21 November 2002
The novel PARP inhibitor 5-aminoisoquinolinone reduces the liver injury caused by ischemia and reperfusion in the rat.Helder Mota-Filipe, Bruno Sepodes, Michelle McDonald, Salvatore Cuzzocrea, Rui Pinto, Christoph Thiemermann
Med Sci Monit 2002; 8(11): BR444-453 :: ID: 4846
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. MATERIAL/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.
Keywords: Cells, Cultured, Immunohistochemistry, Intercellular Adhesion Molecule-1 - blood, Isoquinolines - pharmacology, L-Lactate Dehydrogenase - blood, Lipid Peroxidation, Lipid Peroxidation, Liver - drug effects, Liver - injuries, Liver - metabolism, Poly(ADP-ribose) Polymerases - antagonists & inhibitors, Rats, Rats, Wistar, Reperfusion Injury, Time Factors, Transaminases - blood, gamma-Glutamyltransferase - blood
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