Calpain inhibitor I reduces colon injury caused by dinitrobenzene sulphonic acid in the rat

Background and aims-Inflammatory bowel disease is characterised by oxidativ e and nitrosative stress, leucocyte infiltration, upregulation of expressio n of intercellular adhesion molecule 1 (ICAM-1), and upregulation of P-sele ctin in the colon. The aim of the present study was to examine the effects of calpain inhibitor I in rats subjected to experimental colitis. Methods-Colitis was induced in rats by intracolonic instillation of dinitro benzene sulphonic acid (DNBS). Results-Fats experienced haemorrhagic diarrhoea and weight loss. Four days after administration of DNAB, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as b y an increase in myeloperoxidase activity in the mucosa) was associated wit h upregulation of ICAM-1 and P-selectin as well as high tissue levels of ma londialdehyde. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) showed intense staining in the inflamed colon. Staining of sections of colon obtained from DNBS treated rats with an anti-cyclooxyg enase 2 antibody showed diffuse staining of the inflamed tissue. Furthermor e, expression of inducible nitric oxide synthase was found mainly in macrop hages located within the inflamed colon of DNBS treated rats. Calpain inhib itor I (5 mg/kg daily intraperitoneally) significantly reduced the degree o f haemorrhagic diarrhoea and weight loss caused by administration of DNBS. Calpain inhibitor I also caused a substantial reduction in (i) degree of co lon injury, (ii) rise in myeloperoxidase activity (mucosa), (iii) increase in tissue levels of malondialdehyde, (iv) increase in staining (immunohisto chemistry) for nitrotyrosine and PARP, as well as (v) upregulation of ICAM- 1 and P-selectin caused by DNBS in the colon. Conclusion-Calpain inhibitor I reduces the degree of colitis caused by DNBS . We propose that calpain inhibitor I may be useful in the treatment of inf lammatory bowel disease.