Rebamipide Attenuates 5-Fluorouracil-Induced Small Intestinal Mucositis in a Mouse Model

• Published in: Biological & pharmaceutical bulletin Vol. 38; no. 2; pp. 179 - 183
• Main Authors: Kim, Hyun Jin, Kim, Jin Hyun, Moon, Won, Park, Jongha, Park, Seun Ja, Song, Geun Am, Han, Seung Hee, Lee, Jong Hun
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-02-2015; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: 5-fluorouracil; Alanine - analogs & derivatives; Alanine - pharmacology; Alanine - therapeutic use; Animals; Anti-Ulcer Agents - pharmacology; Anti-Ulcer Agents - therapeutic use; Antimetabolites, Antineoplastic; Apoptosis - drug effects; Disease Models, Animal; Fluorouracil; Glutathione - blood; Glutathione - metabolism; Intestine, Small - drug effects; Intestine, Small - metabolism; Intestine, Small - pathology; Macrophages - drug effects; Male; Mice, Inbred BALB C; mucositis; Mucositis - chemically induced; Mucositis - drug therapy; Mucositis - metabolism; Mucositis - pathology; Nitric Oxide Synthase Type II - metabolism; Quinolones - pharmacology; Quinolones - therapeutic use; rebamipide; small intestine; Transforming Growth Factor beta1 - metabolism; Tumor Necrosis Factor-alpha - blood
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b14-00400

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.