Effect of adenosine A2A receptor agonist (CGS) on ischemia/reperfusion injury in isolated rat liver.

Abstract

Ischemia/reperfusion injury during liver transplantation is a major cause of primary nonfunctioning graft for which there is no effective treatment other than retransplantation. Adenosine prevents ischemia-reperfusion-induced hepatic injury via its A2A receptors. The aim of this study was to investigate the role of A2A receptor agonist on apoptotic ischemia/reperfusion-induced hepatic injury in rats. Isolated rat livers within University of Wisconsin solution were randomly divided into four groups: (1) continuous perfusion of Krebs-Henseleit solution through the portal vein for 165 minutes (control); (2) 30-minute perfusion followed by 120 minutes of ischemia and 15 minutes of reperfusion; (3) like group 2, but with the administration of CGS 21680, an A2A receptor agonist, 30 microg/100 ml, for 1 minute before ischemia; (4) like group 3, but with administration of SCH 58261, an A2A receptor antagonist. Serum liver enzyme levels were measured by biochemical analysis, and intrahepatic caspase-3 activity was measured by fluorometric assay; apoptotic cells were identified by morphological criteria, the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) fluorometric assay, and immunohistochemistry for caspase-3. Results showed that at 1 minute of reperfusion, there was a statistically significant reduction in liver enzyme levels in the animals pretreated with CGS (p < 0.05). On fluorometric assay, caspase-3 activity was significantly decreased in group 3 compared to group 2 (p < 0.0002). The reduction in postischemic apoptotic hepatic injury in the CGS-treated group was confirmed morphologically, by the significantly fewer apoptotic hepatocyte cells detected (p < 0.05); immunohistochemically, by the significantly weaker activation of caspase-3 compared to the ischemic group (p < 0.05); and by the TUNEL assay (p < 0.05). In conclusion, the administration of A2A receptor agonist before induction of ischemia can attenuate postischemic apoptotic hepatic injury and thereby minimize liver injury. Apoptotic hepatic injury seems to be mediated through caspase-3 activity.

• Authors: Z Ben-Ari, O Pappo, J Sulkes, Y Cheporko, B A Vidne, E Hochhauser
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 10 Issue 5 Pg. 955-62 (Oct 2005) ISSN: 1360-8185 [Print] Netherlands
• PMID: 16151631 (Publication Type: Journal Article)

Chemical References

• Adenosine A2 Receptor Agonists
• Phenethylamines
• 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
• Casp3 protein, rat
• Caspase 3
• Caspases
• Adenosine

Topics

• Adenosine (analogs & derivatives, therapeutic use)
• Adenosine A2 Receptor Agonists
• Animals
• Apoptosis (drug effects)
• Caspase 3
• Caspases (metabolism)
• In Situ Nick-End Labeling
• In Vitro Techniques
• Liver (blood supply, enzymology)
• Male
• Phenethylamines (therapeutic use)
• Rats
• Rats, Wistar
• Reperfusion Injury (drug therapy, enzymology, prevention & control)