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 40 mg/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.