Pharmacological studies in the animal model for Alzheimer' s disease with life-style related disease

• Project/Area Number: 17500266
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: FUKUOKA UNIVERSITY
• Principal Investigator: IWASAKI Katsunori Fukuoka University, Pharmaceutical Science, Professor, 薬学部, 助教授 (10183196)
• Co-Investigator(Kenkyū-buntansha): FUJIWARA Michihiro Fukuoka University, Pharmaceutical Science, Professor, 薬学部, 教授 (10091331) ; MISHIMA Kenichi Fukuoka University, Pharmaceutical Science, Assistant Professor, 薬学部, 助手 (00320309) ; EGASHIRA Nobuaki Fukuoka University, Pharmaceutical Science, Assistant Professor, 薬学部, 助手 (80352269)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
• Keywords: Alzheimer's disease / cerebrovascular disease / insulin resistance / amyloid / microdomain / life-style related disease

Research Abstract

The amyloid cascade hypothesis of Alzheimer disease (AD) pathogenesis postulates that β-amyloid peptide (Aβ ) accumulation in critical brain regions was reported to contribute to memory impairment. In the present study, firstly, to elucidate the importance of structural and functional roles of Aβ, we investigated the degree of memory disturbances and hippocampal ACh release using oligomeric form of Aβ. Oligomeric Aβ injected in the brain of the rat which was subjected 10min cerebral ischemia caused significant memory disturbance in 8-arm radial maze task. The degree of the memory disturbances induced by oligomeric Aβ was rather strong than that induced by aggregated Aβ we previously reported. A microdialysis study showed that spontaneous release of acetylcholine (ACh) from dorsal hippocampus tended to decrease in oligomeric Aβ injected rats. The high potassium-evoked increase of hippocampal ACh release strongly decreased by oligomeric Aβ. We previously demonstrated aggregated A β induced apoptosis of CA1 cells of the hippocampus. But oligomeric A R did not induce apoptosis. In the next experiment, to classify the effect of diabetes mellitus on the memory disturbances in Aβ treated rats. Oligomeric AB injected to the diabetic Goto-Kakizaki (GK) rats showed the elevated glucose level and insulin resistance. The swimming time until the rats reached to the platform in Morris water maze task was increased in AB treated GK rats. These findings suggest that oligomeric form of Aβ may strongly affect the neurotransmitter mechanism by its neurotoxicity without showing cellular apoptosis. We represented the influence of life-style related disease such as cerebrovascular disease or diabetes mellitus affect the symptoms of AD using the animal models. These models may be useful for developing new drugs for AD.

Research Products

• [Journal Article] Comparison of Single- and Repeated-Ischemia-Induced Changes in Expression of Flip and Flop Splice Variants of AMPA Receptor Subtypes G1uR1 and GluR2 in the Rats Hippocampus CA1 Subregion. (2007)
  • Author(s): Hatip-Al-Khatib I, Iwasaki K, Egashira N, Ishibashi D, Mishima K, Fujiwara M
  • Journal Title: Journal of Pharmacological Sciences 103 Pages: 83-91
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Nilvadipine prevents the impairment of spatial memory induced by cerebral ischemia combined with be-ta-anyloid in rats. (2007)
  • Author(s): Iwasaki, K, Egashira N, Takagaki, Y, Yoshimitsu, Y, Hatip-Al-Khatib I, Mishima, K, Fujiwara, M
  • Journal Title: Biological ＆ Pharmacceutical Bulletin 30 Pages: 698-701
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Comparison of Single-and Repeated-Ischemia-Induced Changes in Expression of Flip and Flop Splice Variants of AMPA Receptor Subtypes GluR1 and GluR2 in the Rats Hippocampus CA1 Subregion. (2007)
  • Author(s): Hatip-Al-Khatib I, Iwasaki K, Egashira N, Ishibashi D, Mishima K, Fujiwara M.
  • Journal Title: Journal of Pharmacological Sciences 30 Pages: 698-701
  • NAID: 10024312106
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nilvadipine prevents the impairment of spatial memory induced by cerebral ischemia combined with be-ta-amyloid in rats. (2007)
  • Author(s): Iwasaki, K, Egashira N, Takagaki, Y, Yoshimitsu, Y, Hatip-Al-Khatib I, Mishima, K, Fujiwara, M
  • Journal Title: Biological ＆ Pharmacceutical Bulletin 30 Pages: 698-701
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Comparison of Single-and Repeated-Ischemia-Induced Changes in Expression of Flip and Flop Spice Variants of AMPA Receptor Subtypes GluR1 and GluR2 in the Rats Hippocampus CA1 Subregion (2007)
  • Author(s): Hatip-A1-Khatib I, Iwasaki K, Egashira N, Ishibashi D, Mishima K, Fujiwara M
  • Journal Title: J Pharmacol Sci. 103巻1号 Pages: 83-91
• [Journal Article] Cerebral ischemia combined with beta-amyloid impairs spatial memory in the eight-arm radial maze task in rats. (2006)
  • Author(s): Iwasaki, K, Egashira, N, Hatip-Al-Khatib, I, Akiyoshi, Y, Takagaki, Y, Watanabe, T, Mishima, K, Fujiwara,M
  • Journal Title: Brain Research 1097 Pages: 216-223
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cerebral ischemia combined with beta-amyloid impairs spatial memory in the eight-arm radial maze task in rats. (2006)
  • Author(s): Iwasaki, K, Egashira, N, Hatip-Al-Khatib, I, Akiyoshi, Y, Takagaki, Y, Watanabe, T, Mishima, K, Fujiwara, M
  • Journal Title: Brain Research 1097 Pages: 216-223
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cerebral ischemia combined with beta-amyloid impairs spatial memory in the eight-arm radial maze task in rats (2006)
  • Author(s): Iwasaki K, Egashira N, Hatip-Al-Khatibl, Akiyoshi Y, Arai T, Takagaki Y, Watanabe T, Mishima K, Fujiwara M
  • Journal Title: Brain Research 1097巻1号 Pages: 216-223
• [Journal Article] Investigation of mechanisms mediating 8-OH-DPAT-induced impairment of spatial memory : Involvement of 5-HT(IA)receptors in the dorsal hippocampus in rats. (2006)
  • Author(s): Egashira N, Yano A, Ishigami N, Mishima K, Iwasaki K, Fujioka M, Matsushita M, Nishimura R, Fujiwara M
  • Journal Title: Brain Research 1069巻1号 Pages: 54-62
• [Journal Article] Protective effect of Toki-shakuyaku-san on amyloid β25-35-induced neuronal damage in cultured rat cortical neurons (2005)
  • Author(s): Egashira, N, Iwasaki, K, Akiyoshi, Y, Takagaki, Y, Hatip-Al-Khatib, I, Mishima, K, Ikeda, T, Fujiwara,M
  • Journal Title: Phytotherapy Research 19 Pages: 450-453
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of oral administration of zanapezil (TAK-147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats (2005)
  • Author(s): Hatip-Al-Khatib, I, Iwasaki, K, Yoshimitsu, Y, Arai, T, Egashira, N, Mishima, K, Fujiwara,M
  • Journal Title: British Journal of Pharmacology 145 Pages: 1035-1044
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Altered depression-related behavior and neurochemical changes in serotonergic neurons in mutant R406W human tau transgenic mice (2005)
  • Author(s): Egashira, N, Iwasaki, K, Takashima, A, Watanabe, T, Kawabe, H, Matsuda, T, Mishima, K, Fujiwara,M
  • Journal Title: Brain Research 1059 Pages: 7-12
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Protective effect of Toki-shakuyaku-san on amyloid B325-35-induced neuronal damage in cultured rat cortical neurons Hatip-Al- (2005)
  • Author(s): Egashira, N, Iwasaki, K., Akiyoshi, Y, Takagaki, Y, Hatip-Al-Khatib, I, Mishima, K, Ikeda, T, Fujiwara, M
  • Journal Title: Phytotherapy Research 19 Pages: 450-453
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of oral administration of zanapezil (TAK-147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats (2005)
  • Author(s): Hatip-Al-Khatib, I, Iwasaki, K, Yoshimitsu, Y, Arai, T, Egashira, N, Mishima, K, Fujiwara.M
  • Journal Title: British Journal of Pharmacology 145 Pages: 1035-1044
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Altered depression-related behavior and neurochemical changes in serotonergic neurons in mutant R406W human tau transgenic mice (2005)
  • Author(s): Egashira, N, Iwasaki, K, Takashima, A, Watanabe, T, Kawabe, H, Matsuda, T, Mishima, K.Fujiwara, M
  • Journal Title: Brain Research 1059 Pages: 7-12
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 脳虚血とβ-アミロイド投与による新しいアルツハイマー病モデル動物の作成とニルバジピンの有効性 (2005)
  • Author(s): 岩崎克典, 江頭伸昭, 秋吉祐樹, 高垣祐紀, 新井 隆, 三島健一, 藤原道弘
  • Journal Title: Pharma Medica 23巻 Pages: 143-155
• [Journal Article] Protective effect of Toki-shakuyaku-san on amyloid β25-35-induced neuronal damage in cultured rat cortical neurons (2005)
  • Author(s): Nobuaki EGASHIRA, Katsunori IWASAKI, Yuki AKIYOSHI, Yuki TAKAGAKI, Izzettin AL-KHATI B, Kenichi MISHIMA, Kouji KURAUCHI, Tomoaki IKEDA, Michihiro FUJIWARA
  • Journal Title: Phytotherapy Research 19巻 Pages: 450-453
• [Journal Article] Effect of oral administration of zanapezil (TAK-147) for 21 days on acetylcholine and monoamines levels in the ventral hippocampus of freely moving rats (2005)
  • Author(s): Izzettin HATIP-AL-KHATIB, Katsunori IWASAKI, Yoshimitsu YOSHITAKA, Takashi ARAI, Nobuaki EGASHIRA, Kenichi MISHIMA, Tomoaki IKEDA, Michihiro FUJIWARA
  • Journal Title: British Journal of Pharmacology 145 Pages: 1035-1044
• [Journal Article] Altered depression-related behavior and neurochemical changes in serotonergic neurons in mutant R406W human tau transgenic mice (2005)
  • Author(s): Nobuaki EGASKIRA, Katsunori IWASAKI, Akihiko TAKASHIMA, Takuya WATANABE, Hideyuki KAWABE, Tomomi MATSUDA, Kenichi MISHIMA, Shozo CHIDORI, Ryoji NiSHIMURA, Michihiro FUJIWARA
  • Journal Title: Brain Research 1059 Pages: 2468-2474