β-Caryophyllene, a cannabinoid receptor type-2 agonist protects against doxorubicin-induced cardiotoxicity

Introduction: Doxorubicin (Dox) is one of the most widely used and highly active antitumour drugs, but its cumulative cardiotoxicity has been a major concern in cancer therapeutic practice. The cardiotoxic side-effects of Dox are associated with increased oxidative/nitrosative stress, inflammation and apoptosis. β -Caryophyllene (BCP) is a natural bicyclic sesquiterpene commonly found in the essential oils of many vegetables, fruits and spices. It has been approved by the US Food and Drug Administration as a food additive and flavouring agent, and termed as a dietary phytocannabinoid. It has recently been shown that BCP has a number of beneficial effects in different biological systems, which include antioxidant, antineoplastic, antidepressant, anti-inflammatory, cardioprotective and anxiolytic effects. Objectives: BCPs recent identification as a CB2 receptor agonist generated interest to investigate whether it can counter the Dox-induced cardiotoxicity in rats. Materials and methods: BCP (50mg/kg/day) dissolved in corn oil was administered orally to male Wistar rats for 21 days while the Dox control group received 12.5mg/kg/ml intraperitoneally and the vehicle, corn oil, was administered daily and naive rats were used as controls. After 72hours of Dox administration, the animals were sacrificed and hearts were collected. Results: BCP was found to protect against Dox-induced reduction in enzyme activities of superoxide dismutase, catalase and depletion of reduced glutathione and accumulation of malondialdehyde and nitric oxide. BCP pretreatment also significantly reduced the inflammatory markers Il-β 1, IL-6 and TNF-α  and restored the levels of Dox-induced rise of serum glutamic-pyruvic transaminase, serum glutamic oxaloacetic transaminase, serum lactate dehydrogenase and creatine kinase levels. Furthermore, the histopathological changes strengthened the protective effects of BCP against Dox-induced cardiotoxicity. Conclusions: BCP may be a suitable cardioprotective agent to reduce the cardiotoxic effects of Dox by reducing oxidative/nitrosative stress and inflammation. Given the widespread occurrence, safety and efficacy profile, BCP may offer excellent therapeutic/preventative qualities as it appears to be a safe functional non-psychoactive and macrocyclic anti-inflammatory CB2 receptor ligand in foodstuffs.