Hepatoprotective Effects of Dulaglutide against Methotrexate-Induced Liver Injury in Rats

Authors

  • Omar W. Maher

DOI:

https://doi.org/10.63682/jns.v15i1s.10625

Keywords:

Methotrexate, Dulaglutide, Hepatotoxicity, liver function, oxidative stress

Abstract

Background and Objectives: The cellular antioxidant defense system is disrupted, which results in hepatotoxicity. When the antioxidant defence system is weakened, hepatocyte oxidative damage results from an increase in reactive oxygen radicals. The chemotherapeutic and immunosuppressive drug methotrexate (MTX) is often linked to hepatotoxicity, a serious side effect with uncertain consequences. Therefore, the current study looks into the potential preventive effect of dulaglutide (DUL) against liver damage caused by MTX. Methods: The experiment included forty adult male wistar rats, who were divided into four groups: Group 2 was given 14 mg/kg/week of oral MTX for two weeks. On top of the oral MTX, Group 3 also got 0.1 mg/kg/week of subcutaneous DUL. Distributed under the skin, Group 4 was given 0.1 mg/kg/week of DUL. One group served as a control. The animals were sacrificed on the fifteenth day so that histopathological and biochemical testing could be carried out. In these investigations, liver function tests (ALT and AST) and markers of oxidative stress (MDA, GSH, CAT, and SOD) were included.. Results: Our findings showed that MTX significantly raised a number of oxidative stress markers and liver function tests, employing hematoxylin and eosin (H&E) staining to support biochemical data with histological findings. Conclusions: Due to its antioxidant qualities and liver function, DUL significantly protects against MTX-induced hepatotoxicity. This demonstrates its medicinal potential in avoiding hepatotoxicity caused by drugs

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References

1. Abo-Haded, H.M., Elkablawy, M.A., Al-Johani, Z., Al-Ahmadi, O., El-Agamy, D.S. (2017). Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity. PLoS One. 12 (3): e0174295. doi: 10.1371/journal.pone.0174295.

2. Al-Ali, S.Y., Hassan, I.M., Sadek, S. (2005). Ultrastructural changes in rat livers perfused in vitro and in vivo with a high dose of methotrexate. Histol Histopathol, 20 (4): 1131-45. doi: 10.14670/HH-20.1131.

3. Aziz, J., Aidaros, A.E.E, Ali, A.F., Sabry, M.A. (2020). Ameliorating Effect of Alpha-lipoic Acid on Methotrexate-induced Histological and Biochemical Changes in The Lung of Adult Albino Rat. Egypt J Histol, 43 (3): 878-890.

4. Bułdak, Ł., Łabuzek, K., Bułdak, R.J., Machnik, G., Bołdys, A., Okopień, B. (2015). Exenatide (a GLP-1 agonist) improves the antioxidative potential of in vitro cultured human monocytes/macrophages. Naunyn-Schmiedeberg's Arch Pharmacol, 388: 905–919. doi.org/10.1007/s00210-015-1124-3

5. Cechin, S.R., Pérez-Álvarez, I., Fenjves, E., Molano, R.D., Pileggi, A., Berggren, P.O., Ricordi, C., Pastori, R.L. (2012). Anti-inflammatory properties of exenatide in human pancreatic islets. Cell Transplant, 21(4):633-48. doi: 10.3727/096368911X576027.

6. Chiang, J. (2014). Liver Physiology: MetaboLism and Detoxification. In Pathobiology of Human Disease; Academic Press: Oxford, UK, pp. 1770–1782.

7. Conway, R., Carey, J.J. (2017). Risk of liver disease in methotrexate treated patients. World J Hepatol, 9(26):1092-1100. doi: 10.4254/wjh.v9.i26.1092.

8. Cure, E., Kirbas, A., Tumkaya, L., Cure, M.C., Kalkan, Y., Yilmaz, A., Yuce, S. (2015). Protective effect of infliximab on methotrexate-induced liver injury in rats: unexpected drug interaction. J Cancer Res Ther., 11(1):164-9. doi: 10.4103/0973-1482.140809.

9. Daly, A.K. (2010). Drug-induced liver injury: past, present and future. Pharmacogenomics, 11(5):607-11. doi: 10.2217/pgs.10.24.

10. Devrim, E., Cetin, R., Kiliçoğlu, B., Ergüder, BI., Avci, A., Durak, I. (2005). Methotrexate causes oxidative stress in rat kidney tissues. Ren Fail, 27(6):771-3. doi: 10.1080/08860220500244823.

11. Duman, D.G., Kumral, Z.N., Ercan, F., Deniz, M., Can, G., Cağlayan,-Yeğen, B. (2013). Saccharomyces boulardii ameliorates clarithromycin- and methotrexate-induced intestinal and hepatic injury in rats. Br J Nutr., 110 (3): 493-9. doi: 10.1017/S000711451200517X.

12. Fattman, C.L., Schaefer, L.M., Oury, T.D. (2003). Extracellular superoxide dismutase in biology and medicine. Free Radic Biol Med, 35 (3): 236–256.

13. gameil, M., Rozaik, S.E., Elsebaie, A., Marzouk, R. (2020). Influence of liraglutide, dulaglutide versus conventional treatment on fatty liver index and fibrosis-4 score in Egyptian patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease. Medical Journal of Viral Hepatitis, 5.1(1), 25-32. doi: 10.21608/mjvh.2020.125619

14. Hamed, K.M., Dighriri, I.M., Baomar, A.F., Alharthy, B.T., Alenazi, F.E., Alali, G.H., Alenazy, R.H., Alhumaidi, N.T., Alhulayfi, D.H., Alotaibi, Y.B., Alhumaidan, S.S., Alhaddad, Z.A., Humadi, A.A., Alzahrani, S.A., Alobaid, R.H. (2022). Overview of Methotrexate Toxicity: A Comprehensive Literature Review. Cureus, 14(9):e29518. doi: 10.7759/cureus.29518.

15. Kahraman, H., Kurutaş, E., Tokur, M., Bozkurt, S., Çıralık, H., Kabakc, B., Köksal, N., Balkan, V. (2013). Protective Effects of Erythropoietin and N-Acetylcysteine on Methotrexate-Induced Lung Injury in Rats. Balkan Med J, 1: 99-104. doi.org/10.5152/balkanmedj.2012.078

16. Kalantari, E., Zolbanin, N.M., Ghasemnejad-Berenji, M. (2024). Protective effects of empagliflozin on methotrexate induced hepatotoxicity in rats. Biomed Pharmacother. 170:115953. doi: 10.1016/j.biopha.2023.115953.

17. Khan, N., Abbas, A.M., Whang, N., Balart, L.A., Bazzano, L.A., Kelly, T.N. (2012). Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials. Inflamm Bowel Dis, 18(2):359-67. doi: 10.1002/ibd.21820.

18. Krasner, N.M., Ido, Y., Ruderman, N.B., Cacicedo, J.M. (2014). Glucagon-like Peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS ONE, 9 (5): e97554.

19. Krause, G.C., Lima, K.G., Dias, H.B., Da silva, E.F.G., Haute, G.V., Basso, B.S., Gassen, R.B., Marczak, E.S., Nunes, R.S.B., De oliveira, J.R. (2017). Liraglutide, a glucagon-like peptide-1 analog, induce autophagy and senescence in HepG2 cells. Eur. J. Pharmacol, 809, 32–41.

20. Maeda, T., Miyazono, Y., Ito, K., Hamada, K., Sekine, S., Horie, T. (2010). Oxidative stress and enhanced paracellular permeability in the small intestine of methotrexate-treated rats. Cancer Chemother Pharmacol, 65 (6): 1117-23. doi: 10.1007/s00280-009-1119-1.

21. Mahmoud, A.M., Hussein, O.E., Hozayen, W.G., Abd El-Twab, S.M. (2017). Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγ and Nrf2: Protective effect of 18β-Glycyrrhetinic acid. Chem Biol Interact, 270:59-72. doi: 10.1016/j.cbi.2017.04.009.

22. Nauck, M. (2016). Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 18(3):203-16. doi: 10.1111/dom.12591.

23. Navarro, V.J., Senior, J.R. (2006). Drug-related hepatotoxicity. N Engl J Med, 354(7):731-9. doi: 10.1056/NEJMra052270.

24. Mammadov, R., Suleyman, B., Akturan, S., Cimen, F.K., Kurt, N., Suleyman, Z., Malkoc, İ. (2019). Effect of lutein on methotrexate-induced oxidative lung damage in rats: a biochemical and histopathological assessment. Korean J Intern Med, 34(6): 1279–1286. doi: 10.3904/kjim.2018.145.

25. Reuben, A. (2004). Hy's law. Hepatology, 39(2):574-8. doi: 10.1002/hep.20081.

26. Shi, J.X., Huang, Q. (2018). Glucagon like peptide 1 protects mouse podocytes against high glucose induced apoptosis, and suppresses reactive oxygen species production and proinflammatory cytokine secretion, through sirtuin 1 activation in vitro. Mol Med Rep, 18(2):1789-1797. doi: 10.3892/mmr.2018.9085.

27. Trevaskis, J.L., Griffin, P.S., Wittmer, C., Neuschwander-Tetri, B.A., Brunt, E.M., Dolman, C.S., Erickson, M.R., Napora, J., Parkes, D.G., Roth, J.D. (2012). Glucagon-like peptide-1 receptor agonism improves metabolic, biochemical, and histopathological indices of nonalcoholic steatohepatitis in mice. Am J Physiol Gastrointest Liver Physiol, 302(8):G762-72. doi: 10.1152/ajpgi.00476.2011.

28. Türk, E., Güvenç, M., Cellat, M., Uyar, A., Kuzu, M., Ağgül, A.G., Kırbaş, A. (2022). Zingerone protects liver and kidney tissues by preventing oxidative stress, inflammation, and apoptosis in methotrexate-treated rats. Drug Chem Toxicol., 45(3):1054-1065. doi: 10.1080/01480545.2020.1804397.

29. Uzar, E., Koyuncuoglu, H.R., Uz, E., Yilmaz, H.R., Kutluhan, S., Kilbas, S., Gultekin, F. (2006). The activities of antioxidant enzymes and the level of malondialdehyde in cerebellum of rats subjected to methotrexate: protective effect of caffeic acid phenethyl ester. Mol Cell Biochem, 291: 63–68. doi.org/10.1007/s11010-006-9196-5

30. Wang, L.Y., Kong, F.G. (2020). Clinical significance of AST/ALT ratio in serum of patients with liver disease. Cardiovascular Disease Electronic Journal of Integrated Traditional Chinese and Western Medicine, 8:97-8.

31. Walker, T.M., Rhodes, P.C., Westmoreland, C. (2000). The differential cytotoxicity of methotrexate in rat hepatocyte monolayer and spheroid cultures. Toxicol In Vitro. 14(5):475-85. doi: 10.1016/s0887-2333(00)00036-9.

32. Zhang Q, Liu C, Hong S, Min J, Yang Q, Hu M, Zhao Y, Hong L. Excess mechanical stress and hydrogen peroxide remodel extracellular matrix of cultured human uterosacral ligament fibroblasts by disturbing the balance of MMPs/TIMPs via the regulation of TGF β1 signaling pathway. Mol Med Rep. 2017 Jan;15(1):423-430. doi: 10.3892/mmr.2016.5994

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Published

2026-10-01

How to Cite

1.
Maher OW. Hepatoprotective Effects of Dulaglutide against Methotrexate-Induced Liver Injury in Rats. J Neonatal Surg [Internet]. 2026 Oct. 1 [cited 2026 Oct. 1];15(1s):384-91. Available from: https://jneonatalsurg.com/index.php/jns/article/view/10625