Rebamipide attenuates 5-Fluorouracil-induced small intestinal mucositis in a mouse model.
5-Fluorouracil (5-FU)-induced intestinal mucositis is one of the most common morbidities in chemotherapy and involves the reactive oxygen species (ROS) system, apoptosis, and inflammatory cytokines. Rebamipide exerts a mucosal-protective effect, mediated through several mechanisms. The aim of this study was to evaluate the effects of rebamipide in 5-FU-induced mouse small-intestinal mucositis. BALB/c mice were assigned randomly to four groups; (1) control group (n=10; receiving saline orally for 6 d), (2) rebamipide group (n=10; 150 mg/kg rebamipide for 6 d orally), (3) 5-FU group (n=10; 30 mg/kg 5-FU for 5 d, intraperitoneally (i.p.)), and (4) rebamipide +5-FU group (n=10; 150 mg/kg rebamipide for 6 d orally and 30 mg/kg 5-FU for 5 d, i.p.). Body weights and diarrhea scales were assessed. At day 5, the mice were sacrificed. Small intestinal tissue was used for: (1) hematoxylin and eosin (HE) staining for determination of small intestinal villi height, (2) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, (3) immunohistochemistry for inducible nitric oxide synthase (iNOS), F4/80, and transforming growth factor (TGF)-β1, (4) measurement of serum and tissue GSH levels, and (5) measurement of serum tumor necrosis factor (TNF)-α levels. Rebamipide attenuated the severity of mucosal injury reflected by body weight changes, degrees of diarrhea, and heights of villi. Rebamipide reduced the expression of iNOS and TGF-β1, apoptosis, macrophage accumulation, serum TNF-α levels, and prevented reductions in serum and tissue glutathione (GSH) levels by 5-FU administration. These results suggest that rebamipide promotes several mechanisms of mucosal protection and attenuated the 5-FU-induced mucosal injury. In conclusion, administration of rebamipide may have significant protective effects against 5-FU-induced intestinal mucositis.
Department of Internal Medicine and Institute of Health Science, School of Medicine, Gyeongsang National University.
Hyun Jin
HJ
Kim
Jin Hyun
JH
Kim
Won
W
Moon
Jongha
J
Park
Seun Ja
SJ
Park
Geun Am
GA
Song
Seung Hee
SH
Han
Jong Hun
JH
Lee
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D005472:Fluorouracil; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D052016:Mucositis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000897:Anti-Ulcer Agents; D000964:Antimetabolites, Antineoplastic; D015363:Quinolones; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005978:Glutathione; C052785:rebamipide; D000409:Alanine; D005472:Fluorouracil