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Licensed Unlicensed Requires Authentication Published by De Gruyter October 3, 2017

Kolaviron and Garcinia kola attenuate doxorubicin-induced cardiotoxicity in Wistar rats

Ademola Adetokunbo Oyagbemi , Temitayo Olutayo Omobowale , James Olukayode Olopade and Ebenezer Olatunde Farombi EMAIL logo

Abstract

Background

The Garcinia kola seeds have been reported for its antibacterial, antioxidant, antidiabetic and also for its chemoprevention property. The use of doxorubicin as an anticancer drug has been accompanied with avalanche of side effects including cardiotoxicity. The aim of this study was to investigate the cardioprotective effect of Kolaviron and Garcinia kola and their mechanisms of action.

Methods

Sixty male rats (Wistar strain) were used in this study. They were divided into 6 groups (A-F) each containing 10 animals. Group A was the control. Rats in Groups B, C, D, E and F were treated with doxorubicin at the dosage of 15 mg/kg body weight i.p. Prior to this treatment, rats in groups C, D, E and F were pre-treated orally with Kolaviron at the dosage of 100 mg/kg and 200 mg/kg, and Garcinia kola 100 mg/kg and 200 mg/kg for 7 days, respectively.

Results

The results show that doxorubicin caused a significant increase in heart rate and prolonged QT, reduced antioxidant status, increased oxidative stress, inflammation and markers of cardiac damage which were reversed by pre-treatment with Kolaviron and Garcinia kola.

Conclusions

Overall, pre-treatment with Kolaviron or Garcinia kola caused reversal of cardiac damage, ECG alteration and oxidative stress by increasing the activity of antioxidant enzymes and reducing the markers of inflammation on doxorubicin-induced cardiotoxicity.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

[1] Jain A, Kishore K. Doxorubicin-induced dilated cardiomyopathy for modified radical mastectomy: a case managed under cervical epidural anaesthesia. Indian J Anaesth. 2013;57:185–7.10.4103/0019-5049.111852Search in Google Scholar PubMed PubMed Central

[2] Smuder AJ, Kavazis AN, Min K, Powers SK. Doxorubicin-induced markers of myocardial autophagic signaling in sedentary and exercise trained animals. J Appl Physiol. 2013;115:176–85.10.1152/japplphysiol.00924.2012Search in Google Scholar PubMed

[3] Nordgren KK, Wallace KB. Keap1 redox-dependent regulation of doxorubicin-induced oxidative stress response in cardiac myoblasts. Toxicol Appl Pharmacol. 2014;274:107–16.10.1016/j.taap.2013.10.023Search in Google Scholar PubMed

[4] Fouad AA, Yacoubi MT. Mechanisms underlying the protective effect of eugenol in rats with acute doxorubicin cardiotoxicity. Arch Pharmarceut Res. 2011;34:821–8.10.1007/s12272-011-0516-2Search in Google Scholar PubMed

[5] Toko H, Oka T, Zou Y, Sakamoto M, Mizukami M, Sano M, Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy. Hypert Res. 2002;25:597–603.10.1291/hypres.25.597Search in Google Scholar PubMed

[6] Carvalho FS, Burgeiro A, Garcia R, Moreno AJ, Carvalho RA, Oliveira PJ. Doxorubicin-induced cardiotoxicity: From bioenergetic failure and cell death to cardiomyopathy. Med Res Rev. 2014;34:106–35.10.1002/med.21280Search in Google Scholar PubMed

[7] Ren D, Zhu Q, Li J, Ha T, Wang X, Li Y. Overexpression of angiopoietin-1 reduces doxorubicin-induced apoptosis in cardiomyocytes. J Biomed Res. 2012;26:432–8.10.7555/JBR.26.20120006Search in Google Scholar PubMed PubMed Central

[8] Ammar El SM, Said SA, El-Damarawy SL, Suddek GM. Cardioprotective effect of grape-seed proanthocyanidins on doxorubicin-induced cardiac toxicity in rats. Pharmaceut Biol. 2013;51:339–44.10.3109/13880209.2012.729065Search in Google Scholar PubMed

[9] Adaramoye OA. Protective effect of Kolaviron, a biflavonoid from Garcinia kola seeds, in brain of Wistar albino rats exposed to gamma-radiation. Biol Pharmaceut Bullet. 2010;33:260–6.10.1248/bpb.33.260Search in Google Scholar PubMed

[10] Farombi EO, Abarikwu SO, Adedara IA, Oyeyemi MO. Curcumin and Kolaviron ameliorate di-n-butylphthalate-induced testicular damage in rats. Basic Clin Pharmacol Toxicol. 2007;100:43–8.10.1111/j.1742-7843.2007.00005.xSearch in Google Scholar PubMed

[11] Adaramoye OA, Nwaneri VO, Anyanwu KC, Farombi EO, Emerole GO. Possible anti-atherogenic effect of Kolaviron (a Garcinia kola seed extract) in hypercholesterolaemic rats. Clin Exp Pharmacol Physiol. 2005;32:40–6.10.1111/j.1440-1681.2005.04146.xSearch in Google Scholar PubMed

[12] Adaramoye OA, Adeyemi EO. Hepatoprotection of D-galactosamine-induced toxicity in mice by purified fractions from Garcinia kola seeds. Basic Clin Pharmacol Toxicol. 2006;98:135–41.10.1111/j.1742-7843.2006.pto_256.xSearch in Google Scholar PubMed

[13] Olaleye SB, Farombi EO. Attenuation of indomethacin- and HCl/ethanol-induced oxidative gastric mucosa damage in rats by Kolaviron, a natural biflavonoid of Garcinia kola seed. Phytother Res. 2006;20:14–20.10.1002/ptr.1793Search in Google Scholar PubMed

[14] Farombi EO, Adedara IA, Oyenihi AB, Ekakitie E, Kehinde S. Hepatic, testicular and spermatozoa antioxidant status in rats chronically treated with Garcinia kola seed. J Ethnopharmacol. 2013a;146:536–42.10.1016/j.jep.2013.01.018Search in Google Scholar PubMed

[15] Farombi EO, Adedara IA, Ajayi BO, Ayepola OR, Egbeme EE. Kolaviron, a natural antioxidant and anti-inflammatory phytochemical prevents dextran sulphate sodium-induced colitis in rats. Basic Clin Pharmacol Toxicol. 2013b;113:49–55.10.1111/bcpt.12050Search in Google Scholar PubMed

[16] Adedara IA, Vaithinathan S, Jubendradass R, Mathur PP, Farombi EO. Kolaviron prevents carbendazim-induced steroidogenic dysfunction and apoptosis in testes of rats. EnvironToxicol Pharmacol. 2013a;35:444–53.10.1016/j.etap.2013.01.010Search in Google Scholar PubMed

[17] Adedara IA, Farombi EO. Chemoprotective effects of Kolaviron on ethylene glycol monoethyl ether-induced pituitary-thyroid axis toxicity in male rats. Andrologia. 2013;45:111–9.10.1111/j.1439-0272.2012.01321.xSearch in Google Scholar PubMed

[18] Adaramoye OA, Nwosu IO, Farombi EO. Sub-acute effect of N(G)-nitro-l-arginine methyl-ester (L-NAME) on biochemical indices in rats: protective effects of Kolaviron and extract of Curcuma longa L. Pharmacog Res. 2012;4:127–33.10.4103/0974-8490.99071Search in Google Scholar PubMed PubMed Central

[19] Abarikwu SO, Farombi EO, Pant AB. Kolaviron biflavanoids of Garcinia kola seeds protect atrazine-induced cytotoxicity in primary cultures of rat Leydig cells. Int J Toxicol. 2012;31:407–15.10.1177/1091581812445476Search in Google Scholar PubMed

[20] Farombi EO, Adedara IA, Akinrinde SA, Ojo OO, Eboh AS. Protective effects of Kolaviron and quercetin on cadmium-induced testicular damage and endocrine pathology in rats. Andrologia. 2012;44:273–84.10.1111/j.1439-0272.2012.01279.xSearch in Google Scholar PubMed

[21] Igado OO, Olopade JO, Adesida A, Aina OO, Farombi EO. Morphological and biochemical investigation into the possible neuroprotective effects of Kolaviron (Garcinia kola bioflavonoid) on the brains of rats exposed to vanadium. Drug Chem Toxicol. 2012;35:371–80.10.3109/01480545.2011.630005Search in Google Scholar PubMed

[22] Adedara IA, Farombi EO. Chemoprotection of ethylene glycol monoethyl ether-induced reproductive toxicity in male rats by Kolaviron, isolated biflavonoid from Garcinia kola seed. Human Exp Toxicol. 2012;31:506–17.10.1177/0960327111424301Search in Google Scholar

[23] Iwu MM, Igboko OA, Onwuchekwa U, Okunji CO. Evaluation of the anti-hepatotoxicity of the biflavonoids of Garcinia kola seeds. J Ethnopharmacol. 1987;21:127–42.10.1016/0378-8741(87)90123-1Search in Google Scholar

[24] PHS (PUBLIC HEALTH SERVICE). Public health service policy on humane care and the use of laboratory animals. Washington, DC: US Department of Health and Humane services, 1996:99–158.Search in Google Scholar

[25] Shinha KA. Colorimetric assay of Catalase. Anal Biochem. 1972;47:389–94.10.1016/0003-2697(72)90132-7Search in Google Scholar PubMed

[26] Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;217:3170–5.10.1016/S0021-9258(19)45228-9Search in Google Scholar

[27] Habig WH, Pabst MJ, Jacoby WB. Glutathione-S-transferase activity: the enzymic step in mercapturic acid formation. J Biol Chem. 1974;249:130–9.Search in Google Scholar

[28] Lowry OH. Protein measurement with Folin phenol reagent. J Biol Chem. 1951;193:265–75.10.1016/S0021-9258(19)52451-6Search in Google Scholar PubMed

[29] Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR. Bromobenzene-induced liver necrosis; protective role of GSH & evidence for 3, 4 bromobenzene oxide as the hepatotoxic metabolite. Pharmacology. 1974;11:151–69 .10.1159/000136485Search in Google Scholar

[30] Wolff SP. Ferrous ion oxidation in the presence of ferric ion indicator xylenol orange for measurement of hydroperoxides. Methods Enzymol. 1994;233:182–9.10.1016/S0076-6879(94)33021-2Search in Google Scholar

[31] Buetler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med. 1963;61:882–8.Search in Google Scholar PubMed

[32] Akaike T, Ando M, Oda T, Doi T, Ijiri S, Araki S, Dependence on O2- generation by xanthine oxidase of pathogenesis of influenza virus infection in mice. J Clin Invest. 1990;85:739–45.10.1172/JCI114499Search in Google Scholar PubMed PubMed Central

[33] Würzburg U, Hennrich N, Orth HD, Lang H, Prellwitz W, Neumeier D, Quantitative determination of creatine kinase isoenzyme catalytic concentrations in serum using immunological methods. J Clin Chem Clin Biochem. 1977;15:131–7.10.1515/cclm.1977.15.1-12.131Search in Google Scholar PubMed

[34] Henry RJ. Colorimetric determination of lactic dehydrogenase. In: Henry RJ, editor(s). Clinical chemistry: principles and techniques, 2nd edn Hagerstown, MD: Harper & Row, 1974:819–31.Search in Google Scholar

[35] Olaleye SB, Adaramoye OA, Erigbali PP, Adeniyi OS. Lead exposure increases oxidative stress in the gastric mucosa of HCl/ethanol-exposed rats. World J Gastroenterol. 2007;13:5121–6.10.3748/wjg.v13.i38.5121Search in Google Scholar PubMed

[36] Xia Y, Zweier JL. Measurement of myeloperoxidase in leukocyte-containing tissues. Anal Biochem. 1997;245:93–6.10.1006/abio.1996.9940Search in Google Scholar PubMed

[37] Todorich B, Olopade JO, Surguladze N, Zhang X, Neely E, Connor JR. The mechanism of vanadium-mediated developmental hypomyelination is related to destruction of oligodendrocyte progenitors through a relationship with ferritin and iron. Neurotox Res. 2011;19:361–73.10.1007/s12640-010-9167-1Search in Google Scholar PubMed

[38] Jiang B, Zhang L, Wang Y, Li M, Wu W, Guan S, Tanshinone IIA sodium sulfonate protects against cardiotoxicity induced by doxorubicin in vitro and in vivo. Food Chem Toxicol. 2009;47:1538–44.10.1016/j.fct.2009.03.038Search in Google Scholar PubMed

[39] Šimůnek TA, Štěrba MB, Popelová OB, Adamcová MB, Hrdina RA, Gerši V. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Reports. 2009;61:154–71.10.1016/S1734-1140(09)70018-0Search in Google Scholar

[40] Chen JY, Hu RY, Chou HC. Quercetin-induced cardioprotection against doxorubicin cytotoxicity. J Biomed Sci. 2013;20:95.10.1186/1423-0127-20-95Search in Google Scholar PubMed PubMed Central

[41] Adedara IA, Farombi EO. Influence of Kolaviron and vitamin E on ethylene glycol monoethyl ether-induced haematotoxicity and renal apoptosis in rats. Cell Biochem Funct. 2014;32:31–8.10.1002/cbf.2968Search in Google Scholar PubMed

[42] Adedara IA, Vaithinathan S, Jubendradass R, Mathur PP, Farombi EO. Kolaviron prevents carbendazim-induced steroidogenic dysfunction and apoptosis in testes of rats. Environ Toxicol Pharmacol. 2013b;35:444–53.10.1016/j.etap.2013.01.010Search in Google Scholar PubMed

[43] Arafa HM, Abd-Ellah MF, Hafez HF. Abatement by naringenin of doxorubicin-induced cardiac toxicity in rats. J Egypt Cancer Instit. 2005;17:291–300.Search in Google Scholar

[44] Oktem G, Uysal A, Oral O, Sezer ED, Olukman M, Erol A, Resveratrol attenuates doxorubicin-induced cellular damage by modulating nitric oxide and apoptosis. Exp Toxicol Pathol. 2012;64:471–9.10.1016/j.etp.2010.11.001Search in Google Scholar PubMed

[45] Olson RD, Mushlin PS, Brenner DE, Fleischer C, Change BK, Baucek RJ. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Science, USA. 1988;85:3585–9.10.1073/pnas.85.10.3585Search in Google Scholar PubMed PubMed Central

[46] Herman E, Mhatre R, Lee IP, Vick J, Waravdekar VS. A comparison of the cardiovascular actions of daunomycin, adriamycin and N-acetyldaunomycin in hamsters and monkeys. Pharmacol. 1971;6:230–41.10.1159/000136248Search in Google Scholar

[47] Fu X, Kong L, Tang M, Zhang J, Zhou X, Li G, Protective effect of ocotillol against doxorubicin‑induced acute and chronic cardiac injury. Mol Med Report. 2014;9:360–4.10.3892/mmr.2013.1791Search in Google Scholar

[48] Rajadurai M, Stanely Mainzen PP. Preventive effect of naringin on cardiac markers, electrocardiographic patterns and lysosomal hydrolases in normal and isoproterenol-induced myocardial infarction in Wistar rats. Toxicol. 2007;230:178–88.10.1016/j.tox.2006.11.053Search in Google Scholar

[49] Saradha B, Mathur PP. Induction of oxidative stress by lindane in epididymis of adult male rats. Environ Toxicol Pharmacol. 2006;22:90–6.10.1016/j.etap.2005.12.008Search in Google Scholar PubMed

[50] Abdel-Wahhab MA, Abde-Azim SH, El-Nekeety AA. Inula Crithmoides extract protects against ochratoxin A-induced oxidative stress, clastogenic and mutagenic alterations in male rats. Toxicon. 2008;52:566–73.10.1016/j.toxicon.2008.07.006Search in Google Scholar PubMed

[51] Dixit R, Kumar P, Tripathi R, Basu S, Mishra R, Shukla VK. Chromosomal structural analysis in carcinoma of the gallbladder. World J Surg. 2012;10:198.10.1186/1477-7819-10-198Search in Google Scholar

[52] Sharma V, Sharma A, Kansal L. The effect of oral administration of Allium sativum extracts on lead nitrate induced toxicity in male mice. Food Chem Toxicol. 2010;48:928–36.10.1016/j.fct.2010.01.002Search in Google Scholar PubMed

[53] Šimůnek TA, Štěrba MB, Popelová OB, Adamcová MB, Hrdina RA, Gerši V. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Reports. 2009;61:154–71.10.1016/S1734-1140(09)70018-0Search in Google Scholar

[54] Jones DP. Redox potential of GSH/GSSG couple: assay and biological significance. Methods Enzymol. 2002;348:93–112.10.1016/S0076-6879(02)48630-2Search in Google Scholar PubMed

[55] Masella R, Di BR, Vari R, Filesi C, Giovannini C. Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutri Biochem. 2005;16:577–86.10.1016/j.jnutbio.2005.05.013Search in Google Scholar PubMed

[56] Disli OM, Sarihan E, Colak MC, Vardi N, Polat A, Yagmur J, Effects of molsidomine against doxorubicin-induced cardiotoxicity in rats. Eur Surg Res. 2013;51:79–90.10.1159/000354807Search in Google Scholar PubMed

[57] Rajadurai M, Stanely Mainzen PP. Preventive effect of naringin on lipid peroxides and antioxidants in isoproterenol-induced cardiotoxicity in Wistar rats: biochemical and histopathological evidences. Toxicol. 2006;228:259–68.10.1016/j.tox.2006.09.005Search in Google Scholar PubMed

[58] Andreadou I, Mikros E, Ioannidis K, Sigala F, Naka K, Kostidis S, Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism. J Mol Cell Cardiol. 2014;69C:4–16.10.1016/j.yjmcc.2014.01.007Search in Google Scholar PubMed

[59] Elsharkawy AM, Mann DA. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatol. 2007;46:590–7.10.1002/hep.21802Search in Google Scholar PubMed

[60] Abd El-Aziz TA, Mohamed RH, Pasha HF, Abdel-Aziz HR. Catechin protects against oxidative stress and inflammatory-mediated cardiotoxicity in adriamycin-treated rats. Clin Exp Med. 2012;4:233–40.10.1007/s10238-011-0165-2Search in Google Scholar PubMed

Received: 2016-12-27
Accepted: 2017-6-6
Published Online: 2017-10-3

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