Di Paola Rosanna, Genovese Tiziana, Caputi Achille P, Threadgill Mike, Thiemermann Christoph, Cuzzocrea Salvatore
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, via C. Valeria, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy.
Eur J Pharmacol. 2004 May 25;492(2-3):203-10. doi: 10.1016/j.ejphar.2004.03.033.
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.
聚（ADP - 核糖）聚合酶（PARP）是一种由DNA链断裂激活的核酶，在与缺血再灌注和炎症相关的组织损伤中起重要作用。内脏动脉闭塞和再灌注会导致活性氧的生成增加，这有助于休克的病理生理过程。本研究的目的是探讨5 - 氨基异喹啉酮（5 - AIQ），一种有效的聚（ADP - 核糖）聚合酶（PARP）水溶性抑制剂，在内脏动脉闭塞性休克发病机制中的作用。通过夹闭肠系膜上动脉和腹腔动脉45分钟诱导大鼠发生内脏动脉闭塞性休克，随后松开夹子（再灌注）。再灌注60分钟后，处死所有动物进行组织学检查和生化研究。用5 - AIQ（3mg/kg静脉注射）治疗大鼠，可减轻内脏动脉闭塞性休克引起的平均动脉血压下降。5 - AIQ还减轻了回肠损伤以及内脏动脉闭塞性休克引起的回肠组织中髓过氧化物酶和丙二醛水平的升高。免疫组织化学检查还显示，在内脏动脉闭塞性休克大鼠坏死回肠中，聚（ADP - 核糖）（PAR）、硝基酪氨酸和细胞间黏附分子（ICAM - 1）的免疫反应性显著增加。5 - AIQ治疗显著降低了PAR、硝基酪氨酸和ICAM - 1阳性染色的增加。总之，这些结果表明，5 - AIQ，一种新型的聚（ADP - 核糖）聚合酶水溶性有效抑制剂，在内脏动脉闭塞/再灌注休克中发挥多种保护作用。
