Remimazolam alleviates hepatic ischemia-reperfusion injury by activating FOXO1/3 signaling : Remimazolam alleviates hepatic ischemia reperfusion injury.

Background: Hepatic ischemia reperfusion injury (HIRI) frequently gives rise to aggravated liver damage. Currently, there exists a diverse range of anesthetic drugs that possess protective capabilities against ischemia-reperfusion injury (IRI). Nevertheless, the specific functions and underlying mechanisms of remimazolam (RMZL) in HIRI have not been fully elucidated.

Methods: HIRI models of both hepatocytes and mice were successfully established. To evaluate liver function and injury, ELISA, HE and TUNEL staining were employed. The levels of oxidative stress markers and inflammatory factors were measured using commercial kits. Cell viability and apoptosis were measured by CCK-8 and flow cytometry, respectively. The abundance of genes and proteins was determined utilizing RT-qPCR and western blot.

Results: It was observed that RMZL administration greatly alleviated liver damage and repressed oxidative stress and inflammation in HIRI mouse models. In vitro experiments demonstrated that RMZL strongly protected LO2 cells from H/R-induced cell damage, oxidative stress, and inflammatory responses. Moreover, FOXO1 and FOXO3, which function as classic cell protection and anti-oxidative stress factors, were observed to be downregulated in liver tissue from HIRI mouse models and H/R-challenged LO2 cells. Notably, this downregulation could be reversed by the administration of RMZL. Furthermore, FOXO1 or FOXO3 knockdown abolished the protective effects of RMZL, including promoted cell survival and inhibited oxidative stress and inflammation in LO2 cells upon H/R exposure.

Conclusion: These data provided robust support for the notion that RMZL attenuated oxidative stress and inflammation to alleviate HIRI through enhancing FOXO1 and FOXO3 expressions, suggesting that RMZL holds great promise as a potential candidate anesthetic for HIRI treatment.