title: Rebamipide induces the gastric mucosal protective factor, cyclooxygenase-2, via activation of 5'-AMP-activated protein kinase.
abstract: Rebamipide, an amino acid derivative of 2(1H)-quinolinone, has been used for mucosal protection, healing of gastroduodenal ulcers, and treatment of gastritis. Induction of cyclooxygenase (COX)-2, a gastric mucosal protective factor, by rebamipide has been suggested as the major mechanism of the drug action. However, how rebamipide induces COX-2 at the molecular level needs further investigation. In this study, the molecular mechanism underlying the induction of COX-2 by rebamipide was investigated. In gastric carcinoma cells and macrophage cells, rebamipide induced phosphorylation of AMP-activated protein kinase (AMPK), leading to phosphorylation of acetyl-CoA carboxylase (ACC), a substrate of AMPK. The induction of COX-2 by rebamipide was dependent on AMPK activation because compound C, an AMPK inhibitor, abolished COX-2 induction by rebamipide. In a mouse ulcer model, rebamipide protected against hydrochloric acid/ethanol-induced gastric ulcer, and these protective effects were deterred by co-administration of compound C. In parallel, in the gastric tissues, rebamipide increased the phosphorylation AMPK, whereas compound C reduced the levels of COX-2 and phosphorylated ACC, which were increased by rebamipide. Taken together, the activation of AMPK by rebamipide may be a molecular mechanism that contributes to induction of COX-2, probably resulting in protection against gastric ulcers.
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Seongkeun
authors.initials: S
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Wooseong
authors.initials: W
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Dohoon
authors.initials: D
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Yejin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea.
authors.forename: Byung Joo
authors.initials: BJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea. Electronic address: minds@pusan.ac.kr.
authors.forename: Do Sik
authors.initials: DS
authors.lastname: Min
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 609-735, Republic of Korea. Electronic address: jungy@pusan.ac.kr.
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D015363:Quinolones / Q000494:pharmacology*; D013276:Stomach Ulcer / Q000188:drug therapy
chemical_list: D000897:Anti-Ulcer Agents; D015363:Quinolones; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D055372:AMP-Activated Protein Kinases; D015232:Dinoprostone; C052785:rebamipide; D000409:Alanine
keywords: AMP-activated protein kinase; Cyclooxygenase-2; Dorsomorphin (PubChem CID: 11524144); Gastric ulcer; Hydrochloric acid (PubChem CID: 313); Rebamipide; Rebamipide (PubChem CID: 5042)