Beneficial effects of 5-aminoisoquinolinone, a novel, potent, water-soluble, inhibitor of poly (ADP-ribose) polymerase, in a rat model of splanchnic artery occlusion and reperfusion.
Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with ischemia-reperfusion and inflammation. Splanchnic artery occlusion and reperfusion causes an enhanced formation of reactive oxygen species which contribute to the pathophysiology of shock. The aim of the present study was to investigate the effects of 5-aminoisoquinolinone (5-AIQ), a potent water-soluble inhibitor of poly(ADP-ribose) polymerase (PARP), in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion shock was induced in rats by clamping both the superior mesenteric artery and the celiac artery for 45 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, all animals were sacrificed for histological examination and biochemical studies. Treatment of rats with 5-AIQ (3 mg/kg i.v.), attenuated the fall of mean arterial blood pressure caused by splanchnic artery occlusion shock. 5-AIQ also attenuated the ileum injury as well as the increase in the tissue levels of myeloperoxidase and malondialdehyde caused by splanchnic artery occlusion shock in the ileum. The immunohistochemical examination also demonstrated a marked increase in the immunoreactivity to PAR, nitrotyrosine, and intercellular adhesion molecule (ICAM-1) in the necrotic ileum from splanchnic artery occlusion-shocked rats. 5-AIQ treatment significantly reduced the increase of positive staining for PAR, nitrotyrosine and ICAM-I. In conclusion, these results show that 5-AIQ, a new water-soluble potent inhibitor of poly(ADP-ribose) polymerase, exerts multiple protective effects in splanchnic artery occlusion/reperfusion shock.
Di Paola
Rosanna
R
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, via C. Valeria, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy.
Genovese
Tiziana
T
Caputi
Achille P
AP
Threadgill
Mike
M
Thiemermann
Christoph
C
Cuzzocrea
Salvatore
S
D000818:Animals; D002445:Celiac Artery; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D007421:Intestine, Small / Q000098:blood supply*; D007511:Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007546:Isoquinolines / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D017538:Mesenteric Artery, Superior; D008641:Mesenteric Vascular Occlusion / Q000150:complications*; D009195:Peroxidase / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012995:Solubility; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D014867:Water
C411425:5-aminoisoquinolinone; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014867:Water; D018799:Intercellular Adhesion Molecule-1; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D009195:Peroxidase