Effect of long-term administration of rebamipide on Helicobacter pylori infection in mice.
BACKGROUND
It has been suggested that chronic, persistent, uncontrolled inflammations in the stomach could provide the basic step for the beginning of carcinogenesis. One of the potential clinical applications of rebamipide is the inhibition of the immunoinflammatory response in gastric mucosa imposed by Helicobacter pylori.


OBJECTIVE
To determine the implications of long-term rebamipide treatment in H. pylori infection, we studied the underlying moleculo-pathological changes in gastric lesions in mice infected with H. pylori (SS1 strain), following this treatment.


METHODS
C57BL/6 mice were sacrificed 24 and 50 weeks after H. pylori infection, respectively. Colonization rates of H. pylori, degree of gastric inflammation and other pathological changes including atrophic gastritis and metaplasia, serum levels of IL-1beta, TNF-alpha, IFN-gamma and IL-10, mRNA transcripts of various mouse cytokines and chemokines, and NF-kappaB binding activities, and finally the presence of gastric adenocarcinoma were compared between an H. pylori infected group (HP), and an H. pylori infected group administered with long-term rebamipide-containing pellet diets (HPR).


RESULTS
Serum levels of IL-1beta, IFN-gamma and TNF-alpha, the gastric mucosal expression of ICAM-1, HCAM and MMP, and transcriptional regulation of NF-kappaB-DNA binding were all significantly decreased in the HPR group compared with the HP group. An RNase protection assay showed, in the rebamipide administered group, significantly decreased mRNA levels of apoptosis-related genes such as caspase-8, FasL, Fas, TRAIL and various cytokines genes such as IFN-gamma, RANTES, TNF-alpha, TNFR p75, IL-1beta. In the experiment designed to provoke gastric cancer through MNU treatment with H. pylori infection, the incidence of gastric carcinoma was not different in either group. However, long-term administration of rebamipide showed the advantage of decreasing precancerous lesions like chronic atrophic gastritis and showed molecular evidence of attenuation of proliferation.


CONCLUSIONS
The long-term administration of rebamipide should be considered in the treatment of H. pylori since it demonstrated molecular and biological advantages like a lessening of gastric inflammation and a possible chemopreventive effect.
Hahm
K B
KB
Genomic Research Center for Gastroenterology, Ajou Helicobacter Research Group, Ajou University School of Medicine, Suwon, Korea. hahmkb@hotmail.com
Kim
D H
DH
Lee
K M
KM
Lee
J S
JS
Surh
Y J
YJ
Kim
Y B
YB
Yoo
B M
BM
Kim
J H
JH
Joo
H J
HJ
Cho
Y K
YK
Nam
K T
KT
Cho
S W
SW
D000409:Alanine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016207:Cytokines / Q000378:metabolism; D005753:Gastric Mucosa / Q000382:microbiology / Q000473:pathology; D005756:Gastritis / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000188:drug therapy* / Q000473:pathology; D016480:Helicobacter pylori; D007150:Immunohistochemistry; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D015363:Quinolones / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism
D000897:Anti-Ulcer Agents; D016207:Cytokines; D016328:NF-kappa B; D011506:Proteins; D015363:Quinolones; D012333:RNA, Messenger; D020782:Matrix Metalloproteinases; C052785:rebamipide; D000409:Alanine