PJB-2026-92
The methanol extract of Daphne mucronata (Laghenai) protects against doxorubicin-induced cardiac toxicity in H9c2 cell line, and heart failure in Wistar rats via antioxidant action.
Soraj Kishanchand
Abstract
Abstract
Globally, cancer is the leading cause of death. The majority of the chemotherapeutic drugs impose serious adverse effects. Although, anthracyclines belong to a class of chemotherapeutics with proven clinical efficacy. Yet, they produce severe cardiotoxicity via oxidative damage. Among anthracyclines, doxorubicin is a cost-effective option. However, dose-dependent (cumulative: >550 mg/m2) congestive heart failure limits its clinical use making the inclusion of anti-oxidants vital as adjuncts. Coincidingly, Daphne mucronata methanolic extract in our pilot study exhibited anti-oxidant potential. Also, in literature, D. mucronata displayed antioxidative protection against drug-induced oxidative organ damage. Subsequently, the protective effect of D. mucronata methanolic extract (L. E) was explored against doxorubicin-induced cardiotoxicity.
The safety of L.E against H9C2 cells using SRB assay, and intracellular oxidative protection using DCF-DA assay were explored. Next, apoptotic cells by flow cytometry, and gene expression by real-time PCR were analyzed. Furthermore, L.E at 50 mg/kg was assessed in doxorubicin-induced rat cardiotoxic model via functional, biochemical, and histopathological analysis. It was observed that L. E. showed low H9c2 cells injury as indicated by its higher IC50 (155 µg/ml) than quercetin (IC50: 138.66 µg/ml). Also, L.E at 50 µg/ml significantly (P < 0.01) increased viable cells i.e., ~75%, decreased apoptotic (~78%) cells, decreased intracellular oxidative stress by ~1.8 folds as compared to doxorubicin-treated cardiomyocytes. In line, an increase in SOD-2 (~1.28 folds), and Nrf-2 (~2.35 folds) indicated anti-oxidant, while increase in BCL-2 (~2.26 folds), and decrease in BAX (~1.57 folds) indicated anti-apoptotic activity. The preclinical investigation revealed that L. E (50 mg/Kg) significantly increased ejection fraction (~27%), diminished levels of troponin-I (~2.9x), creatine-phosphokinase (1.64x), improved cardiac tissue integrity, and fibrotic content (~46.9%) in doxorubicin-treated rats. It was concluded that D. mucronata methanolic extract prevents doxorubicin-induced cardiac toxicity owing to the reduced cardiomyocyte oxidative damage.
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