TY - JOUR
T1 - GPI 6150, a PARP inhibitor, reduces the colon injury caused by dinitrobenzene sulfonic acid in the rat
AU - Mazzon, Emanuela
AU - Dugo, Laura
AU - Li, Jia He
AU - Di Paola, Rosanna
AU - Genovese, Tiziana
AU - Caputi, Achille P.
AU - Zhang, Jie
AU - Cuzzocrea, Salvatore
PY - 2002/7/15
Y1 - 2002/7/15
N2 - Poly (ADP-ribose) polymerase, a nuclear enzyme activated by DNA strand breaks, has been shown to play an important role in the pathogenesis of inflammatory bowel disease. Here we investigate the effects of 1,11b-dihydro-[2H]benzopyrano [4,3,2-de]isoquinolin-3-one (GPI 6150), a new poly (ADP-ribose) polymerase inhibitor, in animal models of experimental colitis. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulfonic acid. Rats experienced hemorrhagic diarrhea and weight loss. At 4 days after administration of dinitrobenzensulfonic acid, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology and an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1. Immunohistochemistry for poly (ADP-ribose) showed an intense staining in the inflamed colon. GPI 6150 (20 or 40mg/kg daily, i.p.) significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of dinitrobenzensulfonic acid. GPI 6150 also caused a substantial reduction of (i) the degree of colon injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for poly (ADP-ribose), as well as (v) the upregulation of ICAM-1 and P-selectin caused by dinitrobenzensulfonic acid in the colon. Thus, GPI 6150 reduces the degree of colitis caused by dinitrobenzensulfonic acid. We propose that GPI 6150 may be useful in the treatment of inflammatory bowel disease.
AB - Poly (ADP-ribose) polymerase, a nuclear enzyme activated by DNA strand breaks, has been shown to play an important role in the pathogenesis of inflammatory bowel disease. Here we investigate the effects of 1,11b-dihydro-[2H]benzopyrano [4,3,2-de]isoquinolin-3-one (GPI 6150), a new poly (ADP-ribose) polymerase inhibitor, in animal models of experimental colitis. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulfonic acid. Rats experienced hemorrhagic diarrhea and weight loss. At 4 days after administration of dinitrobenzensulfonic acid, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology and an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1. Immunohistochemistry for poly (ADP-ribose) showed an intense staining in the inflamed colon. GPI 6150 (20 or 40mg/kg daily, i.p.) significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of dinitrobenzensulfonic acid. GPI 6150 also caused a substantial reduction of (i) the degree of colon injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for poly (ADP-ribose), as well as (v) the upregulation of ICAM-1 and P-selectin caused by dinitrobenzensulfonic acid in the colon. Thus, GPI 6150 reduces the degree of colitis caused by dinitrobenzensulfonic acid. We propose that GPI 6150 may be useful in the treatment of inflammatory bowel disease.
KW - Bowel disease
KW - Free radicals
KW - GPI 6150
KW - Inflammation
KW - Nitric oxide
KW - Poly (ADP-ribose) synthethase
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UR - http://www.scopus.com/inward/citedby.url?scp=0037099301&partnerID=8YFLogxK
U2 - 10.1016/S0006-2952(02)01075-4
DO - 10.1016/S0006-2952(02)01075-4
M3 - Article
C2 - 12123754
AN - SCOPUS:0037099301
SN - 0006-2952
VL - 64
SP - 327
EP - 337
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 2
ER -