Effect of vitamin B12 on methotrexate-induced cardiotoxicity in rats

Document Type : Original Article

Authors

1 Healthcare Services Department, Niğde Ömer Halisdemir University, Nigde, Turkey

2 Histology-Embryology Department, Faculty of Medicine, Erciyes University, Kayseri, Turkey

3 Histology-Embryology Department, Faculty of Medicine, Bozok University, Yozgat, Turkey

4 Department of Medical Biology, Faculty of Medicine, Istinye University, Istanbul, Turkey

5 Histology-Embryology Department, Faculty of Dentistry, Cappadocia University, Nevşehir, Turkey

6 Gaziantep Islamic Science and Technology University, Department of Histology-Embryology, Gaziantep, Turkey

Abstract

Objective(s): Methotrexate (MTX) is a drug with anti-inflammatory and immunosuppressive effects and is also a folic acid antagonist. Our aim in this study is to determine the molecular mechanisms of cardiotoxicity caused by MTX, a chemotherapeutic drug, and to evaluate the protective effects of vitamin B12 on this toxicity. 
Materials and Methods: A total of 32 rats were used in our study and 4 groups were formed. Control group, Vit B12 group (3 μg/kg B12 for 15 days, IP), MTX group (20 mg/kg MTX single dose on day 8 of the experiment, IP), MTX +Vit B12 group (3 μg/kg, IP ), Vit B12 throughout the 15 days, and a single dose of 20 mg/kg MTX (IP) on day 8 of the experiment. Immunohistochemically, expressions of hypoxia-inducible factor 1α (HIF1-α), vascular endothelial growth factor receptor-2 (VEGFR-2), erythropoietin (EPO), and interleukin-6 (IL-6) were evaluated in the heart tissue. Total catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were measured in the heart tissue. At the same time, ANP and NT-proBNP levels were measured in the blood serum.
Results: In the study, the expression of HIF1-α and VEGFR-2 increased significantly in the MTX group, while IL-6 and EPO significantly decreased. At the same time, CAT and SOD levels were significantly decreased and MDA levels increased significantly in the MTX group. While vitamin B12 significantly corrected all these values, it also greatly reduced the increases in ANP and NT-proBNP levels caused by MTX.
Conclusion: It is important to use Vit B12 before and after MTX administration to replace the folate that MTX has reduced.

Keywords

Main Subjects

References

1. Ali N, Rashid S, Nafees S, Hasan SK, Shahid A, Majed F, et al. Protective effect of chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach. Chem Biol Interact 2017; 272:80-91.
2. Ananthan K, Lyon AR. The role of biomarkers in cardio-oncology. J Cardiovasc Transl Res 2020;13:431-450.
3. Al-Taher AY, Morsy MA, Rifaai RA, Zenhom NM, Abdel-Gaber SA. Paeonol attenuates methotrexate-induced cardiac toxicity in rats by inhibiting oxidative stress and suppressing TLR4-induced NF-κB inflammatory pathway. Mediators Inflamm 2020; 2020: 8641026-8641035.
4. Joerger M, Huitema AD, Illerhaus G, Ferreri AJ. Rational administration schedule for high-dose methotrexate in patients with primary central nervous system lymphoma. Leuk Lymphoma 2012; 53:1867-1875.
5. Cipriani P, Ruscitti P, Carubbi F, Liakouli V, Giacomelli R. Methotrexate: An old new drug in autoimmune disease. Expert Rev Clin Immunol 2014; 10:1519-1530.
6. Polgár L, Lajkó E, Soós P, Láng O, Manea M, Merkely B, et al. Drug targeting to decrease cardiotoxicity - determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells. Beilstein J Org Chem 2018; 14:1583-1594.
7. Bu T, Wang C, Meng Q, Huo X, Sun H, Sun P, et al. Hepatoprotective effect of rhein against methotrexate-induced liver toxicity. Eur J Pharmacol 2018; 834:266-273.
8. Sinatra ST, DeMarco J. Free radicals, oxidative stress, oxidized low density lipoprotein (LDL), and the heart: Antioxidants and other strategies to limit cardiovascular damage. Conn Med 1995; 59:579-588.
9. Karabulut D, Ozturk E, Kuloglu N, Akin AT, Kaymak E, Yakan B. Effects of vitamin B12 on methotrexate hepatotoxicity: evaluation of receptor-interacting protein (RIP) kinase. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:2473-2480.
10. Greibe E, Nymark O, Fedosov SN, Heegaard CW, Nexo E. Dietary intake of vitamin B12 is better for restoring a low B12 status than a daily high-dose vitamin pill: An experimental study in rats. Nutrients 2018;10:1096-1107.
11. Aberle NS, 2nd, Burd L, Zhao BH, Ren J. Acetaldehyde-induced cardiac contractile dysfunction may be alleviated by vitamin B1 but not by vitamins B6 or B12. Alcohol Alcohol 2004; 39:450-454.
12. Zengin E, Sarper N, Caki Kiliç S. Clinical manifestations of infants with nutritional vitamin B deficiency due to maternal dietary deficiency. Acta Paediatr 2009; 98:98-102.
13. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA 2002; 287:3116-3126.
14. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3:721-732.
15. Karabulut D, Öztürk E, Kaymak E, Kuloglu N, Akin AT, Yakan B. Vitamin B12 suppresses GADD153, prevents apoptosis and regulates the testicular function in methotrexate treated rat testis. Biotech Histochem 2022; 97:290-297.
16. Hartman J, Frishman WH. Inflammation and atherosclerosis: A review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev 2014; 22: 147-151.
17. Kaymak E, Akin AT, Öztürk E, Karabulut D, Kuloğlu N, Yakan B. Thymoquinone has a neuroprotective effect against inflammation, oxidative stress, and endoplasmic reticulum stress in the brain cortex, medulla, and hippocampus due to doxorubicin. J Biochem Mol Toxicol 2021; 35:e22888.
18. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines:  The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37:2768-2801.
19. Ozturk E, Karabulut D, Akin AT, Kaymak E, Kuloglu N, Yakan B. Evaluation by different mechanisms of the protective effects of vitamin B12 on methotrexate nephrotoxicity. J Mol Histol 2022; 53:133-143.
20. Conklin KA. Chemotherapy-associated oxidative stress: Impact on chemotherapeutic effectiveness. Integr Cancer Ther 2004; 3:294-300.
21. Perez-Verdia A, Angulo F, Hardwicke FL, Nugent KM. Acute cardiac toxicity associated with high-dose intravenous methotrexate therapy: Case report and review of the literature. Pharmacotherapy 2005; 25:1271-1276.
22. Fuskevåg OM, Kristiansen C, Lindal S, Aarbakke J. Leucovorin and maximum tolerated dose toxicity of methotrexate in rats. Pediatr Hematol Oncol 2000; 17:651-658.
23. Pérez-Pitarch A, Guglieri-López B, Nacher A, Merino V, Merino-Sanjuán M. Impact of undernutrition on the pharmacokinetics and pharmacodynamics of anticancer drugs: A literature review. Nutr Cancer 2017; 69: 555-563.
24. Fuskevag OM, Kristiansen C, Lindal S, et al. Leucovorin and maximum tolerated dose toxicity of methotrexate in rats. Pediatric Hematol Oncol 2000;17:651-658.   
25. Tousson E, Hafez E, Zaki S, Gad A. The cardioprotective effects of L-carnitine on rat cardiac injury, apoptosis, and oxidative stress caused by amethopterin. Environ Sci Pollut Res Int 2016; 23:20600-20608.
26. Arab HH, Salama SA, Maghrabi IA. Camel milk attenuates methotrexate-induced kidney injury via activation of PI3K/Akt/eNOS signaling and intervention with oxidative aberrations. Food Funct 2018; 9:2661-2672.
27. Krzywinska E, Stockmann C. Hypoxia, metabolism and immune cell function. Biomedicines 2018; 6: 56-75.
28. Youyou Z, Yalei Y, Jie Z, Chuhuai G, Liang L, Liang R. Molecular biomarkers of cantharidin-induced cardiotoxicity in Sprague-Dawley rats: Troponin T, vascular endothelial growth factor and hypoxia inducible factor-1α. J Appl Toxicol 2020; 40:1153-1161.
29. Syukri A, Budu, Hatta M, Amir M, Rohman MS, Mappangara I, et al. Doxorubicin induced immune abnormalities and inflammatory responses via HMGB1, HIF1-α and VEGF pathway in progressive of cardiovascular damage. Ann Med Surg (Lond) 2022; 76:103501-103509.
30. El-Derany MO, AbdelHamid SG. Bone marrow mesenchymal stem cells and their derived extracellular vesicles attenuate non-alcoholic steatohepatitis-induced cardiotoxicity via modulating cardiac mechanisms. Life (Basel) 2022; 12:355-376.
31. Semenza GL. Hypoxia-inducible factor 1 and cardiovascular disease. Annu Rev Physiol 2014; 76:39-56.
32. Sarkar K, Cai Z, Gupta R, Parajuli N, Fox-Talbot K, Darshan MS, et al. Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning. Proc Natl Acad Sci U S A 2012; 109:10504-10509.
33. Ramakrishnan S, Anand V, Roy S. Vascular endothelial growth factor signaling in hypoxia and inflammation. J Neuroimmune Pharmacol 2014; 9:142-160.
34. Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW. Erythropoietin biology in cancer. Clin Cancer Res 2006; 12:332-339.
35. Kahraman H, Kurutaş E, Tokur M, Bozkurt S, Cıralık H, Kabakcı B, et al. Protective effects of erythropoietin and N-acetylcysteine on methotrexate-induced lung injury in rats. Balkan Med J 2013; 30:99-104.
36. Erbayraktar S, de Lanerolle N, de Lotbinière A, Knisely JP, Erbayraktar Z, Yilmaz O, et al. Carbamylated erythropoietin reduces radiosurgically-induced brain injury. Mol Med 2006; 12:74-80.
37. Abdel-Daim MM, Khalifa HA, Abushouk AI, Dkhil MA, Al-Quraishy SA. Diosmin attenuates methotrexate-induced hepatic, renal, and cardiac injury: A biochemical and histopathological study in mice. Oxid Med Cell Longev 2017; 2017:3281670.
38. Mahmoud RH, Mohammed MA, Said ES, Morsi EM, Abdelaleem OO, Abdel All MO, et al. Assessment of the cardioprotective effect of liraglutide on methotrexate induced cardiac dysfunction through suppression of inflammation and enhancement of angiogenesis in rats. Eur Rev Med Pharmacol Sci 2021; 25:6013-6024.
39. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008; 88:1379-1406.
40. Zhao Z, Hua Z, Luo X, Li Y, Yu L, Li M, et al. Application and pharmacological mechanism of methotrexate in rheumatoid arthritis. Biomed Pharmacother 2022; 150:113074.
41. Lucas CJ, Dimmitt SB, Martin JH. Optimising low-dose methotrexate for rheumatoid arthritis-A review. Br J Clin Pharmacol 2019; 85:2228-2234.
42. Deger N, Ozmen R, Karabulut D. Thymoquinone regulates nitric oxide synthase enzymes and receptor-interacting serine-threonine kinases in isoproterenol-induced myocardial infarcted rats. Chem Biol Interact 2022; 365:110090.
43. Karabulut D, Ozturk E, Kaymak E, Akin AT, Yakan B. Thymoquinone attenuates doxorubicin-cardiotoxicity in rats. J Biochem Mol Toxicol 2021; 35:e22618.
44. Geiger S, Lange V, Suhl P, Heinemann V, Stemmler HJ. Anticancer therapy induced cardiotoxicity: Review of the literature. Anticancer Drugs 2010; 21:578-590.
Iranian Journal of Basic Medical Sciences
Volume 27, Issue 6
June 2024
Pages 733-739

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