Phyllanthin mitigates doxorubicin-induced acute cardiotoxicity: role of Bax/Bcl2 and Caspase-3 regulation.

Doxorubicin (DOX)-induced toxicity impairs cardiovascular functions. Phyllanthus amarus exhibits anti-inflammatory, antiviral, anticancer, antioxidant, nephroprotective, and hepatoprotective effects. However, its potential against DOX-induced acute cardiotoxicity is lacking. This study aimed to assess the underlying mechanism of action of P. amarus against DOX-induced acute cardiotoxicity in Sprague-Dawley rats. Phyllanthin was isolated from the methanolic extract of the aerial parts of P. amarus and characterized using HPLC-ESI-MS/MS. Its cardioprotective efficacy was evaluated in DOX-intoxicated male Sprague-Dawley rats (200-230 g) at doses of 50, 100, and 200 mg/kg, p.o., by examining electrocardiographic, hemodynamic, histological, and biochemical parameters. In the results, spectral analysis revealed that the isolated phyllanthin has a molecular formula of C24H34O6 and a molecular weight of 418.1534 Da. P. amarus (50 and 100 mg/kg) effectively (P < 0.05) alleviated DOX-induced cardiac injury by ameliorating deviations in heart weight, electrocardiographic and hemodynamic function, and serum biomarkers (CK-MB, LDH, AST, ALP, and ALT). Moreover, it notably (P < 0.05) reduced cardiac oxidative stress and cTn-I, ANP, BNP, ILs, TNF-α, and nitric oxide levels. Additionally, P. amarus effectively (P < 0.05) up-regulated Bcl2 and down-regulated (P < 0.05) caspase-3 and Bax protein levels. Furthermore, it effectively (P<0.05) ameliorated the DOX-induced histological abnormalities in cardiac tissue. In conclusion, this study suggests that Phyllanthin from P. amarus exerts cardioprotective effects by modulating the Bax/Bcl2 and caspase-3 pathways to suppress the expression of pro-inflammatory cytokines, apoptosis, and cardio-oxido-nitrosative stress. Thus, Phyllanthin can be considered as a potential therapy for the treatment of DOX-induced acute cardiotoxicity.