The
cannabinoid type 2
receptor (CB2) has recently emerged as an important therapeutic target for
cancer as well as
cardiovascular diseases. The
CB2 receptor downregulation has been reported in solid
tumors and
cardiovascular diseases, therefore the
CB2 receptor activation has been considered as a viable strategy for
chemotherapy as well as cardioprotection.
Doxorubicin (DOX) is an important drug that continues to be the mainstay of
chemotherapy in solid
tumors,
leukemia, and
lymphoma. However, the use of DOX is often limited due to its lethal
cardiotoxicity. Considering the role of CB2 receptors in
cardiovascular diseases and
cancer, the activation of CB2 receptors may protect against DOX-induced chronic
cardiotoxicity in rats. In the present study, we investigated the cardioprotective effect of a selective
CB2 receptor agonist; β-
Caryophyllene (BCP), a natural bicyclic
sesquiterpene, against DOX-induced chronic
cardiotoxicity in rats.
AM630, a
CB2 receptor antagonist was administered as a pharmacological challenge prior to BCP treatment to demonstrate
CB2 receptor mediated cardioprotective mechanism of BCP. DOX (2.5 mg/kg) was injected intraperitoneally once a week for five weeks to induce chronic
cardiotoxicity in rats. BCP was also injected into rats six days a week for a total duration of five weeks. DOX induced a significant decline in cardiac function and oxidative stress evidenced by the depletion of
antioxidant enzymes,
glutathione, and increased lipid peroxidation. DOX also triggered activation of
nuclear factor kappa B (NF-κB) and increased the levels of pro-inflammatory
cytokines (TNF-α, IL-6, and IL-1β) and expression of the inflammatory mediators (iNOS and COX-2) in the heart. Furthermore, DOX also upregulated the expression of pro-apoptotic markers such as Bax, p53, cleaved PARP, active
caspase-3 and downregulated anti-apoptotic marker Bcl-2 in the myocardium. BCP treatment exerted significant cardioprotective effect by salvaging the heart tissues, improving cardiac function, mitigating oxidative stress,
inflammation, and apoptosis. The histological and ultrastructural studies also appear in line with our findings of biochemical and molecular parameters. The
CB2 receptor-mediated cardioprotective mechanism was further confirmed by the abrogation of the beneficial effects of BCP with prior administration of the
CB2 receptor antagonist;
AM630. Our study revealed the novel mechanism of BCP in cardioprotection against DOX-induced chronic
cardiotoxicity by the activation of CB2 receptors.