Nifuroxazide attenuates experimentally-induced hepatic encephalopathy and the associated hyperammonemia and cJNK/caspase-8/TRAIL activation in rats.

Hyperammonemia is a serious metabolic disorder associating with hepatic encephalopathy (HE) which occurs secondary to several forms of liver injury ranging from simple acute liver failure (ALF) to its most serious form; cirrhosis. The resent study highlights the possible ameliorative effect of oral nifuroxazide (25 mg/kg) against experimentally induced ALF and the subsequent HE in a well-standardized rat model. ALF and HE were induced in a rat model by I.P. injection of thioacetamide (TAA) (200 mg/kg) for 1 week at alternative days. Nifuroxazide administration for 14 days prior to and for further 7 days alongside TAA injection successfully attenuated TAA-induced ALF and HE; as demonstrated by the significant retraction in both brain and serum hyperammonemia with significant improvement in liver function biomarkers; ALT, AST, ALP, GGT, albumin, and serum total protein. This was associated with a significant restoration of both hepatic and brain oxidative stress incidences; MDA, SOD and catalase activities and GSH concentration. The observed improvement was associated with a significant reduction in liver and brain contents of c-Jun N-terminal kinase (cJNK); as an anti-inflammatory biomarker and a modulator of various pro- and anti-apoptotic proteins, caspase-8, and tumor necrosis factor-related apoptosis ligand (TRAIL); as biomarkers of apoptosis. In conclusion; the modulatory effect of nifuroxazide on cJNK/caspase-8/TRAIL signaling appears to underly its hepatoprotective effect and its ameliorative effect on HE progression.