Effects of ZNC-2381, a new oral compound, on several hepatic injury modelsand on hepatocellular apoptosis in mice and rats

The hepatoprotective effect of ZNC-2381 (1-(4-aminophenyl) methyl-3-(3-nitr ophenyl)-1,3-dihydroimidazo[4,5-b]pyridine-2-one), a novel 2-one dihydroimi dazopyridine derivative, has been evaluated in several experimental models of hepatic injury. In mice, oral ZNC-2381, administered at doses of 3, 10 or 30 mg kg(-1), 1 h before induction of hepatic injury with concanavalin A, dose-dependently i nhibited increases in serum alanine aminotransferase (ALT) activity. Apopto sis of liver cells, as indicated by DNA fragmentation (nucleosome assay) an d DNA-ladder formation (electrophoresis), was also inhibited dose-dependent ly. ZNC-2381 dose-dependently inhibited concanavalin A-induced increases in serum tumour necrosis factor (TNF)-alpha levels, and TNF-alpha mRNA expres sion in the liver. Oral ZNC-2381 also dose-dependently inhibited increases in serum ALT activity in mice with hepatic injury induced by Propionibacter ium acnes and a bacterial lipopolysaccharide (LPS) or D-galactosamine-LPS, and in rats with D-galactosamine-induced hepatic injury. These results indicate that oral ZNC-2381 inhibits cytokine (TNF-alpha) pro duction and cytokine-related hepatocellular apoptosis, and might thus preve nt different types of hepatic injury.