Edaravone alleviates sepsis-induced diaphragmatic dysfunction via Sirt1/Nrf2 pathway.

BACKGROUND

The mechanisms underlying the development of sepsis-induced diaphragmatic dysfunction (SIDD) are poorly understood. Activation of the SIRT1/Nrf2 signaling pathway can attenuate oxidative stress damage in skeletal muscle injury. The present study aimed to validate the hypothesis that edaravone (ED) can improve SIDD through modulation of the SIRT1/Nrf2 signaling pathway and to explore the underlying mechanisms.

METHODS

Animal models (mice) were constructed using the cecal ligation and puncture (CLP) method, while the C2C12 cells were stimulated by lipopolysaccharide (LPS). The diaphragmatic function was accessed by diaphragm ultrasonography. We examined the expression levels of proteins involved in the SIRT1/Nrf2 pathway (Sirt1, Nrf2, and HO-1), oxidative stress markers (SOD, ROS, and GPX4), and muscle atrophy-related proteins (MuRF1 and Atrogin-1) to test the role of ED in SIDD.

RESULTS

We found that sepsis-induced a significant decrease in both diaphragmatic excursion and contractile velocity. Administration of ED (5 mg/kg) improved the diaphragmatic function in mice. Moreover, sepsis mice showed increased levels of oxidative stress markers and muscle atrophy-related proteins and a down-regulated pathway of SIRT1/Nrf2. The intervention of ED could modulate the SIRT1/Nrf2 pathway, which in turn protects the diaphragm from SIDD. Similar findings were also observed in vitro experiments with small interfering RNAs.

CONCLUSIONS

Edaravone was demonstrated to potentially alleviate SIDD by activating the SIRT1/Nrf2 pathway.