The novel PARP inhibitor 5-aminoisoquinolinone reduces the liver injury caused by ischemia and reperfusion in the rat.
BACKGROUND
This study was designed to investigate the effects of 5-aminoisoquinolinone (5-AIQ), a water-soluble potent inhibitor of poly-(ADP-ribose) polymerase (PARP) in a rat model of liver ischemia-reperfusion injury.


METHODS
Male Wistar rats were anesthetised with sodium pentobarbital (60 mg/kg, i.p.) and subjected to liver ischemia (for 30 minutes) and reperfusion (for 2 hours). Liver injury was assessed by measuring (i). the serum levels of transaminases, lactate dehydrogenase, gamma-glutamyl transferase, (ii). lipid peroxidation in liver tissue and (iii). by immunohistochemistry for PARP and intracellular adhesion molecule 1 (ICAM-1).


RESULTS
Pre-treatment of rats (five minutes prior to onset of liver ischemia) with the PARP inhibitor 5-AIQ (3 mg/kg, i.v.) rather than vehicle reduced the rise in the serum levels of transaminases, lactate dehydrogenase, and gamma-glutamyl transferase as well as the degree of lipid peroxidation (measured as levels of malondialdehyde in the liver) caused by ischemia-reperfusion of the liver. Liver sections obtained from 5-AIQ treated rats showed reduced PARP activation and less staining for ICAM-1.


CONCLUSIONS
Taken together, these results show that 5-AIQ, a new water-soluble potent inhibitor of poly-(ADP-ribose) polymerase, reduces the tissue injury associated with ischemia-reperfusion of the liver. We propose that 5-AIQ may be useful in the therapy conditions associated with ischemia-reperfusion of the liver which remains an important clinical problem during shock, liver surgery, and liver transplantation.
Mota-Filipe
Helder
H
Unit of Pharmacology and Pharmacotoxicology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal. hfilipe@ff.ul.pt
Sepodes
Bruno
B
McDonald
Michelle C
MC
Cuzzocrea
Salvatore
S
Pinto
Rui
R
Thiemermann
Christoph
C
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D007546:Isoquinolines / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D013997:Time Factors; D000637:Transaminases / Q000097:blood; D005723:gamma-Glutamyltransferase / Q000097:blood
C411425:5-aminoisoquinolinone; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018799:Intercellular Adhesion Molecule-1; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D000637:Transaminases