A stable nitroxide radical effectively decreases mucosal damage in experimental colitis.
TEMPOL, a cyclic nitroxide stable radical blocks biological damage by breaking chain reactions through termination reaction with free radicals, and by inhibiting the catalytic effect of transition metals. This study tested its protective effect on two models of experimental colitis as free radicals play an important part in their pathogenesis. TEMPOL was given intragastrically immediately after induction of colitis with acetic acid or trinitrobenzene sulphonic acid (TNB) and mucosal damage was assessed one, three, or seven days later. Cellular partition of TEMPOL was determined by electron paramagnetic resonance spectroscopy. In vitro experiments showed that TEMPOL immediately penetrates colonic mucosa and, following its intragastric administration, it persists in both gastric and colonic mucosa for several hours. Intragastric administration of TEMPOL, 0.5 g/kg/bw, immediately after intracaecal administration of 5% acetic acid significantly decreased mucosal lesion area, myeloperoxidase activity, and leukotriene B4 and C4 generation when assessed 24 hours after damage induction. Intragastric administration of TEMPOL, 0.5 g/kg/bw, immediately after intracolonic administration of 30 mg TNB in 0.25 ml 50% ethanol, and once daily thereafter, significantly decreased mucosal lesion area assessed after one, three, and seven days, having no effect on LTC4 generation and affecting colonic weight, myeloperoxidase activity, and LTB4 generation only sporadically. In conclusion, TNB and acetic acid induced colitis can be pharmacologically manipulated by TEMPOL. TEMPOL may be beneficial in the treatment or prevention of inflammatory bowel disease.
Karmeli
F
F
Department of Medicine, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel.
Eliakim
R
R
Okon
E
E
Samuni
A
A
Rachmilewitz
D
D
D000085:Acetates; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D003497:Cyclic N-Oxides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D008084:Lipoxygenase / Q000378:metabolism; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid
D000085:Acetates; D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; D007975:Leukotriene B4; D017997:Leukotriene C4; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D008084:Lipoxygenase; C003959:TEMPO