Antiapoptotic effect of DDB against hepatic ischemia-reperfusion injury

Abstract

Background and aim: Dimethyl-Diphenyl-Bicarboxylate (DDB) is a hepatoprotectant used in treatment of chronic viral hepatitis. The mechanism of DDB against liver injury needs further elucidation. Our objective is to explore whether DDB exerts hepatoprotective effect against hepatic ischemia reperfusion injury (I/R) and to identify its potential effect on apoptotic cell death targeting the extrinsic apoptotic pathway.

Methods: Rats were divided into four groups: Group I (sham-operated), Group II (I/R group), Group III (DDB Pretreated group): where rats were treated with DDB at 3 dose levels (100 mg/kg, 300 mg/kg, 500 mg/kg) for 10 days, then subjected to I/R and Group IV (DDB treated group): rats were treated with DDB at the same dose levels but without being subjected to I/R. Serum alanine aminotransferase (ALT) & aspartate aminotransferase (AST), tissue levels of GSH, MDA & tumor necrosis factor alpha (TNF-α), activity of signaling Caspases 3, 8, 9 as well as expression of nuclear factor-κB (NF-κB) were measured. End point of apoptosis was detected by DNA fragmentation.

Results: DDB administration before I/R, significantly attenuated elevated levels of ALT, AST, MDA and TNF-α and increased GSH content. There were significant decrease in caspases activities, expression of NF-κB as well as DNA fragmentation. DDB administration to normal rats, inhibited lipid peroxidation, enhanced antioxidant activity, decreased TNF-α and downregulated expression of NF-κB. These effects are dose-dependent.

Conclusion: DDB exerts potent antioxidant effect in normal and injured livers. It inhibited hepatic I/R induced apoptosis through inhibiting signaling Caspases 3, 8, 9, TNF-α production which regulates the extrinsic apoptotic pathway and down regulates NF-κB expression in liver tissue.