Hepatoprotective effect of melatonin via activation of Nrf2 and anti-apoptotic proteins in burn rats

Abstract Objective: Burn- induced acute hepatic injury due to increased production of lipid peroxides and increased cellular apoptosis. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is essential for cytoprotection against oxidative stress. We hypothesized that melatonin by activation of Nrf2 may shift Bax/Bcl-2 ratio to protect rat hepatocytes against apoptosis and progressive liver injury. The aim of this experimental study was to investigate the protective effects of melatonin against burn-induced apoptotic injury and the relationship between lipid peroxides expression of transcription factor Nrf2 and apoptotic protein in burn rat model. Methods: Melatonin was applied immediately after the burn. The expression of hepatic 4-hydroxynonenal (4-HNE), as a marker of liver peroxidative injury, Nrf2, as a marker of antioxidant defense and apoptosis-related genes Bcl-2 and Bax were evaluated using light immunоhistochemistry. Results: Burns caused an increased expression of 4-HNE, Bax and Bax/Bcl-2 ratio and induced apoptosis of sinusoidal endothelial cells (SECs) in liver tissue. Melatonin treatment augmented the increase in Nrf2 expression, decreased both burn-induced peroxidative damage and hepatic apoptosis as evidenced by reduced expression of Bax, enhanced expression of Bcl-2. In conclusion, our data suggest that activation of transcription factor Nrf2 by melatonin is protective against oxidative stress, apoptosis and hepatic injury in burns. The available information by melatonin`s effect on the redox sensing transcription factor Nrf2, as a regulator of antioxidant enzymes, antioxidants and antioxidant protection of the liver is limited. Melatonin activates the Nrf2/signaling pathway and acts as a natural inducer of anti-apoptotic and antioxidant protection under condition of burn-induced oxidative stress. This is a new cellular mechanism for protection against progressive burn-induced liver damage not only in animals but also in humans.