5-Aminoisoquinolinone reduces colon injury by experimental colitis.
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.
Cuzzocrea
Salvatore
S
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Via C. Valeria, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. salvator@unime.it
Mazzon
Emanuela
E
Di Paola
Rosanna
R
Genovese
Tiziana
T
Patel
Nimesh S A
NS
Muià
Carmelo
C
Threadgill
Michael D
MD
De Sarro
Angelina
A
Thiemermann
Christoph
C
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives* / Q000633:toxicity; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice
C411425:5-aminoisoquinolinone; D007546:Isoquinolines; C045305:2,4-dinitrofluorobenzene sulfonic acid; D004139:Dinitrofluorobenzene