We evaluated the efficacy of
ONO-4819, a newly developed agonist of a
prostaglandin receptor subtype (EP4), on experimental model of acute liver injury in rats. Acute liver injury was induced by simultaneous intraperitoneal (i.p.) administration of D-
galactosamine (GalN, 1 g/kg
body weight) and
lipopolysaccharide (LPS, 100 mg/kg
body weight). The rats received a single
intraperitoneal injection of
ONO-4819 (0.2 mg/kg
body weight) or physiological saline immediately after GalN/LPS administration.
Submassive hepatic necrosis with marked elevation of serum total
bilirubin, serum
aspartate aminotransferase and serum
alanine aminotransferase levels developed 24 h after GalN/LPS administration. The administration of
ONO-4819 significantly inhibited the development of
submassive hepatic necrosis and inhibited the elevation in levels of
biochemical markers that indicate liver function. In addition, the apoptotic index of hepatocytes assessed by the TUNEL method was significantly lower in rats treated with
ONO-4819 than in the control. Although serum levels of
tumor necrosis factor-alpha (
TNF-alpha),
interferon-gamma (IFN-gamma) and
interleukin-8 (IL-8) were markedly elevated after GalN/LPS administration,
ONO-4819 significantly inhibited the elevation of those of
TNF-alpha and IFN-gamma but not that of
IL-8. The beneficial effect of
ONO-4819 for acute liver injury was similar at doses of 0.1, 0.05 and 0.01 mg/kg
body weight. These results suggest that the EP4 agonist,
ONO-4819, may have a protective effect against experimental liver injury in rats through the suppression of inflammatory
cytokines.