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Cardioprotective Effects of Hesperetin against Doxorubicin-Induced Oxidative Stress and DNA Damage in Rat

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Abstract

Doxorubicin is a widely used chemotherapeutic agent; however, its clinical uses are limited due to its cardiotoxicity associated with an induction of oxidative stress. This study was aimed to investigate the protective effect of hesperetin against doxorubicin-induced cardiotoxicity in rats. Doxorubicin was administered at the dosage of 4 mg/kg bw/week, ip for a period of 5 consecutive weeks. Hesperetin was administered at the dosages of 25, 50 and 100 mg/kg bw, po by gavage for 5 consecutive days in a week for 5 weeks. The animals were killed 1 week after the last injection of doxorubicin. Hesperetin at the doses of 50 and 100 mg/kg bw significantly reduced MDA and increased GSH levels in the doxorubicin-treated animals. Further, hesperetin significantly reduced doxorubicin-induced DNA damage as well as apoptosis at 25, 50, and 100 mg/kg bw as evident from the comet and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assays, respectively. Thus, hesperetin ameliorated doxorubicin-induced cardiotoxicity by reducing oxidative stress, abnormal cellular morphology and DNA damage in rat. Moreover, nuclear factor-kappa B, p38, and caspase-3 play a role in the hesperetin-mediated protection against doxorubicin-induced cardiotoxicity. This study indicates the protective effect of hesperetin against doxorubicin-induced cardiotoxicity.

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Abbreviations

DOX:

Doxorubicin

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

NFκB:

Nuclear factor-kappa B

SD:

Sprague–Dawley

CMC:

Carboxy methyl cellulose

H&E:

Hematoxylin and eosin

EtBr:

Ethidium bromide

DMSO:

Dimethylsulfoxide

NMPA:

Normal melting point agarose

LMPA:

Low melting point agarose

EDTA:

Ethylenediamine tetraacetic acid

HBSS:

Hank’s balanced salt solution

ip:

Intraperitoneal

TL:

Tail length

TM:

Tail moment

OTM:

Olive tail moment

% DNA:

% DNA in comet tail

MDA:

Malondialdehyde

GSH:

Reduced glutathione

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Acknowledgments

We wish to acknowledge the financial assistance received from National Institute of Pharmaceutical Education and Research (NIPER), Mohali, to undertake this study. The authors would also like to acknowledge Intas Pharmaceuticals Ltd., Ahmedabad, Gujarat, for benevolently granting the gift sample of doxorubicin.

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None.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab, 160062, India

    P. P. Trivedi, S. Kushwaha, D. N. Tripathi & G. B. Jena

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  1. P. P. Trivedi
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  2. S. Kushwaha
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  3. D. N. Tripathi
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  4. G. B. Jena
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Correspondence to G. B. Jena.

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Trivedi, P.P., Kushwaha, S., Tripathi, D.N. et al. Cardioprotective Effects of Hesperetin against Doxorubicin-Induced Oxidative Stress and DNA Damage in Rat. Cardiovasc Toxicol 11, 215–225 (2011). https://doi.org/10.1007/s12012-011-9114-2

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