β-caryophyllene, a dietary phytocannabinoid attenuates oxidative stress, inflammation, apoptosis and prevents structural alterations of the myocardium against doxorubicin-induced acute cardiotoxicity in rats: An in vitro and in vivo study

Abstract

The present study investigates the cardioprotective effect of β-caryophyllene against doxorubicin-induced acute cardiotoxicity in rats. Doxorubicin (12.5 mg/kg) and β-caryophyllene (25, 50 or 100 mg/kg) were administered intraperitoneally to male albino Wistar rats. Doxorubicin-treated rats showed elevated levels of creatine kinase-MB in serum and oxidative stress in the myocardium as evidenced by decreased superoxide dismutase, catalase and glutathione with a concomitant rise in malondialdehyde levels. Doxorubicin also induced pro-inflammatory cytokines release following activation of the nuclear factor kappa-B and elevated expressions of inducible nitric oxide synthase and cyclooxygenase-2 in the myocardium. Additionally, doxorubicin also increased expression of γ-H2AX, a marker of DNA damage as well as increased expression of proapoptotic (Bax, p53, and active caspase-3) proteins along with the decreased expression of anti-apoptotic protein, Bcl2 in the myocardium. The histological and ultrastructural studies further revealed edema, inflammation and structural degeneration of cardiomyocytes following doxorubicin injection. However, treatment with β-caryophyllene showed significant cardioprotective effects as evidenced by favorable improvement of biochemical and molecular parameters along with remarkable preservation of cardiomyocytes in histological and ultrastructural studies. Results of the present study demonstrate that β-caryophyllene has potential to protect heart against doxorubicin-induced acute cardiotoxicity in rats. Moreover, the antioxidant and free radical scavenging properties of β-caryophyllene was confirmed by in vitro assays. Provided the anticancer and chemosensitizing properties of β-caryophyllene, the cardioprotective effects of β-caryophyllene are suggestive of its multiple properties that provides an additional basis of its possible therapeutic application in chemotherapy-associated cardiotoxicity.

Keywords: Acute cardiotoxicity; Cardioprotection; DNA damage and apoptosis; Doxorubicin; Inflammation; β-Caryophyllene.