5-Aminoisoquinolinone, a novel inhibitor of poly(adenosine disphosphate-ribose) polymerase, reduces microvascular liver injury but not mortality rate after hepatic ischemia-reperfusion.
OBJECTIVE
The aim of this study was to investigate the impact of the novel, potent, water-soluble inhibitor of poly(adenosine diphosphate-ribose) polymerase (PARP) 5-aminoisoquinolinone (5-AIQ) on hepatic microcirculation, hepatocellular injury, and survival in a murine model of hepatic ischemia-reperfusion.


METHODS
Randomized animal study.


METHODS
Research laboratory.


METHODS
C57BL6 mice were subjected to warm either partial (90 mins) or total (75 mins) ischemia of the liver.


METHODS
Either PARP inhibitor 5-AIQ (3 mg/kg) or vehicle was administered to mice intravenously immediately before the start of reperfusion. Sham-operated animals served as controls.


RESULTS
As shown by intravital fluorescence microscopy after 30-60 mins of reperfusion, ischemia-reperfusion significantly enhanced platelet- and leukocyte-endothelial cell interactions in hepatic microvessels and impaired sinusoidal perfusion. Hepatocellular injury was characterized by an increase in the number of necrotic and apoptotic cells, dramatic elevation of aspartate aminotransferase/alanine aminotransferase serum activity, and lipid peroxidation in liver tissue. 5-AIQ treatment attenuated ischemia-reperfusion-induced increases in the numbers of adherent platelets and leukocytes as well as of necrotic and apoptotic cells and ameliorated perfusion failure. Furthermore, PARP inhibition prevented the increase in aspartate aminotransferase activity after ischemia-reperfusion but did not affect postischemic alanine aminotransferase release. However, no protective impact of 5-AIQ on postischemic oxidative stress was observed. Although PARP inhibition did not alter the survival percentage after ischemia-reperfusion (22% in both groups), this approach prolonged survival from 1 to 24 hrs (ischemia-reperfusion + vehicle) up to 48-72 hrs in the treated group.


CONCLUSIONS
PARP inhibition with 5-AIQ during hepatic ischemia-reperfusion attenuates microvascular injury and reduces the extent of necrotic/apoptotic cell damage but does not protect from oxidative injury and does not improve postoperative survival rate.
Khandoga
Andrej
A
Institute for Surgical Research, University of Munich, Germany.
Biberthaler
Peter
P
Enders
Georg
G
Krombach
Fritz
F
D000818:Animals; D017209:Apoptosis; D005260:Female; D007546:Isoquinolines / Q000627:therapeutic use*; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011897:Random Allocation; D015427:Reperfusion Injury / Q000401:mortality* / Q000517:prevention & control*
C411425:5-aminoisoquinolinone; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors