The NF-κB inhibitors attenuate hepatic injury in bile duct ligated rats

Abstract

Cholestasis-induced liver injury during bile duct obstruction causes an inflammatory response and this inflammatory process may be an important source of tissue injury. We hypothesized that NF-kappaB inhibition would decrease liver injury in a rat model of extrahepatic biliary obstruction. A total of 40 female rats of Sprague-Dawley strain were allocated to four groups. First group was sham operated control. The second group underwent common bile duct ligation (BDL) and was monitored for 10 days. Third group of rats underwent BDL and received pyrrolidine dithiocarbomate (PDTC) at a dose of 100 mg/kg/day intraperitoneally. Fourth group underwent BDL and received sulfasalazine at a dose of 100 mg/kg b.w. Both inhibitors were administered once a day throughout last 7 days of the experimental period. Rats were terminated 10 days after sham operation or BDL. Aspartate aminotransferase, alanine aminotransferase, gamma-glutamil transpeptidase, and tumor necrosis factor-alpha levels were elevated in the BDL group as compared to the control group, while this increase was significantly decreased by treatment with PDTC and sulfasalazine (P < 0.05). Hepatic GSH, SOD and catalase levels were significantly depressed by BDL, but were elevated back to control levels in NF-kappaB inhibitor-treated BDL groups. Increases in tissue free radical and MDA levels and MPO activity due to BDL were reduced back to control levels by NF-kappaB inhibitor treatment (P < 0.05). Similarly histological damage in the BDL rats was reduced by treatments. These results indicate that inhibitors of NF-kappaB activity such as PDTB and sulfasalazine exert a therapeutic effect on cholestatic liver injury in rats with BDL through anti-inflammatory and antioxidant actions.

The efficiency of CAPE on retardation of hepatic fibrosis in biliary obstructed rats

“…Pyrrolidine dithiocarbomate given intraperitoneally to the rats with BDL reduced the increases in hepatic MDA concentrations, and restored the decreases levels of hepatic antioxidant enzyme levels. These findings suggest that intraperitoneally administered pyrrolidine dithiocarbomate could exert a preventive effect on an enhancement of oxidative stress and hepatic lipid peroxidation during the progression of cholestatic liver injury in rats with BDL (Demirbilek et al 2006). In the present study, the application of BDL clearly increased the tissue MDA levels and decreased the antioxidant enzyme (SOD, GPx) activities.…”

Effects of sphingosylphosphorylcholine against cholestatic oxidative stress and liver damage in the common bile duct ligated rats

“…However, SPC significantly prevented the increase of MDA concentration in the liver tissue of BDL rats. Furthermore, recent studies suggest that disturbance of the oxidant-antioxidant balance might be responsible for cholestatic liver injury and SOD enzyme is hepatoprotective and plays important roles in preventing the oxidative stress [33]. Decreased SOD activity was observed in BDL rats as compared to control rats, and the SPC treatment reversed these findings.…”

Regulation of glutathione synthesis

“…Chronic retention of toxic bile acids can cause oxidative stress, apoptosis and fibrosis leading to cirrhosis. Although there is conflicting data, many groups showed a fall in GSH level in either livers of animals subjected to experimental cholestasis or hepatocytes treated with toxic bile acids (Neuschwander-Tetri et al, 1996;Montilla et al, 2000;Gumpricht, et al, 2000;Serviddio et al, 2004;Ebrahimkhani, et al, 2005;Demirbilek et al, 2006;ReyesGordillo, et al, 2007). This can further jeopardize antioxidant defense and contribute to injury.…”