Melatonin attenuates streptozotocin induced inflammation and oxidative stress in the rat liver by modulation of NF-kB and Nrf2 signaling

Abstract

Melatonin, a hormone secreted primarly by pineal gland,exhibitsantioxidative and anti-inflammatory properties. We have previously reported antinecrotic effect of melatonin in the liver of streptozotocin (STZ) treated rats. However, molecular mechanisms underlyingmelatonin hepatoprotective rolein oxidative enviroment are still partially known. In this study we investigated effects of melatonin on the role of nuclear factor-kappa B (NF-κB) p65 and nuclear erythroid 2-related factor 2 (Nrf2) in the liver of STZ treated rats.Melatonin at doses of 2 mg/kg/i.p was administrated daily, 3 days before STZ treatment (65mg/kg, i.p), and continued until the end of study at 4 weeks after STZ injection. STZ treatment causeshypoinsulinemia followed by hyperglycemia which increases the production of reactive oxidative species (ROS) leading tooxidative stress. ROS activatedNF-κB p65 in hepatocytes and increased its nuclear expresssion where it enhances expression of genes of proinflammatory cytokines leading to elevated presence of TNFα and IL-6. High TNFα has a cytotoxic activity and may potentiate liver damage.Melatonin reduced the elevated expression of NF-κB p65, TNFα and IL-6.STZ treatmentincreased expression of Nrf2 but reduced its activation which is followed by decrease in superoxide dismutase (SOD), glutathione-S-transferase (GST) and catalase (CAT) expression and activity. Melatonin significantly increases nuclear expression of Nrf2 which enhances the up-regulation of SOD, GST and CAT expression and activity.The results of this study suggest that melatonin improves oxidative–induced liver damage by attenuation of proinflammatory stimuli through decreasing of NF-κB activation cascade and strengthens antioxidative defence through activation of Nrf2 cascade.