Melatonin reduces dinitrobenzene sulfonic acid-induced colitis.
Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. The aim of this study was to examine the effects of the pineal secretory product melatonin in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced bloody diarrhea and a significant loss of body weight. Four days after DNBS administration, the colon damage was characterized by areas of mucosal necrosis. Neutrophil infiltration (indicated by myeloperoxidase [MPO] activity in the mucosa) was associated with up-regulation of ICAM-1, expression of P-selectin, and high levels of malondialdehyde (MDA). Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) synthetase (PARS) showed an intense staining in the inflamed colon. Staining of colon tissue sections obtained from DNBS-treated rats with an anti-cycloxygenase-2 (COX-2) antibody showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase (iNOS) was found mainly in the macrophages of the inflamed colons from DNBS-treated rats. Treatment with melatonin (15 mg/kg daily, intraperitoneally) significantly reduced the appearance of diarrhea 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 MPO activity and MDA levels. Melatonin also reduced the appearance of nitrotyrosine and PARS immunoreactivity in the colon, as well as reducing the up-regulation of ICAM-1 and the expression of P-selectin. The intensity and degree of the stainings for COX-2 and iNOS were markedly reduced in tissue sections obtained from melatonin-treated rats. The results of the this study suggest that the administration of melatonin might be beneficial for the treatment of IBD.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Italy. salvator@www.unime.it
Mazzon
E
E
Serraino
I
I
Lepore
V
V
Terranova
M L
ML
Ciccolo
A
A
Caputi
A P
AP
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives* / Q000633:toxicity; D019084:Fluorescent Antibody Technique, Indirect; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D019007:P-Selectin / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D016166:Free Radical Scavengers; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; C045305:2,4-dinitrofluorobenzene sulfonic acid; D011064:Poly Adenosine Diphosphate Ribose; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D004139:Dinitrofluorobenzene; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008550:Melatonin