Hepato-protective effects of Montelukast against methotrexate-induced hepatotoxicity in rat model
Main Article Content
Keywords
Methotrexate (MTX), Montelukast, Hepatotoxicity, rat
Abstract
Aim: Assessment of the possible Hepato-protective effects of Montelukast against hepatotoxicity induced by MTX in rat model.
Materials and methods: A 24 Albino Wister rats were included in this study, they were randomly divided into 4 groups each of 6. Group 1: control group (administered 0.9% N/S 1ml/kg/d ip) for 5 days. Group 2: MTX group (received MTX in a dose of 20mg/kg/day ip) as a single dose at day 1 and observed till day 5 of the experiment. Group 3: Montelukast group (received MTX in a dose of 20mg/kg/d ip as a single dose then Montelukast 10 mg /kg/ d ip for 5days). Group 4: vehicle group received 1ml/kg ip for each rat (10%DMSO + 40%PEG300 + 5% Tween400 + 45% Normalsalin) vehicle solution for 5 days. At day 5 all animals were sacrificed, serum was aspirated for the assessment of ALT, AST, ALP, TSB levels by colorimetric assay. Liver was removed and divided into 2 parts for histopathological examination and for assessment of tissue TNF-alpha, caspase-3, MDA, total antioxidant capacity, and TLR4 levels by ELISA method.
Results: Mean serum levels of ALT, AST, ALP and TSB as well as tissue MDA, TNFα, TlLR4, Caspse3 were significantly increased in MTX group compared with the control and vehicle groups together with significant reduction in total antioxidant capacity and obvious histological damage. Whereas meanwhile treatment of rats with Montelukast together with MTX resulted in significant reduction in mean serum levels of ALT, AST, ALP and TSB as well as tissue MDA, TNFα,TlLR4, Caspse3 together with significant increment in total antioxidant capacity and near normal restoration of hepatic tissue architecture.
Conclusion: Montelukast has Hepatoprotective effect against MTX induced hepatotoxicity by its antioxidant, anti-inflammatory, and anti- apoptotic properties.
References
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23. Emmanuel R, Karuppiah C, Chen SM, Palanisamy S, Padmavathy S, Prakash P. Green synthesis of gold nanoparticles for trace level detection of a hazardous pollutant (nitrobenzene) causing Methemoglobinaemia. Journal of hazardous materials. 2014; 279, 117-124
24. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. Balanced crystalloids versus saline in critically ill adults. New England Journal of Medicine. 2018; 378(9): 829-839.
25. Emara M, ElSawy H, Bauch G. A spatiotemporal model for peak AoI in uplink IoT networks: Time versus event-triggered traffic. IEEE internet of things journal. 2020; 7(8): 6762-6777.
26. Roghani M, Kalantari H, Khodayar MJ, Khorsandi L, Kalantar M, Goudarzi M, et al. Alleviation of liver dysfunction, oxidative stress and inflammation underlies the protective effect of ferulic acid in methotrexate-induced hepatotoxicity. Drug design, development and therapy. 2020; 1933-1941.
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28. Dogan G, Taskin B. Hydrolytic enzymes producing bacterial endophytes of some poaceae plants. Polish journal of microbiology. 2021; 70(3): 297-304.
29. Sahindokuyucu-Kocasari F, Akyol Y, Ozmen O, Erdemli-Kose SB, Garli S. Apigenin alleviates methotrexate-induced liver and kidney injury in mice. Human & Experimental Toxicology. 2021; 40(10): 1721-1731.
30. Jafaripour L, Naserzadeh R, Alizamani E, Mashhadi SMJ, Moghadam E, Nouryazdan N, et al. Effects of rosmarinic acid on methotrexate-induced nephrotoxicity and hepatotoxicity in Wistar rats. Indian journal of nephrology. 2021; 31(3): 218.
31. Oliveira PJ, Gonçalves L, Monteiro P, Providencia LA, Moreno AJ. Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria? Current vascular pharmacology. 2005; 3(2): 147-158.
32. Özkan E, Yardimci S, Dulundu E, Topaloğlu Ü, Şehirli Ö, Ercan F, et al. Protective potential of Montelukast against hepatic ischemia/reperfusion injury in rats. Journal of Surgical Research. 2010; 159(1): 588-594.
33. El-Baz AM, Shata A, Hassan HM, El-Sokkary MM, Khodir AE. The therapeutic role of Lactobacillus and Montelukast in combination with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress. International Immunopharmacology. 2021; 96: 107757
34. Jafaripour L, Naserzadeh R, Alizamani E, Mashhadi SMJ, Moghadam ER, Nouryazdan N, Ahmadvand H. Effects of rosmarinic acid on methotrexate-induced nephrotoxicity and hepatotoxicity in Wistar rats. Indian journal of nephrology. 2021; 31(3): 218.
35. Oliveira PJ, Seiça R, Coxito PM, Rolo AP, Palmira CM, Santos MS, Moreno AJ. Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS letters. 2003; 554(3): 511-514 .
36. Mohammadalipour A, Karimi J, Solgi G, Hashemnia M, Sheikh N, et al. Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism. Immunopharmacology and immunotoxicology. 2017; 39(1): 19-27.
37. Mazali FC, Johnson RJ, Mazzali M. Use of uric acid-lowering agents limits experimental cyclosporine nephropathy. Nephron Experimental nephrology. 2012; 120(1): e12-e19.
38. Torre SD, Benedusi V, Fontana R, Maggi A. Energy metabolism and fertility-a balance preserved for female health. Nature Reviews Endocrinology. 2014; 10(1): 13-23.
39. Althunibat OY, Abukhalil MH, Aladaileh SH, Qaralleh H, Al-Amarat W, Alfwuaires MA, et al. Formononetin Ameliorates Renal Dysfunction, Oxidative Stress, Inflammation, and Apoptosis and Upregulates Nrf2/HO-1 Signaling in a Rat Model of Gentamicin-Induced Nephrotoxicity. Frontiers in Pharmacology, 2022; 13.
40. Al-khawalde AAMA, Abukhalil MH, Jghef MM, Alfwuaires MA, Alaryani FS, et al. Punicalagin Protects against the Development of Methotrexate-Induced Hepatotoxicity in Mice via Activating Nrf2 Signaling and Decreasing Oxidative Stress, Inflammation, and Cell Death. International Journal of Molecular Sciences. 2022; 23(20): 12334 .
41. Peng J, Chen F, Liu Y, Zhang F, Cao L, You Q, Yang D, Chang Z, et al. A light-driven dual-Nano transformer with deep tumor penetration for efficient chemo-immunotherapy. Theranostics. 2022 Jan 24; 12(4):1756-1768, doi:10.7150/thno.68756.
42. Cheema HI, Haselow D, Dranoff JA. Review of existing evidence demonstrates that methotrexate does not cause liver fibrosis. Journal of Investigative Medicine. 2022; 70(7): 1452-1460.
43. Khalaf MM, Hassanein EH, Shalkami AGS, Hemeida RA, Mohamed WR. Diallyl disulfide attenuates methotrexate-induced hepatic oxidative injury, inflammation and apoptosis and enhances its anti-tumor activity. Current Molecular Pharmacology. 2022; 15(1): 213-226.
44. Di Martino JS, Nobre AR, Mondal C, Taha I, Farias EF, Fertig EJ, A tumor-derived type III collagen-rich ECM niche regulates tumor cell
dormancy. Nature cancer. 2022; 3(1): 90-107.
2. Tukukino C, Wallerstedt SM. Drug information centre queries and responses about drug interactions over 10 years-A descriptive analysis. Basic & clinical pharmacology & toxicology. 2019; 126(1): 65–74.
3. Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. The oncologist. 2016; 21(12): 1471-1482.
4. van de Meeberg MM, Seinen ML, Fidder HH, Lin M, Oldenburg B, de Boer NK, et al. Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn’s disease: a cross-sectional study. BMC gastroenterology. 2022; 22(1): 365.
5. Desouza C, Parulkar A, Lumpkin D, Akers D, Fonseca VA. Acute and prolonged effects of sildenafil on brachial artery flow-mediated dilatation in type 2 diabetes. Diabetes care. 2002; 25(8): 1336-1339.
6. Pandit A, Sachdeva T, Bafna P. Drug-induced hepatotoxicity: a review. Journal of Applied Pharmaceutical Science. 2012; 233-243
7. Abo-Haded HM, Elkablawy MA, Al-Johani Z, Al-Ahmadi O, El-Agamy DS. Hepatoprotective effect of Sitagliptin against methotrexate induced liver toxicity. PLoS one. 2017; 12(3): e0174295.
8. Abdel-Daim MM, Kilany OE, Khalifa HA, Ahmed AA. Allicin ameliorates doxorubicininduced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Cancer chemotherapy and pharmacology. 2017; 80: 745-753.
9. Du K, Ramachandran A, McGill MR, Mansouri A, Asselah T, Farhood A, et al. Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity. Food and Chemical Toxicology. 2017; 108: 339-350 .
10. Negre-Salvayre A, Auge N, Ayala V, Basaga H, Boada J, Brenke R, et al. Pathological aspects of lipid peroxidation. Free radical research. 2010; 44(10): 1125-1171
11. Khodir AE, Ghoneim HA, Rahim MA, Suddek GM. Montelukast attenuates lipopolysaccharideinduced cardiac injury in rats. Human & experimental toxicology. 2016; 35(4): 388-397
12. Lee TH, Oh JY, Hong SP, Lee JM, Roh SM, Kim SH, Park HB. ZIF-8 particle size effects on reverse osmosis performance of polyamide thinfilm Nano composite membranes: Importance of particle deposition. Journal of membrane science. 2019; 570, 23-33.
13. Kishawy HA, Hegab H, Umer U, Mohany A. Application of acoustic emissions in machining processes: analysis and critical review. The International Journal of Advanced Manufacturing Technology. 2018; 98: 1391-1407.
14. Bäck M, Powell WS, Dahlén SE, Drazen JM, Evans JF, Serhan CN, et al. Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7. British journal of pharmacology. 2014; 171(15): 3551-3574
15. Castro‐Rodriguez JA, Rodriguez‐Martinez CE, Ducharme FM. Daily inhaled corticosteroids or Montelukast for preschoolers with asthma or recurrent wheezing: A systematic review. Pediatric pulmonology. 2018; 53(12), 1670-1677.
16. El-Kashef DH, Abdelrahman RS. Montelukast ameliorates Concanavalin A-induced autoimmune hepatitis in mice via inhibiting TNFα/JNK signaling pathway. Toxicology and Applied Pharmacology. 2020; 393: 114931
17. Kuzmich AS, Khomenko TM, Fedorov SN, Makarieva TN, Shubina LK, et al. Cytotoxic and cancer preventive activity of benzotrithioles and
benzotrithioles oxides, synthetic analogues of varacins. Medicinal Chemistry Research. 2017; 26: 397-404 .
18. Lockhart E, Hawker GA, Ivers NM, O’Brien T, Mukerji G, Pariser P, et al. Engaging primary care physicians in care coordination for patients with complex medical conditions. Canadian Family Physician. 2019; 65(4): e155-e162.
19. Emara M, ElSawy H, Bauch G. A spatiotemporal model for peak AoI in uplink IoT networks: Time versus event-triggered traffic. IEEE internet of things journal. 2020; 7(8): 6762-6777.
20. Abdelaziz RM, Abdelazem AZ, Hashem KS, Attia YA. Protective effects of hesperidin against MTX-induced hepatotoxicity in male albino rats. Naunyn-Schmiedebergs Archives of Pharmacology. 2020; 393: 1405-1417.
21. Dogan G, Taskin B. Hydrolytic enzymes producing bacterial endophytes of some poaceae plants. Polish journal of microbiology. 2021; 70(3): 297-304.
22. Kim OS, Cho YJ, Lee K, Yoon SH, Kim M, Na H, et al. Introducing EzTaxon-e: a prokaryotic 16S rRNA gene sequence database with phylotypes that represent uncultured species. International journal of systematic and evolutionary microbiology. 2012; 62(Pt_3): 716-721
23. Emmanuel R, Karuppiah C, Chen SM, Palanisamy S, Padmavathy S, Prakash P. Green synthesis of gold nanoparticles for trace level detection of a hazardous pollutant (nitrobenzene) causing Methemoglobinaemia. Journal of hazardous materials. 2014; 279, 117-124
24. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, et al. Balanced crystalloids versus saline in critically ill adults. New England Journal of Medicine. 2018; 378(9): 829-839.
25. Emara M, ElSawy H, Bauch G. A spatiotemporal model for peak AoI in uplink IoT networks: Time versus event-triggered traffic. IEEE internet of things journal. 2020; 7(8): 6762-6777.
26. Roghani M, Kalantari H, Khodayar MJ, Khorsandi L, Kalantar M, Goudarzi M, et al. Alleviation of liver dysfunction, oxidative stress and inflammation underlies the protective effect of ferulic acid in methotrexate-induced hepatotoxicity. Drug design, development and therapy. 2020; 1933-1941.
27. Abdelaziz RM, Abdelazem AZ, Hashem KS, Attia YA. Protective effects of hesperidin against MTX-induced hepatotoxicity in male albino rats. Naunyn-Schmiedebergs Archives of Pharmacology. 2020; 393: 1405-1417.
28. Dogan G, Taskin B. Hydrolytic enzymes producing bacterial endophytes of some poaceae plants. Polish journal of microbiology. 2021; 70(3): 297-304.
29. Sahindokuyucu-Kocasari F, Akyol Y, Ozmen O, Erdemli-Kose SB, Garli S. Apigenin alleviates methotrexate-induced liver and kidney injury in mice. Human & Experimental Toxicology. 2021; 40(10): 1721-1731.
30. Jafaripour L, Naserzadeh R, Alizamani E, Mashhadi SMJ, Moghadam E, Nouryazdan N, et al. Effects of rosmarinic acid on methotrexate-induced nephrotoxicity and hepatotoxicity in Wistar rats. Indian journal of nephrology. 2021; 31(3): 218.
31. Oliveira PJ, Gonçalves L, Monteiro P, Providencia LA, Moreno AJ. Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria? Current vascular pharmacology. 2005; 3(2): 147-158.
32. Özkan E, Yardimci S, Dulundu E, Topaloğlu Ü, Şehirli Ö, Ercan F, et al. Protective potential of Montelukast against hepatic ischemia/reperfusion injury in rats. Journal of Surgical Research. 2010; 159(1): 588-594.
33. El-Baz AM, Shata A, Hassan HM, El-Sokkary MM, Khodir AE. The therapeutic role of Lactobacillus and Montelukast in combination with metformin in diabetes mellitus complications through modulation of gut microbiota and suppression of oxidative stress. International Immunopharmacology. 2021; 96: 107757
34. Jafaripour L, Naserzadeh R, Alizamani E, Mashhadi SMJ, Moghadam ER, Nouryazdan N, Ahmadvand H. Effects of rosmarinic acid on methotrexate-induced nephrotoxicity and hepatotoxicity in Wistar rats. Indian journal of nephrology. 2021; 31(3): 218.
35. Oliveira PJ, Seiça R, Coxito PM, Rolo AP, Palmira CM, Santos MS, Moreno AJ. Enhanced permeability transition explains the reduced calcium uptake in cardiac mitochondria from streptozotocin-induced diabetic rats. FEBS letters. 2003; 554(3): 511-514 .
36. Mohammadalipour A, Karimi J, Solgi G, Hashemnia M, Sheikh N, et al. Dasatinib prevent hepatic fibrosis induced by carbon tetrachloride (CCl4) via anti-inflammatory and antioxidant mechanism. Immunopharmacology and immunotoxicology. 2017; 39(1): 19-27.
37. Mazali FC, Johnson RJ, Mazzali M. Use of uric acid-lowering agents limits experimental cyclosporine nephropathy. Nephron Experimental nephrology. 2012; 120(1): e12-e19.
38. Torre SD, Benedusi V, Fontana R, Maggi A. Energy metabolism and fertility-a balance preserved for female health. Nature Reviews Endocrinology. 2014; 10(1): 13-23.
39. Althunibat OY, Abukhalil MH, Aladaileh SH, Qaralleh H, Al-Amarat W, Alfwuaires MA, et al. Formononetin Ameliorates Renal Dysfunction, Oxidative Stress, Inflammation, and Apoptosis and Upregulates Nrf2/HO-1 Signaling in a Rat Model of Gentamicin-Induced Nephrotoxicity. Frontiers in Pharmacology, 2022; 13.
40. Al-khawalde AAMA, Abukhalil MH, Jghef MM, Alfwuaires MA, Alaryani FS, et al. Punicalagin Protects against the Development of Methotrexate-Induced Hepatotoxicity in Mice via Activating Nrf2 Signaling and Decreasing Oxidative Stress, Inflammation, and Cell Death. International Journal of Molecular Sciences. 2022; 23(20): 12334 .
41. Peng J, Chen F, Liu Y, Zhang F, Cao L, You Q, Yang D, Chang Z, et al. A light-driven dual-Nano transformer with deep tumor penetration for efficient chemo-immunotherapy. Theranostics. 2022 Jan 24; 12(4):1756-1768, doi:10.7150/thno.68756.
42. Cheema HI, Haselow D, Dranoff JA. Review of existing evidence demonstrates that methotrexate does not cause liver fibrosis. Journal of Investigative Medicine. 2022; 70(7): 1452-1460.
43. Khalaf MM, Hassanein EH, Shalkami AGS, Hemeida RA, Mohamed WR. Diallyl disulfide attenuates methotrexate-induced hepatic oxidative injury, inflammation and apoptosis and enhances its anti-tumor activity. Current Molecular Pharmacology. 2022; 15(1): 213-226.
44. Di Martino JS, Nobre AR, Mondal C, Taha I, Farias EF, Fertig EJ, A tumor-derived type III collagen-rich ECM niche regulates tumor cell
dormancy. Nature cancer. 2022; 3(1): 90-107.
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Mar 1, 2023
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Bayader Abdulhadi Abdul Kadhim, Fadhaa Abdulameer Ghafil, Sahar A. Majeed, Heider Qassam, & Najah R. Hadi. (2023). Hepato-protective effects of Montelukast against methotrexate-induced hepatotoxicity in rat model. Journal of Population Therapeutics and Clinical Pharmacology, 30(1), 363–372. https://doi.org/10.47750/jptcp.2023.1095
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