Melatonin Ameliorates Cerulein-induced Pancreatitis by the Modulation of Nuclear Erythroid 2-related Factor 2 and Nuclear Factor-kappaB in Rats

초록

Melatonin exhibits a wide variety of biological effects, including antioxidant and anti-inflammatory functions. Its antioxidant role impedes the etiopathogenesis of pancreatitis, but little is known about the signaling pathway of melatonin in the induction of antioxidant enzymes in acute pancreatitis. The aim of this study was to determine whether melatonin could prevent cerulein-induced acute pancreatitis through Nrf2 and curtail inflammation by inhibition of NF-κB. Acute pancreatitis was induced by two intraperitoneal (i.p.) injections of cerulein at 2 h intervals (50μg/kg). Melatonin (10 or 50 mg/kg/daily,i.p.) was administered 24 h before each injection of cerulean. The rats were sacrificed 12 h after the last injection. Acinar cell degeneration, pancreatic edema, and inflammatory infiltration were significantly different in cerulean- and melatonin-treated rats. Melatonin significantly reduced amylase, lipase, MPO, and MDA levels, and increased anti-oxidant enzyme activities including SOD and GPx, which were decreasedin acute pancreatitis (p＜0.05). Melatonin increased the expression of NQO1, HO-1, and SOD2, compared to the cerulein-induced acute pancreatitis group (p<0.05). In addition, melatonin increased Nrf2 expression, and decreased expressions of tumor necrosis factor-alpha, IL-1β, IL-6, IL-8, and iNOS. The increased nuclear binding of NF-κB in the cerulein-induced pancreatitis group was inhibited by melatonin. These results show that melatonin increases antioxidant enzymes and Nrf2 expression, and decreases inflammatory mediators in cerulein-induced acute pancreatitis. It is proposed that melatonin may play an important role in oxidative stress via the Nrf2 pathway in parallel with reduction of inflammation by NF-κB inhibition.