Ferulic acid exerts a protective effect against cyclosporine-induced liver injury in rats via activation of the Nrf2/HO-1 signaling, suppression of oxidative stress, inflammatory response, and halting the apoptotic cell death.

Abstract

Drug-induced liver injury is one of the main challenges that leads to the withdrawal of several drugs in the clinical setting. Cyclosporine is one of the drugs that its long-term administration exerts devastating effects on the hepatocytes. In the present study, we aimed to evaluate the effect of ferulic acid, a natural compound found in plants, on cyclosporine-mediated hepatotoxicity. Forty-eight male Wistar rats were treated with cyclosporine and/or ferulic acid to evaluate the function as well as the morphology of liver cells. We found that ferulic acid dose-dependently recovered the functional as well as histopathological parameters of liver cells, as revealed by the improvement of hepatocellular vacuolation, portal fibroplasia, and necrosis. Moreover, this phenolic compound was able to restore the balance of the redox system in cyclosporine-treated rats by activating the nuclear factor (NF) erythroid 2-related factor 2 (Nrf2)/hemeoxygenase-1 (HO-1) signaling axis. Of note, the protective effects of ferulic acid against cyclosporine-mediated liver toxicity were not restricted only to induction of the potential antioxidant property, as in the presence of this agent, the expression of pro-inflammatory cytokines such as NF-κB, tumor necrosis factor (TNF)-α, and interleukin-1β was also diminished. Ferulic acid also shifted the equilibrium between the expression levels of proapoptotic to antiapoptotic proteins and thereby prevented the development of cyclosporine-induced liver injury. Overall, these findings highlighted that ferulic acid can reduce cyclosporine-induced liver injury due to its antioxidant properties.