Effects of ZNC-2381, a new oral compound, on several hepatic injury models and on hepatocellular apoptosis in mice and rats.
The hepatoprotective effect of ZNC-2381 (1-(4-aminophenyl) methyl-3-(3-nitrophenyl)-1,3-dihydroimidazo[4,5-b]pyridine-2-one), a novel 2-one dihydroimidazopyridine derivative, has been evaluated in several experimental models of hepatic injury. In mice, oral ZNC-2381, administered at doses of 3, 10 or 30 mgkg(-1), 1 h before induction of hepatic injury with concanavalin A, dose-dependently inhibited increases in serum alanine aminotransferase (ALT) activity. Apoptosis of liver cells, as indicated by DNA fragmentation (nucleosome assay) and DNA-ladder formation (electrophoresis), was also inhibited dose-dependently. ZNC-2381 dose-dependently inhibited concanavalin A-induced increases in serum tumour necrosis factor (TNF)-alpha levels, and TNF-alpha mRNA expression in the liver. Oral ZNC-2381 also dose-dependently inhibited increases in serum ALT activity in mice with hepatic injury induced by Propionibacterium 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) production and cytokine-related hepatocellular apoptosis, and might thus prevent different types of hepatic injury.
Itokazu
Y
Y
Central Research Laboratories, Zeria Pharmaceutical Company Ltd, Saitama, Japan.
Segawa
Y
Y
Omata
T
T
Inoue
N
N
Tsuzuike
N
N
Nagasawa
M
M
Nishioka
H
H
Kobayashi
T
T
Nakano
Y
Y
Kanda
T
T
D000410:Alanine Transaminase / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003208:Concanavalin A; D053938:DNA Fragmentation / Q000187:drug effects / Q000502:physiology; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
C414810:1-(4-aminophenyl)methyl-3-(3-nitrophenyl)-1,3-dihydroimidazo(4,5-b)pyridine-2-one; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D000410:Alanine Transaminase