The tyrosine kinase inhibitor tyrphostin AG 126 reduced the development of colitis in the rat.
Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, up-regulation of the expression of intercellular adhesion molecule-1 (ICAM-1), and up-regulation of P-selectin in the colon. Here we investigate the effects of the tyrosine kinase inhibitor, Tyrphostin AG 126, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhea and weight loss. Four days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed an intense staining in the inflamed colon. Staining with an anti-COX-2 antibody of sections of colon obtained from DNBS-treated rats showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase was found mainly in macrophages located within the inflamed colon of DNBS-treated rats. Tyrphostin AG 126 (5 mg/kg daily ip) significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of DNBS. Tyrphostin AG 126 also caused a substantial reduction of (1) the phosphorylation of tyrosine residues of proteins (immunoblots of inflamed colon), (2) the degree of colonic injury, (3) the rise in myeloperoxidase activity (mucosa), (4) the increase in the tissue levels of malondialdehyde, (5) the increase in staining (immunohistochemistry) for nitrotyrosine and poly(ADP-ribose) polymerase, as well as (6) the up-regulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that the tyrosine kinase inhibitor Tyrphostin AG126 reduces the degree of colitis caused by DNBS.
Cuzzocrea
S
S
Institute of Pharmacology, School of Medicine, University of Messina, Italy. salvator@www.unime.it
McDonald
M C
MC
Mazzon
E
E
Mota-Filipe
H
H
Lepore
V
V
Ciccolo
A
A
Terranova
M L
ML
Britti
D
D
Caputi
A P
AP
Thiemermann
C
C
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007527:Isoenzymes / Q000096:biosynthesis; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D020032:Tyrphostins / Q000627:therapeutic use*
D016207:Cytokines; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020032:Tyrphostins; C069028:AG 127; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases