Effect of rebamipide on acetic acid-induced gastric ulcer in rats: involvement of hepatocyte growth factor.
BACKGROUND
Rebamipide is used clinically as an anti-ulcer agent, especially in Japan. The major mechanisms of rebamipide include prostaglandin induction and free radical scavenging. Since prostaglandins are inducers of hepatocyte growth factor (HGF), we examined the effect of rebamipide on the expression of HGF, c-met, cyclooxygenase-2 (Cox-2) and subtype of the prostaglandin E2 receptor (EP2) in acetic acid-induced gastric ulcer, a model of human ulcer.


METHODS
Ninety-six male Fisher rats were used in the experiments. Gastric ulcers were produced by injecting 50 microl of 20% acetic acid into subserosa of the border between the fundic and antral gland areas. The rats of the rebamipide group were fed a diet containing 60 mg kg(-1) day(-1) rebamipide and killed on days 10, 30, 60, 90, 120 and 150 after ulceration. Reverse transcription polymerase chain reaction of HGF, c-met, Cox-2 and EP2 gene and immunohistochemistry of proliferating cell nuclear antigen (PCNA) were performed.


RESULTS
In the rebamipide group, gastric ulcer index was significantly smaller than in the control group at each time-point except at 10 days (P < 0.05, each); up-regulation of HGF, c-met, Cox-2 and EP2 mRNA was also observed. The mRNA level of HGF was significantly correlated with that of Cox-2 and EP2 (P < 0.05, each). The PCNA-labelled epithelial cells in the rebamipide group were also greater than in the control group on days 10, 30, 90 and 120 (P < 0.05, each).


CONCLUSIONS
The study suggests that rebamipide has anti-ulcerative effects on gastric mucosal cells via up-regulation of HGF, c-met, Cox-2 and EP2.
Udagawa
A
A
Second Dept. of Internal Medicine, Faculty of Medicine, Tottori University, Yonago, Japan.
Shiota
G
G
Ichiba
M
M
Murawaki
Y
Y
D019342:Acetic Acid; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000897:Anti-Ulcer Agents; D007527:Isoenzymes; D018809:Proliferating Cell Nuclear Antigen; D015363:Quinolones; D018078:Receptors, Prostaglandin E; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D019859:Proto-Oncogene Proteins c-met; C052785:rebamipide; D000409:Alanine; D019342:Acetic Acid