Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice.
BACKGROUND
D-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role. We examined the effects of a highly selective adenosine A2A 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 microg/kg) treatment. Liver injury was assessed biochemically and histologically. Also, TNF-alpha 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 microg/kg per minute ATL146e, P < 0.05. Treatment with ATL-146e significantly reduced serum TNF-alpha 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%.


CONCLUSIONS
The present findings suggest that the highly selective adenosine A2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF-alpha secretion.
Odashima
Masaru
M
Department of Gastroenterology, Akita University School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
Otaka
Michiro
M
Jin
Mario
M
Komatsu
Koga
K
Wada
Isao
I
Matsuhashi
Tamotsu
T
Horikawa
Youhei
Y
Hatakeyama
Natsumi
N
Oyake
Jinko
J
Ohba
Reina
R
Linden
Joel
J
Watanabe
Sumio
S
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001707:Biopsy, Needle; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011687:Purines / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects*
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D014409:Tumor Necrosis Factor-alpha