title: Nobiletin, a citrus flavonoid, ameliorates cognitive impairment, oxidative burden, and hyperphosphorylation of tau in senescence-accelerated mouse.
abstract: Senescence-accelerated mouse prone 8 (SAMP8) is a model of aging characterized by the early onset of learning and memory impairment and various pathological features of Alzheimer's disease (AD). Our recent studies have demonstrated that nobiletin, a polymethoxylated flavone from citrus peels, ameliorates learning and memory impairment in olfactory-bulbectomized mice, amyloid precursor protein transgenic mice, and NMDA receptor antagonist-treated mice. Here, we present evidence that this natural compound improves age-related cognitive impairment and reduces oxidative stress and tau phosphorylation in SAMP8 mice. Treatment with nobiletin (10 or 50mg/kg) reversed the impairment of recognition memory and context-dependent fear memory in SAMP8 mice. Treatment with nobiletin also restored the decrease in the GSH/GSSG ratio in the brain of SAMP8 mice. In addition, increases in glutathione peroxidase and manganese-superoxide dismutase activities, as well as a decrease in protein carbonyl level, were observed in the brain of nobiletin-treated SAMP8 mice. Furthermore, nobiletin reduced tau phosphorylation in the hippocampus of SAMP8 mice. Together, the markedly beneficial effects of nobiletin represent a potentially useful treatment for ameliorating the learning and memory deficits, oxidative stress, and hyperphosphorylation of tau in aging as well as age-related neurodegenerative diseases such as AD.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Graduate School of Medicine, Nagoya University, Tsuruma-cho, Showa-ku, Nagoya 466-8560, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakajima
authors.forename: Yuki
authors.initials: Y
authors.lastname: Aoyama
authors.forename: Thuy-Ty Lan
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Yamada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakai
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokosuka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Mimaki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohizumi
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000188:drug therapy*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005239:Fear / Q000187:drug effects / Q000502:physiology; D047309:Flavones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D050050:Protein Carbonylation / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D047309:Flavones; D016875:tau Proteins; C008661:nobiletin; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005978:Glutathione