Melatonin downregulates nuclear erythroid 2‐related factor 2 and nuclear factor‐kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model

Abstract

Melatonin has potent hepatoprotective effects as an antioxidant. However, the signaling pathway of melatonin in the induction of antioxidant enzymes against acute liver injury is not fully understood. The study aimed to determine whether melatonin could prevent dimethylnitrosamine (DMN)-induced liver injury through nuclear erythroid 2-related factor 2 (Nrf2) and inflammation. Liver injury was induced in rats by a single injection of DMN (30 mg/kg, i.p.). Melatonin treatment (50 mg/kg/daily, i.p.) was initiated 24 hr after DMN injection for 14 days, after which the rats were killed and samples were collected. Serum and antioxidant enzyme activities improved in melatonin-treated rats, compared with DMN-induced liver injury group (P < 0.01). Melatonin reduced the infiltration of inflammatory cells and necrosis in the liver, and increased the expression of NADPH: quinone oxidoreductase-1, heme oxygenase-1, and superoxide dismutase-2, which were decreased by DMN. Melatonin increased expression of novel transcription factor, Nrf2, and decreased expression of inflammatory mediators including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and inducible nitric oxide synthase. The increased nuclear binding of nuclear factor-kappa B (NF-kappaB) in the DMN-induced liver injury group was inhibited by melatonin. Our results show that melatonin increases antioxidant enzymes and Nrf2 expression in parallel with the decrease of inflammatory mediators in DMN-induced liver injury, suggesting that melatonin may play a role of antioxidant defense via the Nrf2 pathway, by reducing inflammation by NF-kappaB inhibition.

Melatonin and ubiquitin: what’s the connection?

“…Melatonin reduces nf-κB binding in spleen [89]. a number of laboratories report melatonin-induced inhibition of nK-κB activity or inhibition of nf-κB activation [90][91][92][93][94][95][96][97][98][99][100]. these results suggest an interaction of melatonin and the ubiquitin-proteasome system in the activation of nf-κB.…”

Melatonin protects against burn-induced hepatic oxidative injury by inducing HO-1 via the Nrf2 pathway

“…Further, melatonin ameliorates oxidative stress through Nrf2 induction in experimental models of hepatic injury (Osburn et al 2006;Aleksunes and Manautou 2007;Crespo et al 2010;Yang et al 2011). Activation of Nrf2 by melatonin has been described to result in an increased expression of the antioxidant enzyme haem oxygenase-1 (HO-1) and a restriction of hepatic injury (Jung et al 2009;Crespo et al 2010). Although experimental and clinical studies have shown that melatonin restrains oxidative liver injury (Ohta et al 2000;Oz et al 2006), we failed to find any reports on a possible protective effect of melatonin on burn-induced hepatic damage by activation of the Nrf2/HO-1 system.…”

“…Melatonin induces the expression of antioxidant enzymes such as superoxide dismutase SOD, catalase and gluthatione peroxidase under conditions of elevated oxidative stress (Rodriguez et al 2004), through activation of Nrf2 (Jung et al 2009). Further, melatonin ameliorates oxidative stress through Nrf2 induction in experimental models of hepatic injury (Osburn et al 2006;Aleksunes and Manautou 2007;Crespo et al 2010;Yang et al 2011).…”

Hepatic Nrf2 expression is altered by quercetin supplementation in X-irradiated rats

“…Liu et al (28) did not observe increased Nrf2 levels in mouse brain after 12 h of a single 4 Gy radiation dose, but did observe an increase with increasing concentrations of melatonin (1-10 mg/kg). Similarly, following dimethylnitrosamine-induced ROS increase, melatonin (50 mg/kg) administration over 14 days was able to double the nuclear levels of Nrf2 (29).…”