Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity

https://doi.org/10.1016/j.etap.2013.04.018Get rights and content

Highlights

  • Doxorubicin cardiotoxicity is related to oxidative stress and inflammation of cardiac tissue.

  • Cannabidiol has antioxidant and anti-inflammatory activities.

  • Cannabidiol treatment ameliorated doxorubicin cardiotoxicity in rats via its antioxidant and anti-inflammatory effects.

Abstract

The potential protective effect of cannabidiol, the major non-psychotropic Cannabis constituent, was investigated against doxorubicin cardiotoxicity in rats. Cardiotoxicity was induced by six equal doses of doxorubicin (2.5 mg kg−1 i.p., each) given at 48 h intervals over two weeks to achieve a total dose of 15 mg kg−1. Cannabidiol treatment (5 mg kg−1/day, i.p.) was started on the same day of doxorubicin administration and continued for four weeks. Cannabidiol significantly reduced the elevations of serum creatine kinase-MB and troponin T, and cardiac malondialdehyde, tumor necrosis factor-α, nitric oxide and calcium ion levels, and attenuated the decreases in cardiac reduced glutathione, selenium and zinc ions. Histopathological examination showed that cannabidiol ameliorated doxorubicin-induced cardiac injury. Immunohistochemical analysis revealed that cannabidiol significantly reduced the expression of inducible nitric oxide synthase, nuclear factor-κB, Fas ligand and caspase-3, and increased the expression of survivin in cardiac tissue of doxorubicin-treated rats. These results indicate that cannabidiol represents a potential protective agent against doxorubicin cardiac injury.

Introduction

Doxorubicin is an anthracycline anticancer antibiotic commonly used for treatment of hematological malignancies and solid tumors. Despite the broad therapeutic effectiveness, the clinical use of doxorubicin is often limited because of its dose-dependent cardiotoxic adverse effects which frequently lead to congestive heart failure (Singal and Iliskovic, 1998, Minotti et al., 2004). Oxidative stress and inflammation play an important role in the pathogenesis of doxorubicin cardiotoxicity; indeed, several antioxidants and anti-inflammatory agents were proved effective in protecting against cardiac tissue damage induced by doxorubicin (Andreadou et al., 2007, Jiang et al., 2008, Ammar et al., 2011, Xin et al., 2011).

Cannabidiol is the major non-psychoactive cannabinoid component derived from the plant Cannabis sativa. It possesses powerful antioxidant and anti-inflammatory activities, although the exact mechanisms of action of cannabidiol remain obscure. In contrast to the other cannabinoids, cannabidiol is known to have a very low affinity for the cannabinoid CB1 and CB2 receptors. The antioxidant and anti-inflammatory activities of cannabidiol may be due to its direct action or mediated through a new cannabinoid, non-CB1 and non-CB2, receptor (Begg et al., 2005, De Petrocellis and Di Marzo, 2010). Cannabidiol may also exert its beneficial effects by inhibiting adenosine uptake and activating transient receptor potential vanilloid-1 (Bisogno et al., 2001, Carrier et al., 2006). Previous reports showed that cannabidiol may have therapeutic utility in a number of conditions involving inflammation and oxidative stress, including diabetes mellitus, rheumatoid arthritis, neurodegenerative disorders and ischemia/reperfusion tissue injury (Blake et al., 2006, Durst et al., 2007, Iuvone et al., 2009, Rajesh et al., 2010). However, to the best of our knowledge, the protective effect of cannabidiol against doxorubicin cardiotoxicity was not yet investigated.

Hence, we have conducted the present study to evaluate the potential cardioprotective effect of cannabidiol in rats which received doxorubicin, and to investigate the possible mechanisms underlying this protective effect.

Section snippets

Animals

Male Sprague-Dawley rats, weighing 250 ± 10 g were obtained from the Animal House, College of Medicine, King Faisal University. The animals were kept at standard housing facilities (24 ± 1 °C, 45 ± 5% humidity and 12 h light/dark cycle). They were supplied with standard laboratory chow and water ad libitum, and left to acclimatize for 1 week before the experiments. The experimental protocol was approved by the Ethical Committee, Deanship of Scientific Research, King Faisal University (approval number:

Effects of cannabidiol on the measured biochemical parameters

Significant increases of serum CK-MB and troponin T, and cardiac tissue levels of MDA, TNF-α, and NO, associated with a significant reduction in cardiac GSH resulted from doxorubicin administration as compared to the control values (p < 0.05). Cannabidiol treatment significantly attenuated the elevations of serum CK-MB and troponin T, and suppressed lipid peroxidation, reduced the elevations of TNF-α and NO, and prevented the depletion of GSH in cardiac tissue as compared to the doxorubicin group

Discussion

The present study revealed that cannabidiol treatment for four weeks provided a significant protective effect against doxorubicin-induced cardiotoxicity in rats. Also, the present results, in accordance with previous studies, showed that oxidative stress, depletion of antioxidant defenses and increased production of inflammatory mediators are implicated in the pathogenesis of doxorubicin cardiotoxicity (Andreadou et al., 2007, Jiang et al., 2008, Ammar et al., 2011, Xin et al., 2011). In

Conflict of interest statement

The authors declare that there is no conflict to disclose.

Acknowledgments

Special thanks to the Deanship of Scientific Research, King Faisal University for continuous encouragement and support. Also, special thanks to Dr Mohamed A. Morsy for his valuable advices.

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