Edaravone is a Therapeutic Candidate for Doxorubicin-Induced Cardiomyopathy by Activating the Nrf2 Pathway.

Doxorubicin (DOXO) has long been used clinically and remains a key drug in cancer therapy. DOXO-induced cardiomyopathy (DICM) is a chronic and fatal complication that severely limits the use of DOXO. However, there are very few therapeutic agents for DICM, and there is an urgent need to identify those that can be used for a larger number of patients. The most likely pathogenic mechanism of DICM is the involvement of reactive oxygen species (ROS) and promotion of cell death. In this study, we investigated the efficacy and mechanism of action of edaravone (EDA), a known radical scavenger in DICM. Two methods of EDA administration were employed: daily and weekly. Our results showed that the daily administration group had prolonged survival periods and preserved the left ventricular ejection fraction in DICM mice. In contrast, in the weekly treatment group, slight improvements were observed in these indicators compared with those in DICM mice; however, none of them were statistically significant. These results show that the daily administration group had a higher efficacy than the weekly administration group. Gene-expression results showed that Nrf2 and its related genes were upregulated in the daily group but not in the weekly group. Based on these results, we hypothesized that the Sirt1/Nrf2/HO-1 and ABCB4 pathways were involved in EDA. However, there is limited evidence that EDA is effective against DICM. The findings obtained herein bolster the evidence in DICM by demonstrating prolonged survival and continued preservation of cardiac function and proposing a possible mechanism.