Effects of a novel hepatoprotective drug, ZNC-2381, on Fas-induced hepatocellular caspase-3 activity and apoptosis in mice

We examined the effects of ZNC-2381 (1-(4-aminophenyl)methyl -3-(3-nitrophe nyl)- 1,3-dihydroimidazo[4,5-b] pyridine-2-one), a new oral hepatoprotectiv e agent, on hepatocellular caspase-3 activity and apoptosis induced by anti -mouse Fas antibody (anti-Fas ab) in mice. Oral ZNC-2381, administered at d oses of 10, 30 and 100 mg/kg h before inducing hepatic injury with anti-fas ab, dose-dependently inhibited the increase in serum alanine aminotransfer ase (s-ALT) activity 8 h after injection of anti-fas ab. Increases in DNA f ragmentation (nucleosome assay) and caspase-3 activity in the liver 2 h aft er injection of anti-fas ab were also inhibited by ZNC-2381 in a dose-depen dent manner. As shown by histopathological examination, ZNC-2381 dose-depen dently inhibited the appearance of TUNEL-positive apoptotic cells in the li ver. Moreover, in studies in vitro, ZNC-2381 (1-100 mu mol/l) concentration -dependently inhibited increases in DNA fragmentation and caspase-3 activit y caused by anti-fas ab in isolated mouse hepatocytes. N-Acetyl-Asp-Glu-Val -Asp aldehyde (Ac-DEVD-cho), a caspase-3-specific inhibitor, inhibited hepa tocellular apoptosis caused by anti-fas ab both in vivo and in vitro, as we ll as the increase in s-ALT activity in vivo. These results demonstrate tha t orally administered ZNC-2381 inhibits hepatocellular apoptosis induced by anti-fas ab and presents the progression of hepatic injury. We propose tha t the mechanism of action of ZNC-2381 may involve blockade of the signal tr ansduction pathway (caspase-3) of apoptosis mediated by anti-fas ab. Copyri ght (C) 2001 S.Karger AG, Basel.