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

Abstract

Ganka Bekyarova, Minka Hristova, Maria Tzaneva, Andrey Kotzev

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 (OS). We hypothesized that the melatonin by activation of Nrf2 may shift the 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 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. Conclusion: Our data suggest that the activation of the transcription factor Nrf2 by melatonin is protective against OS, 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 the condition of burn-induced OS. This is a new cellular mechanism for protection against progressive burn-induced liver damage not only in animals but also in humans