Mechanism for anti-AD effect of approved medicines

2013 Fiscal Year Final Research Report

• Project/Area Number: 24659037
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: Keio University
• Principal Investigator: MIZUSHIMA Tohru 慶應義塾大学, 薬学部, 教授 (00264060)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: アルツハイマー病

Research Abstract

Transforming growth factor (TGF)-B1 stimulates this phagocytosis. We recently reported that the APP23 mouse model for AD showed fewer AD-related phenotypes when these animals were crossed with transgenic mice expressing heat shock protein (HSP) 70. We here examined the effect of geranylgeranylacetone, an inducer of HSP70 expression, on the AD-related phenotypes. Repeated oral administration of geranylgeranylacetone to APP23 mice for 9 months not only improved cognitive function but also decreased levels of AB, AB plaque deposition and synaptic loss. The treatment also up-regulated the expression of an AB-degrading enzyme and TGF-B1 but did not affect the maturation of APP and secretase activities. These outcomes were similar to those observed in APP23 mice genetically modified to overexpress HSP70. A single oral administration of geranylgeranylacetone significantly increased the level of HSP70 when AB was concomitantly injected directly into the hippocampus.

Research Products

• [Journal Article] Diclofenac protects cultured human corneal epithelial cells against hyperosmolarity and ameliorates corneal surface damage in a rat model of dry eye (2014)
  • Author(s): Sawazaki, R., Ishihara, T., Usui, S., Hayashi, E., Tahara, K., Hoshino, T., Higuchi, A., Nakamura, S., Tsubota, K. and Mizushima, T.
  • Journal Title: Invest. Ophthalmol. Vis. Sci. Volume: 55 Pages: 2547-2556
  • DOI: 10.1167/iovs.13-1385
• [Journal Article] Superiority of pulmonary administration of mepenzolate bromide over other routes as treatment for chronic obstructive pulmonary disease (2014)
  • Author(s): Tanaka, K., Kurotsu, S., Asano, T., Yamakawa, N., Kobayashi D., Yamashita, Y., Yamazaki, H., Ishihara, T., Watanabe, H., Maruyama, T., Suzuki, H. and Mizushima, T.
  • Journal Title: Sci. Rep. Volume: 28 Pages: 4510
• [Journal Article] Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity (2014)
  • Author(s): Yamakawa, N., Suzuki, K., Yamashita, Y., Katsu, T., Hanaya, K., Shoji, M., Sugai, T. and Mizushima, T.
  • Journal Title: Bioorg. & Medic. Chem. Volume: 22 Pages: 2529-2534
  • DOI: 10.1016/j.bmc.2014.02.032
• [Journal Article] Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease (2013)
  • Author(s): Tanaka, K., Ishihara, T., Sugizaki, T., Kobayashi D., Yamashita, Y., Tahara, K., Yamakawa, N., Iijima, K., Mogushi, K., Tanaka, H., Sato, K., Suzuki, H. and Mizushima, T.
  • Journal Title: Nature Communications Volume: 4 Pages: 2686
• [Journal Article] Suppression of Alzheimer's disease-related phenotypes by geranylgeranylacetone in mice (2013)
  • Author(s): Hoshino, T., Suzuki, K., Matsushima, T., Yamakawa, N., Suzuki, T. and Mizushima, T.
  • Journal Title: PLoS One Volume: 8 Pages: e76306
  • DOI: 10.1371/journal.pone.0076306
• [Journal Article] Chemo-enzymatic enantioconvergent approach toward ethyl shikimate from ethyl 5-hydroxy-3,4-isopropylidenedioxycycloh ex-1-enecarboxylate (2013)
  • Author(s): Yamashita, Y., Hanaya, K., Sugai, T., Mizushima, T. and Shoji, M.
  • Journal Title: Tetrahedron Volume: 69 Pages: 6527-6532
• [Journal Article] Prostaglandin E1-encapsulated nanoparticles improve walking activity in an experimental rat model of intermittent claudication (2013)
  • Author(s): Ishihara, T., Yamashita, Y., Takasaki, N., Yamamoto, S., Hayashi, E., Tahara, K., Takenaga, M., Yamakawa, N., Ishihara, T., Kasahara, T. and Mizushima, T.
  • Journal Title: J. Pharm. Pharmacol. Volume: 65 Pages: 1187-1194
• [Journal Article] Long-acting human serum albumin-thioredoxin fusion protein suppresses bleomycin-induced pulmonary fibrosis progression (2013)
  • Author(s): Tanaka, R., Watanabe, H., Kodama, A., Chuang, VTG., Ishima, Y., Hamasaki, K., Tanaka, K, Mizushima, T., Otagiri, M. and Maruyama, T.
  • Journal Title: J. Pharmacol. Exp. Ther. Volume: 345 Pages: 271-283
  • DOI: 10.1124/jpet.112.201814
• [Journal Article] Comparison of pharmacokinetics between loxoprofen and its derivative with lower ulcerogenic activity, fluoro-loxoprofen (2013)
  • Author(s): Yamakawa, N., Suemasu, S., Watanabe, H., Tahara, K., Tanaka, K., Okamoto, Y., Ohtsuka, M., Maruyama, T. and Mizushima, T.
  • Journal Title: Drug Metab. Pharmacokinet Volume: 28 Pages: 118-124
• [Journal Article] Suppression of UV-induced wrinkle formation by induction of HSP70 expression in mice (2013)
  • Author(s): Matsuda, M., Hoshino, T., Yamakawa, N., Tahara, K., Adachi, H., Sobue, G., Maji, D., Ihn, H. and Mizushima, T.
  • Journal Title: J. Invest. Dermatol. Volume: 113 Pages: 19-28
  • DOI: 10.1038/jid.2012.383
• [Journal Article] Attenuation of acetic acid-induced gastric ulcer formation in rats by glucosylceramide synthase inhibitors (2013)
  • Author(s): Nakashita, M., Suzuki, H., Miura, S., Taki, T., Uehara, K., Mizushima, T., Nagata, H. and Hibi, T.
  • Journal Title: Dig. Dis. Sci. Volume: 58 Pages: 354-362
  • DOI: 10.1007/s10620-012-2350-x
• [Journal Article] Expression of 150-kDa oxygen-regulated protein (ORP150) stimulates bleomycin-induced pulmonary fibrosis and dysfunction in mice (2012)
  • Author(s): Tanaka, K., Shirai, A., Ito, Y., Namba, T., Tahara, K., Yamakawa, N. and Mizushima, T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 425 Pages: 818-824
  • DOI: 10.1016/j.bbrc.2012.07.158
• [Journal Article] Identification of a unique NSAID, fluoro-loxoprofen with gastroprotective activity (2012)
  • Author(s): Suemasu, S., Yamakawa, N., Ishihara, T., Asano, T. Tahara, K., Tanaka, K., Matsui, M., Okamoto, Y., Otsuka, M., Takeuchi, K., Suzuki, S. and Mizushima, T.
  • Journal Title: Biochem. Pharmacol. Volume: 84 Pages: 1470-1481
  • DOI: 10.1016/j.bcp.2012.09.016
• [Journal Article] Effects of lecithinized superoxide dismutase and/or pirfenidone against bleomycin-induced pulmonary fibrosis (2012)
  • Author(s): Tanaka, K., Azuma, A., Miyazaki, Y., Sato, K. and Mizushima, T.
  • Journal Title: Chest Volume: 142 Pages: 1011-1019
• [Journal Article] Development of NSAIDs with lower gastric side effect (2012)
  • Author(s): Mizushima, T
  • Journal Title: Frontier of Gastrointestinal Research Volume: 30 Pages: 71-78
  • DOI: 10.1159/000338396
• [Journal Article] Synthesis and biological evaluation of derivatives of 2-{2-fluoro-4-[(2-oxocyclopentyl)methyl ]phenyl}propanoic acid : Non-steroidal anti-inflammatory drugs with low gastric ulcerogenic activity (2012)
  • Author(s): Yamakawa, N., Suemasu, S., Okamoto, Y., Tanaka, K., Ishihara, T., Asano, T., Miyata, k., Ohtsuka, M. and Mizushima, T.
  • Journal Title: J. Med. Chem. Volume: 55 Pages: 5143-5150
  • DOI: 10.1021/jm300049g2012
• [Journal Article] Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice (2012)
  • Author(s): Tanaka, K., Sato, K., Aoshiba, K., Azuma, A. and Mizushima, T.
  • Journal Title: Am. J. Physiol. Lung Cell. Mol. Physiol. Volume: 302 Pages: L1250-L1261
  • DOI: 10.1152/ajplung.00019.2012
• [Journal Article] Effects ofβ-(1,3-1,6)-D-glucan on irritable bowel syndrome-related colonic hypersensitivity (2012)
  • Author(s): Asano, T., Tanaka, K. Suemasu, S., Ishihara, T., Tahara, K., Suzuki, T., Suzuki, H., Fukudo, S. and Mizushima, T.
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 420 Pages: 444-449
  • DOI: 10.1016/j.bbrc.2012.03.015
• [Journal Article] purification and characterization of hsp-inducers from eupatorium lindleyanum (2012)
  • Author(s): Yamashita, Y., Ikeda, T., Matsuda, M., Maji, D., Hoshino, T. and Mizushima, T.
  • Journal Title: Biochem. Pharmacol. Volume: 82 Pages: 909-922
• [Journal Article] Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP_4 receptor (2012)
  • Author(s): Hoshino, T., Namba, T., Takehara, M., Murao, N., Sugimoto, Y., Narumiya, S., Matsushima, T., Suzuki, T. and Mizushima, T.
  • Journal Title: J. Neurochem. Volume: 120 Pages: 795-805
  • DOI: 10.1111/j.1471-4159.2011.07567
• [Journal Article] Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities
  • Author(s): Yamashita, Y., Tanaka, K., Asano, T., Yamakawa, N., Kobayashi D., Ishihara, T., Hanaya, K., Shoji, M., Sugai, T., Wada, M., Mashimo, T., Fukunishi, Y. and Mizushima, T.
  • Journal Title: Bioorg. & Medic. Chem. Volume: (in press)
• [Journal Article] Ameliorative effect of mepenzolate bromide against pulmonary fibrosis
  • Author(s): Kurotsu, S., Tanaka, K., Niino, T., Sugizaki, T., Azuma, A., Suzuki, H. and Mizushima, T.
  • Journal Title: J. Pharmacol. Exp. Ther. Volume: (in press)