Poly(ADP-ribose) polymerases (PARP) comprise a family of
enzymes which catalyse poly(ADP-ribosyl)ation of
DNA-binding proteins. Multiple researches indicate the importance of PARP in promoting cell recruitment and thereby inducing organ injury in various forms of
inflammation, such as
colitis. We have evaluated the effects of two
PARP inhibitors,
nicotinamide and
1,5-dihydroxyisoquinoline, in acute
colitis induced by trinitrobenzensulfonic
acid (TNBS) in rats.
Nicotinamide (20-40 mg/kg) and
1,5-dihydroxyisoquinoline (4-8 mg/kg) were administered 48, 24 and 1 h prior to the induction of
colitis as well as 24 h later. 48 h after
colitis induction the lesions were blindly scored and quantified as
ulcer index. Histological study and colonic
inflammation were assessed by gross appearance and
myeloperoxidase (MPO) activity.
Prostaglandin E2 (
PGE2) synthesis and,
cyclooxygenase-1 and
cyclooxygenase-2 expressions by Western blotting and immunohistochemistry were also performed.
Inflammation following TNBS induction was characterized by increased colonic wall thickness, oedema, diffuse inflammatory cells infiltration in the mucosa and
necrosis. Furthermore, increased MPO activity,
cyclooxygenase-2 expression and
PGE2 synthesis were significantly augmented after TNBS instillation. On the contrary, treatment with
1,5-dihydroxyisoquinoline significantly reduced the degree of colon injury and also caused a substantial reduction in the rise in MPO activity, in the increase of staining for
cyclooxygenase-2, as well as in the up-regulation of
PGE2 caused by TNBS in the colon. Although
nicotinamide significantly did not reduce macroscopic damage, it decreased both MPO activity and
PGE2 colonic levels. In conclusion, we demonstrated that PARP inhibition can exert beneficial effects in experimental
colitis and may, therefore, be useful in the treatment of
ulcerative colitis.