Download PDF
Drug Res (Stuttg) 2015; 65(11): 574-580
DOI: 10.1055/s-0034-1394457
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

The Effects of Mangiferin (Mangifera indica L) in Doxorubicin-induced Cardiotoxicity in Rats

W. Arozal
1   Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
,
F. D. Suyatna
1   Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
,
V. Juniantito
2   Division of Veterinary Pathology, Faculty of Veterinary Medicine, Bogor Agricultural University, Bogor, Indonesia
,
D. S. Rosdiana
1   Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
,
S. Amurugam
3   Department of Clinical Pharmacology, Faculty of Pharmacy, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan
,
R. Aulia
4   Postgraduate student in Biomedical Science, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
,
E. R. Monayo
4   Postgraduate student in Biomedical Science, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
,
R. Siswandi
5   Division of Veterinary Surgery and Radiology, Faculty of Veterinary Medicine, Bogor Agricultural University, Bogor, Indonesia
› Author Affiliations
Further Information

Publication History

received 07 May 2014

accepted 18 October 2014

Publication Date:
26 November 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Aim: The cardiotoxicity effect of doxorubicin (DOX), a widely used antitumor agent has restricted its clinical application. The aim of the current study was to explore the potential protective effect of mangiferin, a naturally occurring glucosylxanthone, that have antioxidant activity by its iron-complexing ability in mitochondria, against DOX-induced cardiac toxicity in rats in comparison with other antioxidants namely Sylimarin (SYL) and Vitamin E (VitE).

Methods: Mangiferin was given orally to rats at a dose of 50, and 100 mg/kg for 5 weeks, and DOX was injected at a total dose of 15 mg/kg. Cardiac toxicity was evaluated by lactate dehydrogenase and creatine kinase in the serum, malondialdehyde (MDA) level in plasma and cardiac tissue, and antioxidant enzyme superoxide dismutase (SOD) in cardiac tissue.

Results: Mangiferin protected against DOX-induced increased mortality and electrocardiogram abnormality and decreased biochemical markers of cardiac toxicity i. e., lactate dehydrogenase and creatine phosphokinase isoenzyme. In addition, elevation of plasma and cardiac tissue levels of MDA in response to DOX treatment were significantly attenuated. The reduction of cardiac activity of SOD was significantly reduced in contrast with the other antioxidant SYL and Vit E. Histopathologically, mangiferin treatment showed significant reduction in inflammatory cell number, fibrotic area, and necrotic foci as compared with DOX only-treated rats.

Conclusion: These results suggested that mangiferin had better protective effect against DOX-induced cardiac toxicity in comparison with SYL and VitE, thus besides the antioxidant activity, different mechanism may be involved in the action of mangiferin and need to be clarified in the future studies.

Key words

mangiferin - doxorubicin - cardiotoxicity - antioxidant
 

  • References

  • 1 Danessi R, Fogli S, Gennari A et al. Pharmakokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. Clin Pharmacokin 2002; 41: 431-444
    CrossrefPubMedGoogle Scholar
  • 2 Hrdina R, Gersl V, Klimtova I et al. Anthracycline-induced cardiotoxicity. Acta Medica (Hradec Kralove) 2000; 43: 75-82
    PubMedGoogle Scholar
  • 3 Jovanovic D, Jovovic D, Mihailovic-Stanoievic N et al. Influence of carvedilol on chronic renal failure progression in spontaneously hypertensive rats with adriamycin nephropathy. Clin Nephrol 2005; 63: 446-453
    CrossrefPubMedGoogle Scholar
  • 4 Simunek T, Stirba M, Popelova O et al. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular ion. Pharmacol Rep 2009; 91: 154-171
    PubMedGoogle Scholar
  • 5 Zhang J, Herman EH, Ferrans VJ. Effects of ICRF-186 [(L)1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] on the toxicity of doxorubicin in spontaneously hypertensive rats. Toxicology 1994; 92: 179-192
    CrossrefPubMedGoogle Scholar
  • 6 Gianni L, Herman EH, Lipshultz SE et al. Anthracyline cardiotoxicity: from bench to bedside. J Clin Oncol 2008; 26: 3777-3784
    CrossrefPubMedGoogle Scholar
  • 7 Peng X, Chen B, Lim CC et al. The cardiotoxicity of anthracycline chemotherapeutic: translating molecular into preventive medicine. Mol Interv 2005; 5: 163-171
    CrossrefPubMedGoogle Scholar
  • 8 Vyas A, Syeda K, Ahmad A et al. Perspectives on medicinal properties of mangiferin. Mini Rev Med Chem 2012; 12: 412-425
    CrossrefPubMedGoogle Scholar
  • 9 Dar A, Faizi S, Naqvi S et al. Analgesic and antioxidant activity of magniferin and its derivates: the structure activity relationship. Biol Pharm Bull 2005; 28: 596-600
    CrossrefPubMedGoogle Scholar
  • 10 De A, Chattopadhyay S. The variation in cytoplasmic distribution of mouse peritoneal macrophage during phagocytosis modulated by mangiferin, an immunomodulator. Immunobiology 2009; 214: 367-376
    CrossrefPubMedGoogle Scholar
  • 11 Purwaningsih EH, Hanani E, Amalia P et al. The chelating effect of Mangifera foetida water extract on serum thalassemic patients. J Indon Med Assoc 2011; 61: 321-325
    PubMedGoogle Scholar
  • 12 Arozal W, Watanabe K, Veeraveedu PT et al. Protective effect of carvedilol on daunorubicin-induced cardiotoxicity and nephrotoxicity in rats. Toxicology 2010; 274: 18-26
    CrossrefPubMedGoogle Scholar
  • 13 Andreu GP, Delgado R, Velho JA et al. Iron complexing activity of mangiferin, a naturally occurring glucosyl xanthone, inhibits mitochondrial lipid peroxidation induced by Fe2+-citrate. Eur J Pharmacol 2005; 513: 47-55
    CrossrefPubMedGoogle Scholar
  • 14 Nair PS, ShyamalaDevi CS. Efficacy of mangiferin on serum and heart tissue lipids in rats subjected to isoproterenol induced cardiotoxicity. Toxicology 2006; 228: 135-139
    CrossrefPubMedGoogle Scholar
  • 15 Ibrahim MA, Ashour OM, Ibrahim YF et al. Angiotensin-converting enzyme inhibition and angiotensin AT(1)-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacol Res 2009; 60: 378-381
    PubMedGoogle Scholar
  • 16 Buhl SN, Jackson KY. Optimal conditions and comparison of lactate dehydrogenase catalysis of the lactate-to-pyruvate and pyruvate-to-lactate reactions in human serum at 25, 30, and 37 degrees C. Clin Chem 1978; 5: 828-831
    PubMedGoogle Scholar
  • 17 Szasz G, Gruber W, Bernt E. Creatine kinase in serum: 1. Determination of optimum reaction conditions. Clin Chem 1976; 22: 650-656
    PubMedGoogle Scholar
  • 18 Uchiama M, Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 8: 271-278
    PubMedGoogle Scholar
  • 19 McCord JM, Fridovich I. The reduction of cytochrome c by milk xanthine oxidase. J Biol Chem 1968; 243: 5753-5760
    PubMedGoogle Scholar
  • 20 Bradford MM. A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 2: 248-254
    PubMedGoogle Scholar
  • 21 Li T, Singal PK. Adriamycin-induced early changes in myocardial antioxidant enzymes and their modulation by probucol. Circulation 2000; 102: 2105-2110
    CrossrefPubMedGoogle Scholar
  • 22 Hayward R, Hydock DS. Doxorubicin cardiotoxicity in the rat: an in vivo characterization. J Am Assoc Lab Anim Sci 2007; 46: 20-32
    PubMedGoogle Scholar
  • 23 Kelishomi RB, Ejtemaeemehr S, Tavangar SM et al. Morphine is protective against doxorubicin-induced cardiotoxicity in rat. Toxicology 2008; 243: 96-104
    CrossrefPubMedGoogle Scholar
  • 24 Herman E, Mhatre R, Lee IP et al. A comparison of the cardiovascular actions of daunomycin, adriamycin and N-acetyldaunomycin in hamsters and monkeys. Pharmacology 1971; 6: 230-241
    CrossrefPubMedGoogle Scholar
  • 25 Iqbal M, Dubey K, Anwer T et al. Protective effects of telmisartan against acute doxorubicin-induced cardiotoxicity in rats. Pharmacol Rep 2008; 60: 382-390
    PubMedGoogle Scholar
  • 26 Jiang DJ, Tan GS, Ye F et al. Protective effects of xanthones against myocardial ischemia-reperfusion injury in rats. Acta Pharmacol Sin 2003; 24: 175-180
    PubMedGoogle Scholar
  • 27 Kang YJ. Cardiac Hypertrophy: A risk factor for QT-prolongation and cardiac sudden death. Toxicol Pathol 2006; 34: 58-66
    CrossrefPubMedGoogle Scholar
  • 28 Muruganandan S, Lal J, Gupta PK. Immunotherapeutic effects of mangiferin mediated by the inhibition of oxidative stress to activated lymphocytes, neutrophils and macrophages. Toxicology 2005; 215: 57-68
    CrossrefPubMedGoogle Scholar
  • 29 Marchant DJ, Boyd JH, Lin DC et al. Inflammation in myocardial diseases. Circ Res 2012; 110: 126-144
    CrossrefPubMedGoogle Scholar
  • 30 Pal PB, Sinha K, Sil PC. Mangiferin, a natural xanthone, protects murine liver in pb(ii) induced hepatic damage and cell death via map kinase, nfkb and mitochondria dependent pathways. PLoS ONE 2013; 8: e56894
    CrossrefPubMedGoogle Scholar
  • 31 Cecen E, Dost T, Culhaci N et al. Protective effects of silymarin against doxorubicin-induced toxicity. Asian Pac J Cancer Prev 2011; 12: 2697-2704
    PubMedGoogle Scholar
  • 32 Leiro JM, Alvarez E, Arranz JA et al. In vitro effects of mangiferin on superoxide concentrations and expression of the inducible nitric oxide synthase, tumour necrosis factor-alpha and transforming growth factor-beta genes. Biochem Pharmacol 2003; 65: 1361-1371
    CrossrefPubMedGoogle Scholar
  • 33 Lipinski B. Hydroxyl radical and its scavengers in health and disease. Oxid Med Cell Longev 2011; 809696 DOI: 10.1155/2011/809696.
    PubMedGoogle Scholar