Protective effect of rebamipide on indomethacin-induced intestinal damage in rats.
OBJECTIVE
We evaluated the effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid), a novel anti-ulcer drug, on indomethacin-induced small intestinal lesions in rats.


METHODS
The animals were administered indomethacin (10 mg/kg, s.c.), and they were killed 24 h later. Rebamipide (30-300 mg/kg) was administered p.o. twice, 30 min before, and 6 h after indomethacin.


RESULTS
Indomethacin caused hemorrhagic lesions in the rat small intestine, accompanied by an increase in enterobacterial translocation, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) activities, as well as thiobarbituric acid (TBA) reactants, and these changes were significantly prevented by the supplementation with 16,16-dimethyl prostaglandin E2 (dmPGE2; 10 microg/kg, i.v.) or the pretreatment of animals with the antibiotic ampicillin. Treatment of the animals with rebamipide dose-dependently prevented the development of intestinal lesions, and this effect was mimicked by i.v. administration of superoxide dismutase (SOD: 3000 U/kg) + catalase (CAT: 5000 U/kg). The protection by rebamipide was accompanied by a significant suppression of the increase in both MPO and iNOS activities, and a complete inhibition of the increase in TBA reactants, while SOD + CAT significantly inhibited the increase of MPO activity and TBA reactants, but not iNOS activity. The bacterial translocation following indomethacin was also significantly decreased by either rebamipide or SOD + CAT.


CONCLUSIONS
These results confirmed the importance of enterobacteria and iNOS/NO in the pathogenesis of indomethacin-induced small intestinal lesions, and suggested that rebamipide prevents the development of these lesions, probably by its radical scavenging action.
Mizoguchi
H
H
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
Ogawa
Y
Y
Kanatsu
K
K
Tanaka
A
A
Kato
S
S
Takeuchi
K
K
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D018988:Bacterial Translocation / Q000187:drug effects; D002374:Catalase / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004755:Enterobacteriaceae / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007213:Indomethacin; D007410:Intestinal Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D015227:Lipid Peroxidation; D008297:Male; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D009195:Peroxidase / Q000096:biosynthesis; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000494:pharmacology
D000897:Anti-Ulcer Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D000667:Ampicillin; D002374:Catalase; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; C052785:rebamipide; D000409:Alanine; D007213:Indomethacin