A novel prostaglandin E receptor subtype agonist, 0N0-4819, attenuates acute experimental liver injury in rats

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 (GaIN, 1 g/kg bodyweight) 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. (C) 2001 Published by Elsevier Science Ireland Ltd.