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
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
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DOI：
10.1016/j.ejphar.2004.03.033
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发表时间：
2004-05-25
影响因子：
5
通讯作者：
Cuzzocrea, S
中科院分区：
文献类型：
--
作者：
Di Paola, R;Genovese, T;Cuzzocrea, S
聚腺苷二磷酸核糖聚合酶(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发挥着重要作用。内脏动脉闭塞和再灌注导致体内活性氧物质的增加，从而参与休克的病理生理过程。本研究旨在探讨水溶性聚腺苷二磷酸核糖聚合酶(PARP)抑制剂5-氨基异喹诺酮(5-AIQ)在内脏动脉闭塞性休克发病机制中的作用。夹闭大鼠肠系膜上动脉和腹膜动脉45min，然后松开夹闭(再灌流)，造成内脏动脉阻塞性休克。再灌流60min后处死动物，进行组织学和生化检查。静脉注射5-AIQ(3 mg/kg)可减轻内脏动脉阻塞性休克引起的平均动脉压下降。5-AIQ还可减轻内脏动脉闭塞休克后回肠组织髓过氧化物酶和丙二醛含量的升高，减轻回肠损伤。免疫组织化学检查还显示内脏动脉闭塞休克大鼠坏死性回肠中PAR、硝基酪氨酸和细胞间黏附分子(ICAM-1)的免疫反应明显增强。经5-AIQ处理后，PAR、硝基酪氨酸和ICAM-1阳性染色的增加明显减少。综上所述，5-AIQ是一种新型的水溶性聚腺苷二磷酸核糖聚合酶抑制剂，对内脏动脉闭塞/再灌流休克具有多重保护作用。(C)2004爱思唯尔B.V.保留所有权利。
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 reperfasion 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-1. 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. (C) 2004 Elsevier B.V. All rights reserved.