5-Aminoisoquinolinone reduces colon injury by experimental colitis

被引:0
作者
Salvatore Cuzzocrea
Emanuela Mazzon
Rosanna Di Paola
Tiziana Genovese
Nimesh S. A. Patel
Carmelo Muià
Michael D. Threadgill
Angelina De Sarro
Christoph Thiemermann
机构
[1] University of Messina,Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine
[2] Queen Mary,Centre for Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute
[3] University of London,Department of Pharmacy and Pharmacology
[4] University of Bath,undefined
来源
Naunyn-Schmiedeberg's Archives of Pharmacology | 2004年 / 370卷
关键词
Colitis; 5-AIQ; PARP; Inflammatory infiltration; ICAM-1;
D O I
暂无
中图分类号
学科分类号
摘要
Poly (ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the colon injury associated with experimental colitis. The aim of the present study was to examine the effects of 5-aminoisoquinolinone (5-AIQ), a novel and potent inhibitor of PARP activity, in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Compared with DNBS-treated mice, mice treated with 5-AIQ (3 mg/kg i.p.) or 3-aminobenzamide (3-AB; 10 mg/kg i.p. twice a day) and subjected to DNBS-induced colitis experienced a significantly lower rate in the extent and severity of the histological signs of colon injury. DNBS-treated mice experienced diarrhea and weight loss. Four days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase [MPO] activity in the mucosa) was associated with an up-regulation of intercellular adhesion molecule-1 (ICAM-1). Immunohistochemistry for PAR showed an intense staining in the inflamed colon. On the contrary, the treatment of DNBS-treated mice with 5-AIQ or with 3-AB significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of DNBS. 5-AIQ also caused a substantial reduction in the degree of colon injury, in the rise in MPO activity (mucosa), in the increase in staining (immunohistochemistry) for PAR, as well as in the up-regulation of ICAM-1 caused by DNBS in the colon. Thus, 5-AIQ treatment reduces the degree of colitis caused by DNBS. We propose that 5-AIQ treatment may be useful in the treatment of inflammatory bowel disease.
引用
收藏
页码:464 / 473
页数:9
相关论文
共 173 条
[1]  
Aiko S(1995)Spontaneous intestinal inflammation and nitric oxide metabolism in HLA-B27 transgenic rats Gastroenterology 109 142-150
[2]  
Grisham MB(1995)Reactivation of hapten-induced colitis and its prevention by anti-inflammatory drugs Am J Physiol 269 G119-G125
[3]  
Appleyard CB(1992)Specific inhibitors of poly (ADP-ribose)synthetase and mono (ADP-ribose) transferase J Biol Chem 267 1569-1575
[4]  
Wallace JL(1985)Poly(ADP-ribose) in the cellular response to DNA damage Radiat Res 101 4-15
[5]  
Banasik M(1993)Nitric oxide synthase activity in ulcerative colitis and Crohn’s disease Lancet 341 338-340
[6]  
Komura H(2000)Inhibitors of poly (ADP-ribose) synthetase reduce renal ischemia–reperfusion injury in the anesthetized rat in vivo FASEB J 14 641-651
[7]  
Shimoyama M(2002)Poly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited Trends Pharmacol Sci 23 22-129
[8]  
Berger NA(1995)Time course of ICAM-1 expression and leukocyte subset infiltration in rat forebrain ischemia Mol Chem Neuropathol 26 213-230
[9]  
Boughton-Smith NK(2002)New inhibitors of poly (ADP-ribose) polymerase and their potential therapeutic targets Exp Opin Ther Patents 12 1047-1071
[10]  
Evans SM(1997)Beneficial effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase in a rat model of splanchnic artery occlusion and reperfusion Br J Pharmacol 121 1065-1074