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

Doxorubicin (DOX)-induced toxicity impairs cardiovascular functions. <i>Phyllanthus amarus</i> 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 <i>P. amarus</i> against DOX-induced acute cardiotoxicity in Sprague-Dawley rats. Phyllanthin was isolated from the methanolic extract of the aerial parts of <i>P. amarus</i> 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. <i>P. amarus</i> (50 and 100 mg/kg) effectively (<i>P</i> < 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 (<i>P</i> < 0.05) reduced cardiac oxidative stress and cTn-I, ANP, BNP, ILs, TNF-α, and nitric oxide levels. Additionally, <i>P. amarus</i> effectively (<i>P</i> < 0.05) up-regulated Bcl2 and down-regulated (<i>P</i> < 0.05) caspase-3 and Bax protein levels. Furthermore, it effectively (<i>P</i><0.05) ameliorated the DOX-induced histological abnormalities in cardiac tissue. In conclusion, this study suggests that Phyllanthin from <i>P. amarus</i> 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.