Attenuation of Doxorubicin Induced Cardiotoxicity in Wistar Rats by Extracts of Fruits of Ziziphus jujuba Lam

Jump To References Section


  • Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune - 411038 Maharashtra ,IN
  • Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune - 411038 Maharashtra ,IN
  • Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune - 411038 Maharashtra ,IN
  • Department of Pharmacognosy, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune - 411038 Maharashtra ,IN
  • Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune - 411038 Maharashtra ,IN
  • Department of Cardiology, Shri Sathya Sai Institute of Higher Medical Sciences, Whitefield, Bangalore – 560066, Karnataka ,IN
  • Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune - 411038 Maharashtra ,IN



Cardioprotective, Doxorubicin, ECG Parameters, Hemodynamic Parameters, Nebivolol, Ziziphus jujuba Lam


The objective of the study was to evaluate the cardioprotective activity of fruits of Ziziphus jujuba Lam. in doxorubicin induced cardiotoxicity in Wistar rats. The ethanolic and aqueous extract of fruits of Z. jujuba has been prepared. Male Wistar rats were divided into seven groups. Vehicle control was Group 1. Doxorubicin 5 mg/kg i.p. was administered to Group 2 animals on the 7th and 14th day. Animals in groups 3 and 4 were dosed with ethanolic extracts of 200 and 400 mg/kg p.o. while groups 5 and 6 received aqueous extracts of 200 and 400mg/kg i.p. Animals from group 7 were given nebivolol 5 mg/kg p.o. All the animals were treated for 28 days. Doxorubicin (2.5 mg/kg) was injected intraperitoneally to group 2 to group 7 on day 7th and day 14th. Body weight, ECG, blood pressure, CK-MB, Cardiac troponin-I and LDH were the study parameters. The histology of the heart was performed at the end of the study. Doxorubicin showed cardiotoxicity manifested by changes in serum marker enzymes, ECG and hemodynamic parameters which were further confirmed by histology of the heart. These changes induced by doxorubicin were attenuated by treatment with extracts of the fruit of Ziziphus jujuba Lam. It is concluded that aqueous extract of the fruit of Ziziphus jujuba Lam. (400 mg/kg p.o.) treatment for 28 days protects the heart of rats in doxorubicin induced cardiotoxicity.


Download data is not yet available.



How to Cite

Tambekar, O. P., Shiranal, P., Muthal, A. P., Shinde, V. M., Kulkarni, R. G., Baikampady, S. V., & Bodhankar, S. L. (2023). Attenuation of Doxorubicin Induced Cardiotoxicity in Wistar Rats by Extracts of Fruits of <i>Ziziphus jujuba</i> Lam. Toxicology International, 30(2), 161–171.
Received 2022-09-26
Accepted 2023-04-13
Published 2023-05-11



Schirone L, D’Ambrosio L, Forte M, Genovese R, Schiavon S, Spinosa G, Iacovone G, Valenti V, Frati G, Sciarretta S. Mitochondria and doxorubicin-Induced cardiomyopathy: A complex interplay. Cells. 2022; 11(13):2000. PMid:35805084 PMCid:PMC9266202 DOI:

Balaei MR, 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(2-3):193-8. ejphar.2010.05.046 PMid:20534381 DOI:

Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021; 139:111708. PMid:34243633 DOI:

Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: Analysis of prevailing hypotheses. FASEB J. 1990; 4(13):3076-86. DOI:

Elberry AA, Abdel-Naim AB, Abdel-Sattar EA, Nagy AA, Mosli HA, Mohamadin AM, Ashour OM. Cranberry (Vaccinium macrocarpon) protects against doxorubicininduced cardiotoxicity in rats. Food Chem Toxicol. 2010; 48(5):1178-84. PMid:20146931 DOI:

Abdel-Wahab MH, El-Mahdy MA, Abd-Ellah MF, Helal GK, Khalifa F, Hamada FM. Influence of p-coumaric acid on doxorubicin-induced oxidative stress in rat’s heart. Pharmacol Res. 2003; 48(5):461-5. S1043-6618(03)00214-7 PMid:12967591 DOI:

Hamza A, Amin A, Daoud S. The protective effect of a purified extract of Withania somnifera against doxorubicin- induced cardiac toxicity in rats. Cell Biol Toxicol. 2008; 24(1):63-73. PMid:17520333 DOI:

Xin YF, Wan LL, Peng JL, Guo C. Alleviation of the acute doxorubicin-induced cardiotoxicity by Lycium barbarum polysaccharides through the suppression of oxidative stress. Food Chem Toxicol. 2011; 49(1):259-64. https://doi. org/10.1016/j.fct.2010.10.028 PMid:21056614 DOI:

El-Dayem SM, Fouda FM, Ali EH, Motelp BA. The antitumor effects of tetrodotoxin and/or doxorubicin on Ehrlich ascites carcinoma-bearing female mice. Toxicol Ind Health. 2013; 29(5):404-17. PMid:22317827 DOI:

Oliveira PJ, Bjork JA, Santos MS, Leino RL, Froberg MK, Moreno AJ, Wallace KB. Carvedilol-mediated antioxidant protection against doxorubicin-induced cardiac mitochondrial toxicity. Toxicol Appl Pharmacol. 2004; 200(2):159-68. PMid:15476868 DOI:

Weiss R. Nebivolol: A novel beta-blocker with nitric oxideinduced vasodilatation. Vasc Health Risk Manag. 2006; 2(3):303-8. PMid:17326335 PMCid:PMC1993984 DOI:

Priyadarsini KI, Khopde SM, Kumar SS, Mohan H. Free radical studies of ellagic acid, a natural phenolic antioxidant. J Agric Food Chem. 2002; 50(7):2200-6. https://doi. org/10.1021/jf011275g PMid:11902978 DOI:

Türk G, Ateşşahin A, Sönmez M, Ceribaşi AO, Yüce A. Improvement of cisplatin-induced injuries to sperm quality, the oxidant-antioxidant system, and the histologic structure of the rat testis by ellagic acid. Fertil Steril. 2008; 89(5 Suppl):1474-81. 2007.04.059 PMid:17681317 DOI:

Ghanbari-Niaki A, Hosseini F, Broom DR, Tejenjari B, Rahmati-Ahmadabad S. Combined effects of high-intensity aerobic exercise training and Ziziphus jujuba extract on tissue nesfatin-1 in Rats. Front Endocrinol (Lausanne). 2022; 13:845014. PMid:35592780 PMCid:PMC9110837 DOI:

Mesaik AM, Poh HW, Bin OY, Elawad I, Alsayed B. In vivo anti-inflammatory, anti-bacterial and anti-diarrhoeal activity of Ziziphus Jujuba fruit extract. Open Access Maced J Med Sci. 2018; 6(5):757-766. 2018.168 PMid:29875842 PMCid:PMC5985874 DOI:

Sakthivel M, Elanchezhian R, Ramesh E, Isai M, Jesudasan CN, Thomas PA, Geraldine P. Prevention of seleniteinduced cataractogenesis in Wistar rats by the polyphenol, ellagic acid. Exp Eye Res. 2008; 86(2):251-9. https://doi. org/10.1016/j.exer.2007.10.016 PMid:18068705 DOI:

Kannan MM, Quine SD. Ellagic acid ameliorates isoproterenol induced oxidative stress: Evidence from electrocardiological, biochemical and histological study. Eur J Pharmacol. 2011; 659(1):45-52. ejphar.2011.02.037 PMid:21385579 DOI:

Beserra AM, Calegari PI, Souza Mdo C, Dos Santos RA, Lima JC, Silva RM, Balogun SO, Martins DT. Gastroprotective and ulcer-healing mechanisms of ellagic acid in experimental rats. J Agric Food Chem. 2011; 59(13):6957-65. https:// PMid:21644797 DOI:

Suzuki N, Masamune A, Kikuta K, Watanabe T, Satoh K, Shimosegawa T. Ellagic acid inhibits pancreatic fibrosis in male Wistar Bonn/Kobori rats. Dig Dis Sci. 2009; 54(4):802-10. PMid:18651219 DOI:

Kaeidi A, Taati M, Hajializadeh Z, Jahandari F, Rashidipour M. Aqueous extract of Zizyphus jujuba fruit attenuates glucose induced neurotoxicity in an in vitro model of diabetic neuropathy. Iran J Basic Med Sci. 2015; 18(3):301-6

Lu Y, Bao T, Mo J, Ni J, Chen W. Research advances in bioactive components and health benefits of jujube (Ziziphus jujuba Mill.) fruit. J Zhejiang Univ Sci B. 2021; 22(6):431-449. PMid:34128368 PMCid:PMC8214949 DOI:

Hemmati M, Zohoori E, Mehrpour O, Karamian M, Asghari S, Zarban A, Nasouti R. Anti-atherogenic potential of jujube, saffron and barberry: Anti-diabetic and antioxidant actions. EXCLI J. 2015; 14:908-15

Bhatt N, Deshpande M. A critical review and scientific prospective on contraceptive therapeutics from ayurveda and allied ancient knowledge. Front Pharmacol. 2021; 12:629591. PMid:34149405 PMCid:PMC8210421 DOI:

Shad AA, Ahmad S, Ullah R, AbdEl-Salam NM, Fouad H, Ur Rehman N, Hussain H, Saeed W. Phytochemical and biological activities of four wild medicinal plants. Scientific World Journal. 2014; 2014:857363. https:// PMid:25374941 PMCid:PMC4211140 DOI:

O’Bryan RM, Baker LH, Gottlieb JE, Rivkin SE, Balcerzak SP, Grumet GN, Salmon SE, Moon TE, Hoogstraten B. Dose response evaluation of adriamycin in human neoplasia. Cancer. 1977; 39(5):1940-8. https://doi.rg/10.1002/1097-0142(197705)39:5<1940::AIDCNCR2820390505> 3.0.CO;2-0 PMid:858124 DOI:<1940::AID-CNCR2820390505>3.0.CO;2-0

Namiki M. Antioxidants/antimutagens in food. Crit Rev Food Sci Nutr. 1990; 29(4):273-300. https://doi. org/10.1080/10408399009527528 PMid:2257080 DOI:

Horenstein MS, Vander Heide RS, L’Ecuyer TJ. Molecular basis of anthracycline-induced cardiotoxicity and its prevention. Mol Genet Metab. 2000; 71(1-2):436-44. PMid:11001837 DOI:

Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012; 52(6):1213-25. yjmcc.2012.03.006 PMid:22465037 DOI:

Griffith OW, Stuehr DJ. Nitric oxide synthases: properties and catalytic mechanism. Annu Rev Physiol. 1995; 57:707- 36. PMid:7539994 DOI:

Speth PA, van Hoesel QG, Haanen C. Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet. 1988; 15(1):15-31. 00002 PMid:3042244 DOI:

Chen Y, Huang T, Shi W, Fang J, Deng H, Cui G. Potential targets for intervention against doxorubicin-induced cardiotoxicity based on genetic studies: A systematic review of the literature. J Mol Cell Cardiol. 2020; 138:88-98. https:// PMid:31751567 DOI:

Schlame M, Rua D, Greenberg ML. The biosynthesis and functional role of cardiolipin. Prog Lipid Res. 2000; 39(3):257-88. 7827(00)00005-9 PMid:10799718 DOI:

Atessahin A, Yilmaz S, Karahan I, Ceribasi AO, Karaoglu A. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology. 2005; 212(2-3):116-23. PMid:15946783 DOI:

Upaganlawar A, Balaraman R. Cardioprotective effects of Lagenaria siceraria fruit juice on isoproterenol-induced myocardial infarction in Wistar rats: A biochemical and histoarchitecture study. J Young Pharm. 2011; 3(4):297-303. PMid:22224036 PMCid:PMC3249742 DOI:

De Beer EL, Bottone AE, Voest EE. Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: A review. Eur J Pharmacol. 2001;415(1):1-11. 00765-8 PMid:11245845 DOI:

Kilickap S, Akgul E, Aksoy S, Aytemir K, Barista I. Doxorubicin-induced second degree and complete atrioventricular block. Europace. 2005; 7(3):227-30. PMid:15878560 DOI:

Panchal SK, Poudyal H, Arumugam TV, Brown L. Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. J Nutr. 2011 Jun; 141(6):1062-9. PMid:21508207 DOI:

Jiménez R, Duarte J, Perez-Vizcaino F. Epicatechin: Endothelial function and blood pressure. J Agric Food Chem. 2012; 60(36):8823-30. jf205370q PMid:22440087 DOI:

Jubaidi FF, Zainalabidin S, Taib IS, Hamid ZA, Budin SB. The potential role of flavonoids in ameliorating diabetic cardiomyopathy via alleviation of cardiac oxidative stress, inflammation and apoptosis. Int J Mol Sci. 2021; 22(10):5094. PMid:34065781 PMCid:PMC8151300 DOI:

Xue X, Zhao A, Wang Y, Ren H, Du J, Li D, Li Y. Composition and content of phenolic acids and flavonoids among the different varieties, development stages, and tissues of Chinese Jujube (Ziziphus jujuba Mill.). PLoS One. 2021; 16(10):e0254058. pone.0254058 PMid:34648512 PMCid:PMC8516285 DOI:

Hou XW, Jiang Y, Wang LF, Xu HY, Lin HM, He XY, He JJ, Zhang S. Protective role of granulocyte colony-stimulating factor against adriamycin induced cardiac, renal and hepatic toxicities. Toxicol Lett. 2009; 187(1):40-4. https:// PMid:19429242 DOI:

Gliszczyńska-Swigło A, Ciska E, Pawlak-Lemańska K, Chmielewski J, Borkowski T, Tyrakowska B. Changes in the content of health-promoting compounds and antioxidant activity of broccoli after domestic processing. Food Addit Contam. 2006; 23(11):1088-98. https://doi. org/10.1080/02652030600887594 PMid:17071511 DOI: