Selective A_2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice

Abstract

Background

d-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor-α (TNF-α) plays a pivotal role. We examined the effects of a highly selective adenosine A_2A receptor agonist (ATL-146e) on GalN/LPS-induced fulminant hepatic failure.

Methods

Mice were given an intraperitoneal dose of GalN (800 mg/g body weight)/LPS (100 ng/g body weight) with and without ATL-146e (0.01 µg/kg) treatment. Liver injury was assessed biochemically and histologically. Also, TNF-α levels in the serum were determined.

Results

The serum liver enzyme (ALT) level in vehicle-treated mice was 20 960 ± 2800 IU/ml and was reduced by 63% to 7800 ± 1670 IU/ml by treatment with 0.01 µg/kg per minute ATL146e, P < 0.05. Treatment with ATL-146e significantly reduced serum TNF-α and greatly reduced inflammation assessed by histopathologic examination compared with control mice treated with GalN/LPS. ATL-146e also reduced lethality at 12 h from 65% to 13%.

Conclusion

The present findings suggest that the highly selective adenosine A_2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF-α secretion.