Methyl Jasmonate Attenuates Doxorubicin-induced Myocardial Damage Through Multifaceted Cellular and Molecular Mechanisms: An Integrated In Vitro, In Vivo Approach.

INTRODUCTION: Doxorubicin (Dox) is a widely used antineoplastic drug that often causes cardiomyopathy, leading to congestive heart failure through the production of Reactive Oxygen Species (ROS) within the myocardium. This investigation examines the protective effects of Methyl Jasmonate (MeJA) against Dox-induced cardiotoxicity by modulating cellular signaling pathways through in vitro and in vivo analyses. METHODS: Initially, physicochemical properties were evaluated via in silico (ADMET) studies to assess MeJA's pharmacokinetic profile, including Ames toxicity, in comparison with the reference drug amifostine. Additionally, an in vitro cytotoxicity assay was performed on embryonic rat cardiac myoblasts (H9c2 cells) using the MTT method, along with measurements of proapoptotic, oxidative, and pro-inflammatory markers. Furthermore, in vivo studies assessed the impact of MeJA on Dox-induced cardiotoxicity in rats, employing hemodynamic measurements (e.g., ST height, heart rate, SAP, MAP, DAP), biochemical analyses (e.g., cardiac injury, liver enzymes, oxidative and pro-inflammatory markers), and histopathological examinations. RESULTS: In silico ADMET analysis via the BOILED-Egg model indicated that MeJA exhibits excellent Blood-Brain Barrier (BBB) penetration and lacks Ames toxicity. In vitro, MeJA significantly reduced Dox-induced cytotoxicity, oxidative stress, and inflammation in H9c2 cells. DISCUSSION: MeJA protects rat cardiac tissues by enhancing hemodynamic functions, lowering cardiac injury indicators, and averting histological damage, according to in vivo investigations that supported these findings. CONCLUSION: Together, the findings of this study suggest that MeJA possesses cardioprotective potential against Dox-induced cardiotoxicity. The observed changes in inflammatory and apoptosis- related biomarkers are consistent with a potential protective role of MeJA; however, further molecular, preclinical, and clinical studies are required to confirm its mechanisms and therapeutic applicability.