J Rheum Dis 2017; 24(4): 192-202  
Metabolomics Approach to Explore the Effects of Rebamipide on Inflammatory Arthritis Using Ultra Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry
Su-Jin Moon1*, Soo Hyun Lee2*, Byung-Hwa Jung3, Jun-Ki Min1
1Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, 2Department of Medical Records and Health Information Management, College of Nursing and Health, Kongju National University, Gongju, 3Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Korea
Correspondence to: Jun-Ki Min, Division of Rheumatology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327 Sosa-ro, Wonmi-gu, Bucheon 14647, Korea. E-mail:min6403@catholic.ac.kr
Byung-Hwa Jung, Molecular Recognition Research Center, Korea Institute of Science and Technology, 5, Hwarang-ro 14-gil, Seongbuk-gu, Seoul 02792, Korea. E-mail : jbhluck@kist.re.kr
*These authors contributed equally to this work.
Received: January 25, 2017; Revised: April 21, 2017; Accepted: April 22, 2017; Published online: August 31, 2017.
© Korean College of Rheumatology. All rights reserved.

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Abstract
Objective. Rebampide is a gastroprotective agent used to treat gastritis. It possesses anti-inflammatory and anti-arthritis effects, but the mechanisms of these effects are not well understood. The objective of this study was to explore mechanisms underlying the therapeutic effects of rebamipide in inflammatory arthritis. Methods. Collagen-induced arthritis (CIA) was induced in DBA/1J mice. DBA/1J mice were immunized with chicken type II collagen, then treated intraperitoneally with rebamipide (10 mg/kg or 30 mg/kg) or vehicle (10% carboxymethylcellulose solution) alone. Seven weeks later, plasma samples were collected. Plasma metabolic profiles were analyzed using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolomics study and metabolite biomarkers were identified through multivariate data analysis. Results. Low dose rebamipide treatment reduced the clinical arthritis score compared with vehicle treatment, whereas high dose rebamipide in CIA aggravated arthritis severity. Based on multivariate analysis, 17 metabolites were identified. The plasma levels of metabolites associated with fatty acids and phospholipid metabolism were significantly lower with rebamipide treatment than with vehicle. The levels of 15-deoxy-Δ12,14 prostaglandin J2 and thromboxane B3 decreased only in high dose-treated groups. Certain peptide molecules, including enterostatin (VPDPR) enterostatin and bradykinin dramatically increased in rebamipide-treated groups at both doses. Additionally, corticosterone increased in the low dose-treated group and decreased in the high dose-treated group. Conclusion. Metabolomics analysis revealed the anti-inflammatory effects of rebamipide and suggested the potential of the drug repositioning in metabolism- and lipid-associated diseases.
Keywords: Rebamipide, Arthritis, Metabolomics, Anti-oxidant


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