Anti-Inflammatory and Antioxidative Effects of Sumatriptan Against Doxorubicin-Induced Cardiotoxicity in Rat


The clinical use of doxorubicin as a potent chemotherapeutic agent is limited due to its dose-dependent cardiotoxicity. Oxidative stress and inflammatory pathways have a pivotal role in doxorubicin-induced cardiotoxicity. Sumatriptan, a 5-hydroxytryptamine (5-HT)1B/1D agonist that is mainly used to relieve migraine pain, has suggested exerting protective effects in numerous pathological conditions through antiinflammatory properties. The aim of the present study was to investigate the effects of sumatriptan on doxorubicin-induced cardiotoxicity and the contribution of anti-inflammation and antioxidative responses. Cardiotoxicity was induced by the administration of doxorubicin three times a week (2.5 mg/kg i.p) for two consecutive weeks on male rats. The animals were divided into four groups, including Control, Sumatriptan (0.1 mg/kg) received group, doxorubicin received group, and Doxorubicin+Sumatriptan (0.1 mg/kg) received group. Sumatriptan was administered 30 min before every injection of doxorubicin. On the last day of the second week, the body weight, mortality rate, electrocardiogram (ECG) and histopathological changes, cardiac inotropic study, and biochemical factors were evaluated. The loss of body weight, mortality rate, ECG parameters, reduction of papillary muscle contractility force as well as histopathological scores following administration of doxorubicin indicated severe cardiac damage. However, treatment with sumatriptan inhibited the functional and structural impairment induced by doxorubicin. In addition, sumatriptan could significantly reduce cardiac tissue levels of malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α), which were increased in the doxorubicin-treated rats. This study illustrated the protective effects of sumatriptan on decreasing doxorubicin-induced cardiac toxicity and mortality rate in part through inhibition of inflammatory and oxidative stress pathways.

1. Hortobagyi G. Anthracyclines in the treatment of cancer. Drugs 1997;54:1-7.
2. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med 1998;339:900-5.
3. Von Hoff DD, Layard MW, Basa P, Davis Jr HL, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-lnduced congestive heart failure. Ann Intern Med 1979;91:710-7.
4. Rossi F, Filippelli W, Russo S, Filippelli A, Berrino L. Cardiotoxicity of doxorubicin: effects of drugs inhibiting the release of vasoactive substances. Pharmacol Toxicol 1994;75:99-107.
5. Khalilzadeh M, Abdollahi A, Abdolahi F, Abdolghafari AH, Dehpour AR, Jazaeri F. Protective effects of magnesium sulfate against doxorubicin-induced cardiotoxicity in rats. Life Sci 2018;207:436-41.
6. Maia TN, Araujo GBRd, Teixeira JAC, Alves Junior EdD, Dias KP. Cardiotoxicity of doxorubicin treatment and physical activity: A systematic review. Int J Cardiovasc Sci 2017;30:70-80.
7. Ojha S, Al Taee H, Goyal S, Mahajan UB, Patil CR, Arya D, et al. Cardioprotective potentials of plant-derived small molecules against doxorubicin associated cardiotoxicity. Oxid Med Cell Longev 2016;2016:5724973.
8. Lehenbauer Ludke AR, Al-Shudiefat AA, Dhingra S, Jassal DS, Singal PK. A concise description of cardioprotective strategies in doxorubicin-induced cardiotoxicity. Can J Physiol Pharmacol 2009;87:756-63.
9. Pecoraro M, Del Pizzo M, Marzocco S, Sorrentino R, Ciccarelli M, Iaccarino G, et al. Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity. Toxicol Appl Pharmacol 2016;293:44-52.
10. Nakamura Y, Kitamura Y, Sumiyoshi Y, Naito N, Kan S, Ushio S, et al. Involvement of 5-HT2A receptor hyperfunction in the anxiety-like behavior induced by doxorubicin and cyclophosphamide combination treatment in rats. J Pharmacol Sci 2018;138:192-7.
11. Kwatra M, Jangra A, Mishra M, Sharma Y, Ahmed S, Ghosh P, et al. Naringin and Sertraline Ameliorate Doxorubicin-Induced Behavioral Deficits Through Modulation of Serotonin Level and Mitochondrial Complexes Protection Pathway in Rat Hippocampus. Neurochem Res 2016;41:2352-66.
12. Mohammad‐Zadeh L, Moses L, Gwaltney‐Brant S. Serotonin: a review. J Vet Pharmacol Ther 2008;31:187-99.
13. Vanhoutte PM. Serotonin and the vascular wall. Int J Cardiol 1987;14:189-203.
14. Haddadi NS, Ostadhadi S, Shakiba S, Afshari K, Rahimi N, Foroutan A, et al. Pharmacological evidence of involvement of nitric oxide pathway in anti‐pruritic effects of sumatriptan in chloroquine‐induced scratching in mice. Fundam Clin Pharmacol 2018;32:69-76
15. Rutz S, Riegert C, Rothmaier AK, Buhot MC, Cassel JC, Jackisch R. Presynaptic serotonergic modulation of 5-HT and acetylcholine release in the hippocampus and the cortex of 5-HT1B-receptor knockout mice. Brain Res Bull 2006;70:81-93.
16. Araldi D, Ferrari LF, Levine JD. Gi-protein coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming. Pain 2016;157:1773-82.
17. Gooshe M, Ghasemi K, Rohani MM, Tafakhori A, Amiri S, Aghamollaii V, et al. Biphasic effect of sumatriptan on PTZ-induced seizures in mice: Modulation by 5-HT1B/D receptors and NOS/NO pathway. Eur J Pharmacol 2018;824:140-7.
18. Sheibani M, Faghir-Ghanesefat H, Dehpour S, Keshavarz-Bahaghighat H, Sepand MR, Ghahremani MH, et al. Sumatriptan protects against myocardial ischaemia–reperfusion injury by inhibition of inflammation in rat model. Inflammopharmacology 2019;27:1071-80.
19. Vera–Portocarrero LP, Ossipov MH, King T, Porreca F. Reversal of inflammatory and noninflammatory visceral pain by central or peripheral actions of sumatriptan. Gastroenterology 2008;135:1369-78.
20. Ikeda Y, Jimbo H, Shimazu M, Satoh K. Sumatriptan scavenges superoxide, hydroxyl, and nitric oxide radicals: in vitro electron spin resonance study. Headache 2002;42:888-92.
21. Brahadeesh M, Suresha R. Screening of the drug Amiodarone for its Antiinflammatory potential in albino rats. Int J Pharm Life Sci 2016;7:5042-6.
22. Dejban P, Rahimi N, Takzare N, Jahansouz M, Dehpour AR. Protective effects of sumatriptan on ischaemia/reperfusion injury following torsion/detorsion in ipsilateral and contralateral testes of rat. Andrologia 2019;51:e13358.
23. Sheibani M, Nezamoleslami S, Faghir-Ghanesefat H, hossein Emami A, Dehpour AR. Cardioprotective effects of dapsone against doxorubicin-induced cardiotoxicity in rats. Cancer Chemother Pharmacol 2020;85:563-71.
24. Sumitra M, Manikandan P, Rao KVK, Nayeem M, Manohar BM, Puvanakrishnan R. Cardiorespiratory effects of diazepam-ketamine, xylazine-ketamine and thiopentone anesthesia in male Wistar rats-a comparative analysis. Life Sci 2004;75:1887-96.
25. Faghir‐Ghanesefat H, Rahimi N, Yarmohammadi F, Mokhtari T, Abdollahi AR, Ejtemaei Mehr S, et al. The expression, localization and function of α7 nicotinic acetylcholine receptor in rat corpus cavernosum. J Pharm Pharmacol 2017;69:1754-61.
26. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8.
27. Olson RD, Boerth RC, Gerber JG, Nies AS. Mechanism of adriamycin cardiotoxicity: evidence for oxidative stress. Life Sci 1981;29:1393-401.
28. Xiong Y, Liu X, Lee CP, Chua BH, Ho YS. Attenuation of doxorubicin-induced contractile and mitochondrial dysfunction in mouse heart by cellular glutathione peroxidase. Free Radic Biol Med 2006;41:46-55.
29. Haddadi NS, Foroutan A, Shakiba S, Afshari K, Ostadhadi S, Daneshpazhooh M, et al. Attenuation of serotonin-induced itch by sumatriptan: possible involvement of endogenous opioids. Arch Dermatol Res 2018;310:165-72.
30. de Lima Junior EA, Yamashita AS, Pimentel GD, De Sousa LG, Santos RVT, Gonçalves CL, et al. doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. J Cachexia Sarcopenia Muscle 2016;7:615-25.
31. Hiensch AE, Bolam KA, Mijwel S, Jeneson JA, Huitema AD, Kranenburg O, et al. Doxorubicin‐induced skeletal muscle atrophy: Elucidating the underlying molecular pathways. Acta Physiol (Oxf) 2020;229:e13400.
32. Hoekman K, van der Vijgh WJ, Vermorken JB. Clinical and preclinical modulation of chemotherapy-induced toxicity in patients with cancer. Drugs 1999;57:133-55.
33. O’Connell JL, Romano MMD, Pulici ECC, Carvalho EE, de Souza FR, Tanaka DM, et al. Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes. Exp Toxicol Pathol 2017;69:213-9.
34. Mitry MA, Edwards JG. Doxorubicin induced heart failure: Phenotype and molecular mechanisms. Int J Cardiol Heart Vasc 2016;10:17-24.
35. Antoniou CK, Dilaveris P, Manolakou P, Galanakos S, Magkas N, Gatzoulis K, et al. QT prolongation and malignant arrhythmia: how serious a problem? Eur Cardiol 2017;12:112-20.
36. Ribeiro-Rodrigues TM, Martins-Marques T, Morel S, Kwak BR, Girão H. Role of connexin 43 in different forms of intercellular communication–gap junctions, extracellular vesicles and tunnelling nanotubes. J Cell Sci 2017;130:3619-30.
37. Pecoraro M, Sorrentino R, Franceschelli S, Del Pizzo M, Pinto A, Popolo A. Doxorubicin-mediated cardiotoxicity: role of mitochondrial connexin 43. Cardiovasc Toxicol 2015;15:366-76.
38. Pecoraro M, Ciccarelli M, Fiordelisi A, Iaccarino G, Pinto A, Popolo A. Diazoxide improves mitochondrial connexin 43 expression in a mouse model of doxorubicin-induced cardiotoxicity. Int J Mol Sci 2018;19:757.
39. Kelishomi RB, Ejtemaeemehr S, Tavangar SM, Rahimian R, Mobarakeh JI, Dehpour AR. Morphine is protective against doxorubicin-induced cardiotoxicity in rat. Toxicology 2008;243:96-104.
40. Rahimi_Balaei M, Momeny M, Babaeikelishomi R, Mehr SE, Tavangar SM, Dehpour AR. The modulatory effect of lithium on doxorubicin-induced cardiotoxicity in rat. Eur J Pharmacol 2010;641:193-8.
41. Oliveira PJ, Bjork JA, Santos MS, Leino RL, Froberg MK, Moreno AJ, et al. Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol 2004;200:159-68.
42. Kaiserová H, Šimůnek T, Van Der Vijgh WJ, Bast A, Kvasničková E. Flavonoids as protectors against doxorubicin cardiotoxicity: role of iron chelation, antioxidant activity and inhibition of carbonyl reductase. Biochim Biophys Acta 2007;1772:1065-74.
43. Foroutan A, Haddadi NS, Ostadhadi S, Sistany N, Dehpour AR. Chloroquine-induced scratching is mediated by NO/cGMP pathway in mice. Pharmacol Biochem Behav 2015;134:79-84.
44. Mobasheran P, Rajai N, Kohansal P, Dehpour AR, Shafaroodi H. The effects of acute Sumatriptan treatment on renal ischemia/reperfusion injury in rat and the possible involvement of nitric oxide. Can J Physiol Pharmacol 2020;98:252-8.
IssueVol 59, No 7 (2021) QRcode
Doxorubicin Sumatriptan Cardiotoxicity Oxidative stress Inflammation

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Sheibani M, Faghir-Ghanesefat H, Azizi Y, Mokhtari T, Yousefi‐Manesh H, Sattarzadeh Badkoubeh R, Emami AH, Dehpour AR. Anti-Inflammatory and Antioxidative Effects of Sumatriptan Against Doxorubicin-Induced Cardiotoxicity in Rat. Acta Med Iran. 2021;59(7):406-415.