Melatonin restores zinc levels, activates the Keap1/Nrf2 pathway, and modulates endoplasmic reticular stress and HSP in rats with chronic hepatotoxicity

BACKGROUND: Melatonin (MLT) is a potent antioxidant molecule that is shown to have a beneficial effect in various pathological situations, due to its action against free radicals. AIM: To evaluate the effect of MLT on carbon tetrachloride (CCl(4)) induced liver injury in rats in terms of oxidative stress, reticular stress, and cell damage. METHODS: Twenty male Wistar rats (230-250 g) were divided into four groups: Control rats, rats treated with MLT alone, rats treated with CCl(4) alone, and rats treated with CCl(4) plus MLT. CCl(4) was administered as follows: Ten doses every 5 d, ten every 4 d, and seven every 3 d. MLT was administered intraperitoneally at a dose of 20 mg/kg from the 10(th) wk to the end of the experiment (16(th) wk). RESULTS: MLT was able to reduce the release of liver enzymes in the bloodstream and to decrease oxidative stress in CCl(4) treated rats by decreasing the level of thiobarbituric acid reactive substances and increasing superoxide dismutase activity, with a lower reduction in serum zinc levels, guaranteeing a reduction in liver damage; additionally, it increased the expression of nuclear factor (erythroid-derived 2)-like 2 and decreased the expression of Kelch-like ECH-associated protein 1. MLT also decreased the expression of the proteins associated with endoplasmic reticulum stress, i.e., glucose-regulated protein 78 and activating transcription factor 6, as well as of heat shock factor 1 and heat shock protein 70. CONCLUSION: MLT has a hepatoprotective effect in an experimental model of CCl(4)-induced liver injury, since it reduces oxidative stress, restores zinc levels, and modulates endoplasmic reticulum stress.