Protective effects of M40403, a superoxide dismutase mimetic, in a rodent model of colitis.
Inflammatory bowel disease is characterised by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. The aim of the present study was to examine the effects of M40403, a superoxide dismutase mimetic, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of trinitrobenzene sulfonic acid (TNBS). Rats experienced bloody diarrhoea and significant loss of body weight. At 4 days after TNBS administration, the colon damage was characterised by areas of mucosal necrosis. Neutrophil infiltration (indicated by myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and expression of P-selectin and high levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) synthetase showed an intense staining in the inflamed colon. Treatment with M40403 (5 mg/kg daily i.p.) significantly reduced the appearance of diarrhoea and the loss of body weight. This was associated with a remarkable amelioration of the disruption of the colonic architecture as well as a significant reduction of colonic myeloperoxidase activity and malondialdehyde levels. M40403 also reduced the appearance of nitrotyrosine and poly (ADP-ribose) synthetase immunoreactivity in the colon as well as reduced the up-regulation of ICAM-1 and the expression of P-selectin. The results of this study suggested that administration of a superoxide dismutase mimetic may be beneficial for treatment of inflammatory bowel disease.
Cuzzocrea
S
S
Institute of Pharmacology, University of Messina, Messina, Italy.
Mazzon
E
E
Dugo
L
L
Caputi
A P
AP
Riley
D P
DP
Salvemini
D
D
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008345:Manganese; D009942:Organometallic Compounds / Q000494:pharmacology*; D019007:P-Selectin / Q000096:biosynthesis / Q000187:drug effects; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology*; D016019:Survival Analysis; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000187:drug effects
D016207:Cytokines; D016166:Free Radical Scavengers; D009942:Organometallic Compounds; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; C121876:imisopasem manganese; C002744:3-nitrotyrosine; D014443:Tyrosine; D008345:Manganese; D009195:Peroxidase; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases