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First published on July 26, 2005; DOI: 10.1124/mol.105.015784

0026-895X/05/6804-1156-1161$20.00
Mol Pharmacol 68:1156-1161, 2005

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Geranylgeranylacetone Protects Membranes against Nonsteroidal Anti-Inflammatory Drugs

Hironori Ushijima, Ken-Ichiiro Tanaka, Miho Takeda, Takashi Katsu, Shinji Mima, and Tohru Mizushima

Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan (H.U., K.-I.T., M.T., S.M., T.M.); and Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan (T.K.)

Direct gastric mucosal cell damage mediated by nonsteroidal anti-inflammatory drugs (NSAIDs) is involved in the formation of NSAID-induced gastric lesions. We recently suggested that this direct cytotoxicity of NSAIDs is caused by their membrane-permeabilization activity. Geranylgeranylacetone (GGA), a clinically used antiulcer drug, can protect gastric mucosa against lesion formation mediated by NSAIDs. However, the mechanism by which this occurs is not fully understood. In this study, we show that GGA acts to stabilize membranes against NSAIDs. GGA suppressed NSAID-induced permeabilization of calcein-loaded liposomes and NSAID-induced stimulation of K+-efflux across the cytoplasmic membrane in cells. GGA was effective even when coadministered with NSAIDs and was also able to restore membrane fluidity that had been compromised by NSAIDs. This mechanism seems to play an important role in the antiulcer activity of GGA.

Received June 17, 2005; accepted July 26, 2005

Address correspondence to: Dr. Tohru Mizushima, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. E-mail: mizu{at}gpo.kumamoto-u.ac.jp




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K.-i. Tanaka, S. Tsutsumi, Y. Arai, T. Hoshino, K. Suzuki, E. Takaki, T. Ito, K. Takeuchi, A. Nakai, and T. Mizushima
Genetic Evidence for a Protective Role of Heat Shock Factor 1 against Irritant-Induced Gastric Lesions
Mol. Pharmacol., April 1, 2007; 71(4): 985 - 993.
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