The Cytoprotective Effects of Melatonin on Gastric Ulcer: A Rat Model
DOI:
https://doi.org/10.32007/jfacmedbaghdad2467Keywords:
Indomethacin, Melatonin, Rats, Stomach UlcerAbstract
Background: Gastric ulcer is a prevalent gastrointestinal disorder caused by environmental factors and a higher intake of non-steroidal anti-inflammatory drugs (NSAIDs).
Objective: To investigate the prophylactic effects of melatonin on the histology, severity of gastric ulcers, and levels of inflammatory and oxidative stress markers (Interleukin-1beta (IL-1β) and Malondialdehyde (MDA)) in a rat model of indomethacin-induced ulcers.
Methods: This study was performed at Al-Mustansiriyah University's Research Center for Cancer and Medical Genetics from November 2023 to May 2024. Fifty healthy male albino rats weighing between 150 - 250 grams were used. After 24 hours of fasting, these rats were divided into five groups, each with 10 rats. Group A: Received 1 ml of indomethacin vehicle (carboxymethylcellulose 1%) orally (negative control). Group B: Received 60 mg/ kg of indomethacin orally (positive control). Group C: Received 20 mg/ kg of omeprazole orally 30 minutes before indomethacin induction. Group D: Received 20 mg/ kg of melatonin solution orally 30 minutes before indomethacin induction. Group E: Received 30 mg/ kg of pioglitazone solution orally. After 1 hour, rats received a melatonin solution of 20 mg/ kg and waited for 30 minutes before induction.
Results: The group that received melatonin pretreatment at a dosage of 20 mg/kg exhibited a statistically significant reduction in the severity of stomach ulcers and histological damage score. The administration of melatonin at a dose of 20 mg/kg to the pre-treated group reduced inflammatory and oxidative stress markers (IL-1β and MDA) levels similar to those observed with the reference medication.
Conclusions: Melatonin alone or a combination of pioglitazone and melatonin effectively reduce gastric mucosal injury, oxidative stress, and pro-inflammatory cytokine levels, comparable to standard omeprazole drugs.
Received: Sept. 2024
Revised: Nov. 2024
Accepted: Dec. 2024
Published: April 2025
Downloads
References
1. Imad R, Al-Qadh HI. The protective effects of Cilostazol on indomethacin-induced gastric ulcer in rat model. HIV Nurs. 2022;22(2):3578-83.
2. Dafalla SE, Alghamdi HYA, Alsaedi AM, Alzain MAI, Alsaedi ODA, Khormi MA, et al. Awareness of the general population in Jeddah about peptic ulcer disease. Int J Med Dev Ctries. 2021;5(2):656-62. https://doi.org/10.24911/IJMDC.51-1609363527.
3. Al-Marzooq TJ, Naji RE, Al-Majidi AK, Abbas Y. The use of serum Amylase as a predictive factor for mortality in Perforated Duodenal Ulcer. J Fac Med Baghdad. 2015;57(4):295-8. https://doi.org/10.32007/med.1936/jfacmedbagdad.v57i4.8.
4. Jahnavi K, Reddy PP, Vasudha B, Narender B. Non-steroidal anti-inflammatory drugs: an overview. J Drug Deliv Ther. 2019;9(1-s):442-8. https://doi.org/10.22270/jddt.v9i1-s.2287.
5. Ju Z, Li M, Xu J, Howell DC, Li Z, Chen FE. Recent development on COX-2 inhibitors as promising anti-inflammatory agents: The past 10 years. Acta Pharm Sin B. 2022;12(6):2790-807. https://doi.org/10.1016/j.apsb.2022.01.002.
6. Zhang M, Xia F, Xia S, Zhou W, Zhang Y, Han X, et al. NSAID-associated small intestinal injury: an overview from animal model development to pathogenesis, treatment, and prevention. Front Pharmacol. 2022;13:818877. https://doi.org/10.3389/fphar.2022.818877.
7. Matloub SYN, Manna MJ. The cytoprotective effect of different doses of Sildenafil on indomethacin-induced gastric mucosal damage in rats. J Fac Med Baghdad. 2010;52(4):426-31. https://doi.org/10.32007/jfacmedbagdad.524950.
8. Mohamed YT, Naguib IA, Abo-Saif AA, Elkomy MH, Alghamdi BS, Mohamed WR. Role of ADMA/DDAH-1 and iNOS/eNOS signaling in the gastroprotective effect of tadalafil against indomethacin-induced gastric injury. Biomed Pharmacother. 2022;150:113026. https://doi.org/10.1016/j.biopha.2022.113026.
9. Choudhary P, Roy T, Chatterjee A, Mishra VK, Pant S, Swarnakar S. Melatonin rescues swim stress induced gastric ulceration by inhibiting matrix metalloproteinase-3 via down-regulation of inflammatory signaling cascade. Life Sci. 2022;297:120426. https://doi.org/10.1016/j.lfs.2022.120426.
10. Matloub SYN. Captopril versus enalapril in the protection of the gastric mucosa against NSAID induced gastric mucosal injury in rats. J Fac Med Baghdad. 2011;53(2):236-40. https://doi.org/10.32007/jfacmedbagdad.532882.
11. Küçükler S, Kandemir FM, Yıldırım S. Protective effect of chrysin on indomethacin induced gastric ulcer in rats: role of multi-pathway regulation. Biotech Histochem. 2022;97(7):490-503. https://doi.org/10.1080/10520295.2021.2014569.
12. Panchal NK, Sabina EP. Non-steroidal anti-inflammatory drugs (NSAIDs): A current insight into its molecular mechanism eliciting organ toxicities. Food Chem Toxicol. 2023;172:113598. https://doi.org/10.1016/j.fct.2022.113598.
13. Rébé C, Ghiringhelli F. Interleukin-1β and cancer. Cancers (Basel). 2020;12(7):1791. https://doi.org/10.3390/cancers12071791.
14. Wang J, Liu H, Wang Y, Wu J, Wang C, Liu K, et al. The polymorphisms of interleukin-12B gene and susceptibility to inflammatory bowel diseases: a meta-analysis and trial sequential analysis. Immunol Invest. 2021;50(8):987-1006. https://doi.org/10.1080/08820139.2020.1863981.
15. Ajao AA, Sibiya NP, Moteetee AN. Sexual prowess from nature: A systematic review of medicinal plants used as aphrodisiacs and sexual dysfunction in sub-Saharan Africa. South African J Bot. 2019; 122:342-59. https://doi.org/10.1016/j.sajb.2018.08.011.
16. Chrustek A, Olszewska-Słonina D. Melatonin as a powerful antioxidant. Acta Pharm. 2021;71(3):335-54. https://doi.org/10.2478/acph-2021-0027.
17. Waleed S, Taha ATM, Uthman AT. Effect of Salivary Melatonin on Ionizing Radiation Worker and its Effect on Periodontal Disease. J Fac Med Baghdad. 2024;66(1):79-84. https://doi.org/10.32007/jfacmedbagdad.6612183.
18. Ivanov DO, Evsyukova II, Mironova ES, Polyakova VO, Kvetnoy IM, Nasyrov RA. Maternal melatonin deficiency leads to endocrine pathologies in children in early ontogenesis. Int J Mol Sci. 2021;22(4):2058. https://doi.org/10.3390/ijms22042058.
19. Bilici D, Süleyman H, Banoğlu ZN, Kiziltunç A, Avci B, Çiftçioğlu A, et al. Melatonin prevents ethanol-induced gastric mucosal damage possibly due to its antioxidant effect. Dig Dis Sci. 2002;47:856-61. https://doi.org/10.1023/A:1014764705864.
20. Morvaridzadeh M, Sadeghi E, Agah S, Nachvak SM, Fazelian S, Moradi F, et al. Effect of melatonin supplementation on oxidative stress parameters: a systematic review and meta-analysis. Pharmacol Res. 2020; 161:105210. https://doi.org/10.1016/j.phrs.2020.105210.
21. Ganguly K, Maity P, Reiter RJ, Swarnakar S. Effect of melatonin on secreted and induced matrix metalloproteinase‐9 and‐2 activity during prevention of indomethacin‐induced gastric ulcer. J Pineal Res. 2005;39(3):307-15. https://doi.org/10.1111/j.1600-079X.2005.00250.x.
22. Majumder R, Datta M, Chattopadhyay A, Bandyopadhyay D. Melatonin promotes gastric healing by modulating the components of matrix metalloproteinase signaling pathway: a novel scenario for gastric ulcer management. Melatonin Res. 2021;4(2):213-31. https://doi.org/10.32794/mr11250092.
23. Sánchez AB, Clares B, Rodríguez-Lagunas MJ, Fábrega MJ, Calpena AC. Study of melatonin as preventive agent of gastrointestinal damage induced by sodium diclofenac. Cells. 2020;9(1):180. https://doi.org/10.3390/cells9010180.
24. Bhatia A, Saikia PP, Dkhar B, Pyngrope H. Anesthesia protocol for ear surgery in Wistar rats (animal research). Anim Model Exp Med. 2022;5(2):183-8. https://doi.org/10.1002/ame2.12198.
25. Jafari A, Andishfar N, Esmaeilzadeh Z, Khezri MR, Ghasemnejad‐Berenji M. Gastroprotective effect of topiramate on indomethacin‐induced peptic ulcer in rats: Biochemical and histological analyses. Basic Clin Pharmacol Toxicol. 2022;130(5):559-68. https://doi.org/10.1111/bcpt.13718.
26. Nonaka H, Mino T, Sakamoto S, Oh JH, Watanabe Y, Ishikawa M, et al. Revisiting PFA-mediated tissue fixation chemistry: FixEL enables trapping of small molecules in the brain to visualize their distribution changes. Chem. 2023;9(2):523-40. https://doi.org/10.1016/j.chempr.2022.11.005.
27. Ekbbal R, Iqubal A, Ansari MA, Ahmad S, Haque SE. Evaluation of cardioprotective potential of isolated swerchirin against the isoproterenol-induced cardiotoxicity in wistar albino rats. Pharmacogn Mag. 2022;18(77). https://doi.org/10.4103/pm.pm_500_20.
28. Song H, Hou X, Zeng M, Chen X, Chen X, Yang T, et al. Traditional Chinese Medicine Li-Zhong-Tang accelerates the healing of indomethacin-induced gastric ulcers in rats by affecting TLR-2/MyD88 signaling pathway. J Ethnopharmacol. 2020;259:112979. https://doi.org/10.1016/j.jep.2020.112979.
29. Antonisamy P, Arasu MV, Dhanasekaran M, Choi KC, Aravinthan A, Kim NS, et al. Protective effects of trigonelline against indomethacin-induced gastric ulcer in rats and potential underlying mechanisms. Food Funct. 2016;7(1):398-408. https://doi.org/10.1039/C5FO00403A,
30. Maity P, Bindu S, Dey S, Goyal M, Alam A, Pal C, et al. Indomethacin, a non-steroidal anti-inflammatory drug, develops gastropathy by inducing reactive oxygen species-mediated mitochondrial pathology and associated apoptosis in gastric mucosa: a novel role of mitochondrial aconitase oxidation. J Biol Chem. 2009;284(5):3058-68. https://doi.org/10.1074/jbc.M805329200.
31. Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. https://doi.org/10.1016/j.bcp.2020.114147.
32. Lichtenberger LM, Zhou Y, Dial EJ, Raphael RM. NSAID injury to the gastrointestinal tract: evidence that NSAIDs interact with phospholipids to weaken the hydrophobic surface barrier and induce the formation of unstable pores in membranes. J Pharm Pharmacol. 2006;58(11):1421-8. https://doi.org/10.1211/jpp.58.10.0001.
33. Bindu S, Mazumder S, Dey S, Pal C, Goyal M, Alam A, et al. Nonsteroidal anti-inflammatory drug induces proinflammatory damage in gastric mucosa through NF-κB activation and neutrophil infiltration: Anti-inflammatory role of heme oxygenase-1 against nonsteroidal anti-inflammatory drug. Free Radic Biol Med. 2013;65:456-67. https://doi.org/10.1016/j.freeradbiomed.2013.07.027
34. Abdel-Tawab MS, Tork OM, Mostafa-Hedeab G, Hassan ME, Elberry DA. Protective effects of quercetin and melatonin on indomethacin induced gastric ulcers in rats. Reports Biochem Mol Biol. 2020;9(3):278. https://doi.org/10.29252/rbmb.9.3.278.
35. Konturek SJ, Konturek PC, Brzozowski T. Melatonin in gastroprotection against stress-induced acute gastric lesions and in healing of chronic gastric ulcers. J Physiol Pharmacol. 2006;57:51. https://pubmed.ncbi.nlm.nih.gov/17233075.
36. Celinski K, Konturek SJ, Konturek PC, Brzozowski T, Cichoz‐Lach H, Slomka M, et al. Melatonin or l‐tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole. J Pineal Res. 2011;50(4):389-94. https://doi.org/10.1111/j.1600-079X.2011.00855.x.
37. Pal PK, Chattopadhyay A, Bandyopadhyay D. Functional interplay of melatonin in the bile duct and gastrointestinal tract to mitigate disease development: An overview. Melatonin Res. 2021;4(1):118-40. https://doi.org/10.32794/mr11250086
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Hela A. Muayad, Huda I. AlQadhi
This work is licensed under a Creative Commons Attribution 4.0 International License.
Creative Commons Attribution 4.0 International license..
