and loratadine via regulation of the PI3K/Akt/Nrf2 signalling pathway and pro-inflammatory cytokine release

Document Type : Original Article

Authors

Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt

Abstract

Objective(s): Ulcerative colitis is a chronic inflammatory bowel disease (IBD) that causes inflammation and ulcers in the rectum and the innermost layer of the large intestine. Our study aimed to elucidate the ameliorative effect of cetirizine (CTZ) and loratadine (LOR) against acetic acid-induced ulcerative colitis in rats via assessment of the PI3K/p-Akt/Nrf2 signaling pathway and proinflammatory cytokine release.
Materials and Methods: Thirty-two rats were allocated into four groups (n=8). Group (I) was considered normal control. Acetic acid (AA) was injected intrarectally in groups (2-4). Group (2) was kept untreated. Group (3) was administered CTZ (20 mg/kg/day) for 7 days. Group (4) was administered LOR (10 mg/kg/day) for 7 days.
Results: AA showed severe macroscopic colonic lesions associated with increased ulcer number, area, and severity with significantly elevated PI3K, p-Akt, Nrf2, TNF-α, and IL-6 in colorectal tissue as compared to the normal control group. All the aforementioned indicators were greatly improved by CTZ and LOR therapy.
Conclusion: This is the first study to elucidate the ameliorative effect of CTZ and LOR against AA-induced UC in rats. CTZ and LOR treatment mitigates UC via amelioration of the PI3K/p-Akt/Nrf2 pathway and proinflammatory cytokine release.

Keywords

Main Subjects


1. Abraham B, Quigley EMM. Antibiotics and probiotics in inflammatory bowel disease: When to use them? Frontline Gastroenterol 2020 ;11:62-69. 
2. Cohen LJ, Cho JH, Gevers D, Chu H. Genetic factors and the intestinal microbiome guide development of microbe-based therapies for inflammatory bowel diseases. Gastroenterology 2019;156:2174-2189.
3. Ulcerative Colitis: Symptoms, Treatment & Living With It & Diagnosis [Internet]. [cited 2023 Sep 26]. Available from: https://my.clevelandclinic.org/health/diseases/10351-ulcerative-colitis
4. Berre C Le, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet 2023;402:571-584.
5. Wang R, Li Z, Liu S, Zhang D. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: A systematic analysis based on the Global Burden of Disease Study 2019. BMJ Open 2023;13:e065186-65199.
6. Xia B, Shivananda S, Zhang GS, Yi JY, Crusius JB, Peka AS. Inflammatory bowel disease in the Hubei Province of China. World J Gastroenterol 1997;3:119-120.
7. Owusu G, Obiri DD, Ainooson GK, Osafo N, Antwi AO, Duduyemi BM, et al. Acetic acid-induced ulcerative colitis in sprague dawley rats is suppressed by hydroethanolic extract of cordia vignei leaves through reduced serum levels of TNF- α and IL-6. Int J chronic Dis 2020;2020:1-11.
8. Rafeeq M, Murad HAS, Abdallah HM, El-Halawany AM. Protective effect of 6-paradol in acetic acid-induced ulcerative colitis in rats. BMC Complement Med Ther 2021; 21:28-37.
9. Kucharzik T, Koletzko S, Kannengießer K, Dignaß A. Ulcerative colitis-diagnostic and therapeutic algorithms. Dtsch Arztebl Int 2020;117:564–573.
10. Meier J, Sturm A. Current treatment of ulcerative colitis. World J Gastroenterol 2011;17:3204.
11. Ercan G, Yigitturk G, Erbas O. Therapeutic effect of adenosine on experimentally induced acute ulcerative colitis model in rats. Acta Cirúrgica Bras. 2019; 34:e201901204-201901212.
12. Naqvi A, Gerriets V. Cetirizine. xPharm Compr Pharmacol Ref 2023; 30: 1-6.
13. Levi-Schaffer F, Eliashar R. Mast cell stabilizing properties of antihistamines. J Invest Dermatol 2009;129:2549-2551.
14. Banks CN, Lein PJ. A review of experimental evidence linking neurotoxic organophosphorus compounds and inflammation. Neurotoxicology 2012;33:575-584.
15. AlMasoud N, Bakheit AH, Alshammari MFM, Abdel-Aziz HA, AlRabiah H. Loratadine. Profiles Drug Subst Excipients Relat Methodol 2022;47:55-90.
16. Huang Y, Zhang N, Bachert C. Innovative treatments for severe uncontrolled chronic rhinosinusitis with nasal polyps. Expert Rev Clin Immunol 2023; 19: 837-845.
17. Maurer M, Church MK, Gonçalo M, Sussman G, Sánchez‐Borges M. Management and treatment of chronic urticaria (CU). J Eur Acad Dermatol Venereol 2015; 29: 16-32.
18. Church MK, Church DS. Pharmacology of Antihistamines. Indian J Dermatol 2013;58:219.
19. Corsico AG, Leonardi S, Licari A, Marseglia G, Miraglia Del Giudice M, Peroni DG, et al. Focus on the cetirizine use in clinical practice: A reappraisal 30 years later. Multidiscip Respir Med 2019;14:1-7.
20. Kajanne R, Miettinen P, Mehlem A, Leivonen SK, Birrer M, Foschi M, et al. EGF‐R regulates MMP function in fibroblasts through MAPK and AP‐1 pathways. J Cell Physiol 2007; 212:489-497.
21. Fouad MR, Salama RM, Zaki HF, El-Sahar AE. Vildagliptin attenuates acetic acid-induced colitis in rats via targeting PI3K/Akt/NFκB, Nrf2 and CREB signaling pathways and the expression of lncRNA IFNG-AS1 and miR-146a. Int Immunopharmacol 2021:92:107354.
22. Edström A, Ekström PAR. Role of phosphatidylinositol 3-kinase in neuronal survival and axonal outgrowth of adult mouse dorsal root ganglia explants. J Neurosci Res 2003;74:726-735.
23. Xia T, Liu X, Wang N, Jiang Y, Bai H, Xu W, et al. PI3K/AKT/Nrf2 signalling pathway is involved in the ameliorative effects of xanthohumol on amyloid β-induced oxidative damage and bone loss. J Pharm Pharmacol 2022;74:1017-1026.
24. Owusu G, Obiri DD, Ainooson GK, Osafo N, Antwi AO, Duduyemi BM, et al. Acetic acid-induced ulcerative colitis in sprague dawley rats is suppressed by hydroethanolic extract of Cordia vignei leaves through reduced serum levels of TNF-α and IL-6. Int J Chronic Dis 2020; 2020: 1-11.
25. Mostafa RE, Abdel-Rahman RF. Ezetimibe alleviates acetic acid-induced ulcerative colitis in rats: targeting the Akt/NF-κB/STAT3/CXCL10 signaling axis. J Pharm Pharmacol 2023;75:533-543.
26. Shimizu T, Nishihira J, Watanabe H, Abe R, Ishibashi T, Shimizu H. Cetirizine, an H1-receptor antagonist, suppresses the expression of macrophage migration inhibitory factor: its potential anti-inflammatory action. Clin Exp Allergy 2004; 34: 103-109.
27. Ricardo Alves B, Sutti R, Ismael da Silva Jr P, Bertani R, Guilherme Santos-Junior J, Augusto Alves Rocha Silva T, et al. Non-clinical evidence supports anti-inflammatories as more effective medication than antihistamines against tarantula local effects envenomation. BioRxiv 2021;4:1-26.
28. Mostafa RE, Abdel-Rahman RF. Ezetimibe alleviates acetic acid-induced ulcerative colitis in rats: targeting the Akt/NF-κB/STAT3/CXCL10 signaling axis. J Pharm Pharmacol 2023; 75: 533-543.
29. Helal OK, Yousef MM, Elnaa M. Possible protective effect of gum arabic on experimentally induced gastric ulcer in adult male albino rats. Egypt J Histol 2011;34:546-553.
30. Khalefa AA, Abd-Alaleem DI, Attiaa KI. The protective effects of ghrelin and leptin against stress-induced gastric ulcer in rats. Arab J Gastroenterol 2010;11:74-78.
31. Dvornikova KA, Platonova ON, Bystrova EY. Inflammatory bowel disease: Crosstalk between histamine, immunity, and disease. Int J Mol Sci 2023;24:9937-9956.
32. Abdelmonaem AA, Abdelzaher WY, Abd-El Gaber SA, Abdel Hafez SM, Hafez HM. Possible protective effects of sulfasalazine on acetic acid-induced colitis in rats through its effect on oxidative stress and proinflammatory mediators. Minia J Med Res 2021; 32:30-37.
33. Randhawa PK, Singh K, Singh N, Jaggi AS. A review on chemical-induced inflammatory bowel disease models in rodents. Korean J Physiol Pharmacol 2014;18:279-288.
34. Al-Rejaie SS, Abuohashish HM, Al-Enazi MM, Al-Assaf AH, Parmar MY, Ahmed MM. Protective effect of naringenin on acetic acid-induced ulcerative colitis in rats. World J Gastroenterol 2013;19:5633-5644.
35. Shahid M, Raish M, Ahmad A, Bin Jardan YA, Ansari MA, Ahad A, et al. Sinapic acid ameliorates acetic acid-induced ulcerative colitis in rats by suppressing inflammation, oxidative stress, and apoptosis. Molecules 2022;27:4139-4153.
36. Peng S, Shen L, Yu X, Zhang L, Xu K, Xia Y, et al. The role of Nrf2 in the pathogenesis and treatment of ulcerative colitis. Front Immunol 2023; 14: 1200111-1200129.
37. Wu JZ, Liu YH, Liang JL, Huang QH, Dou YX, Nie J, et al. Protective role of β-patchoulene from Pogostemon cablin against indomethacin-induced gastric ulcer in rats: Involvement of anti-inflammation and angiogenesis. Phytomedicine 2018;39:111-118.
38. Ansari MN, Rehman NU, Karim A, Soliman GA, Ganaie MA, Raish M, et al. Role of oxidative stress and inflammatory cytokines (TNF-α and IL-6) in acetic acid-induced ulcerative colitis in rats: Ameliorated by otostegia fruticosa. Life 2021;11:1-17.
39. Huang XL, Xu J, Zhang XH, Qiu BY, Peng L, Zhang M, et al. PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis. Inflamm Res 2011;60:727-734.
40. Tokuhira N, Kitagishi Y, Suzuki M, Minami A, Nakanishi A, Ono Y, et al. PI3K/AKT/PTEN pathway as a target for Crohn’s disease therapy (Review). Int J Mol Med 2015;35:10-16.
41. Yan S, Hui Y, Li J, Xu X, Li Q, Wei H. Glutamine relieves oxidative stress through PI3K/Akt signaling pathway in DSS-induced ulcerative colitis mice. Iran J Basic Med Sci 2020; 23: 1124-1129.
42. Abdel-Fattah MM, Hassanein EHM, Sayed AM, Alsufyani SE, El-Sheikh AAK, Arab HH, et al. Targeting SIRT1/FoxO3a/Nrf2 and PI3K/AKT pathways with rebamipide attenuates acetic acid-induced colitis in rats. Pharmaceuticals 2023;16:533-556.
43. Canonica W, Blaiss M. Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: A review of the evidence. World Allergy Organ J 2011;4:47-53.
44. Jang J, Hunto ST, Kim JW, Lee HP, Kim HG, Cho JY. Anti-inflammatory activities of an anti-histamine drug, loratadine, by suppressing TAK1 in AP-1 pathway. Int J Mol Sci 2022;23:3986-4000.
45. Song Y, Yuan M, Xu Y, Xu H. Tackling inflammatory bowel diseases: Targeting proinflammatory cytokines and lymphocyte homing. Pharmaceuticals 2022 ;15:1080-1102.