QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.140293v1 326/3/739    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Onozuka, H. Articles by Ohizumi, Y. Search for Related Content PubMed PubMed Citation Articles by Onozuka, H. Articles by Ohizumi, Y.

NEUROPHARMACOLOGY

Nobiletin, a Citrus Flavonoid, Improves Memory Impairment and Aβ Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences (H.O., A.N., K.M., T.Y., Y.O.), Division of Pharmacotherapy, Graduate School of Pharmaceutical Sciences (A.N., D.S., N.T., T.Y.), Department of Neurological Science, Graduate School of Medicine (R.-W.S.), and Research Center of Supercritical Fluid Technology, Graduate School of Engineering (Y.O.), Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan; Molecular Medical Science Institute, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan (K.O.); Laboratory of Medicinal Plant Science, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo, Japan (A.Y., Y.S., Y.M.); and Yokohama College of Pharmacy, Tozuka-ku, Yokohama, Japan (Y.O.)

Increasing evidence suggests that the elevation of β-amyloid (Aβ) peptides in the brain is central to the pathogenesis of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, enhances cAMP/protein kinase A/extracellular signal-regulated kinase/cAMP response element-binding protein signaling in cultured hippocampal neurons and ameliorates Aβ-induced memory impairment in AD model rats. For the first time, we report that this natural compound improves memory deficits in amyloid precursor protein (APP) transgenic mice that overexpress human APP695 harboring the double Swedish and London mutations [APP-SL 7-5 transgenic (Tg) mice]. Our enzyme-linked immunosorbent assay (ELISA) also showed that administration of nobiletin to the transgenic mice for 4 months markedly reduced quantity of guanidine-soluble Aβ_1–40 and Aβ_1–42 in the brain. Furthermore, consistent with the results of ELISA, by immunohistochemistry with anti-Aβ antibody, it was evidently shown that the administration of nobiletin decreased the Aβ burden and plaques in the hippocampus of APP-SL 7-5 Tg mice. These findings suggest that this natural compound has potential to become a novel drug for fundamental treatment of AD.

Address correspondence to: Dr. Tohru Yamakuni, Division of Pharmacotherapy, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: yamakuni{at}mail.pharm.tohoku.ac.jp