1997 Fiscal Year Annual Research Report

アルツハイマー型老年期痴呆動物モデルの作製

Research Project

Project/Area Number	07557009
Research Institution	Nagoya University
Principal Investigator	鍋島俊隆名古屋大学, 医学部, 教授 (70076751)
Co-Investigator(Kenkyū-buntansha)	斎藤健一三菱化学株式会社, 主任研究員長谷川高明名古屋大学, 医学部, 助教授 (80198720)
Keywords	アルツハイマー型痴呆 / β-アミロイド蛋白 / 学習・記憶 / モデル動物 / アセチルコリン / 神経伝達 / 治療薬
Research Abstract	補助金を交付された期間(平成7〜9年度)に我々が得た知見は以下の通りである。 β-アミロイド蛋白(Aβ)を2週間脳室内へ持続的に注入されたラットでは、・学習・記憶が障害されていた。・学習・記憶に重要な役割を果たしている大脳皮質及び海馬において、Aβが沈着していた、また、アセチルコリン合成酵素活性が低下していた。海馬においてグリオーシスの指標であるglial fibrillary acidic proteinの免疫化学的反応が増強していた。毛様体神経栄養因子の含量が大脳皮質、海馬及び小脳で増加していた。 in vivo brain-microdialysis法を用いて大脳皮質/海馬におけるアセチルコリン及び線条体におけるドパミンの遊離量を測定したところ、高カリウムあるいはニコチンにより刺激したときの遊離量の増加が低下していた。海馬錐体細胞においてニコチンに対する電気生理学的な反応性が低下していた。学習・記憶のメカニズムとして考えらる長期増強形成能が低下していた。海馬錐体細胞においてニコチンによるpaired-pulse facilitationの増強作用が低下していた。・学習・記憶改善作用を有するnefiracetam、propentofylline、アルギニンバソプレッシン誘導体、idebenoneおよびα-tocopherolの投与によりこのラットにおける学習・記憶障害が改善された。以上の結果は、我々が開発した手法により臨床像に非常に類似したアルツハイマー型痴呆の動物モデルが作製可能であることおよびこのモデル動物を使用することにより抗痴呆薬の評価が可能であることを示しており、新規のアルツハイマー型痴呆治療薬の開発に大きく貢献するものと思われる。

Research Products
(35 results)

All Other

All Publications (35 results)

[Publications] Eguchi et al.: "Effects of MCI-225 on memory and glucose utilization in basal forebrain-lesioned rats." Pharmacol.Biochem.Behav.51. 935-939 (1995)
[Publications] Yamada et al.: "Role of nitric oxide in learning and memory and in monoamine metabolism in the rat brain." Br.J.Pharmacol.115. 852-858 (1995)
[Publications] Yamada et al.: "Decresed interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer-type dementia." Neurosci.Lett.186. 219-221 (1995)
[Publications] Yamada et al.: "Changes in ciliary neurotrophic factor content in the rat brain after continuous intracerebroventricular infusion of β-amyloid(1-40)protein." Neurosci.Lett.201. 155-158 (1995)
[Publications] 鍋島俊隆: "アルツハイマー型老年期痴呆に対する神成長因子戦略とモデル動物の作製" 薬学雑誌. 115. 499-512 (1995)
[Publications] 鍋島俊隆: "アルツハイマー型痴呆モデル動物" Bio.Clinica. 10. 688-691 (1995)
[Publications] 鍋島俊隆: "アルツハイマー病モデル動物作製の試み" 日本神経精神薬理学雑誌. 15. 411-418 (1995)
[Publications] 野田幸裕、鍋島俊隆: "抗痴呆薬の開発と今後" 臨床と研究. 72. 2746-2750 (1995)
[Publications] 吉田維志ら: "アルツハイマー型痴呆治療薬の開発状況" Dementia. 9. 233-245 (1995)
[Publications] Bessho et al.: "Effects of the novel high affinity choline uptake enhancer 2-(2-oxopyrrolidin-l-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)'acetoamide on deficits of water maze learning in rats." Arzneim.-Forsch./Drug Res.46. 369-373 (1996)
[Publications] Itoh et al.: "Dysfunction of cholinergic and dopaminergic neuronal systems in β-amyloid protein-infused rats." J.Neurochem.66. 1113-1117 (1996)
[Publications] Nitta et al.: "Age-related changes in learning and memory and cholinergic neuronal function in senescence aceelerated mice(SAM)." Behav.Brain.Res.72. 49-55 (1996)
[Publications] Nitta et al.: "Propentofylline prevents neuronal dysfunction induced by infusion of anti-nerve growth factor antibody into the rat septum." Eur.J.Pharmacol.307. 1-6 (1996)
[Publications] Yamada et al.: "Reduction in the number of NADPH-diaphorase'-positive cells in the cerebral cortex and striatum in aged rats." Neurosci.Res.24. 393-402 (1996)
[Publications] Yamada et al.: "Role of nitric oxide and cyclic GMP in the dizocilpine-induced impairment of spontaneous alternation behavior in mice." Neuroscience. 74. 365-374 (1996)
[Publications] Yamada et al.: "The role of nitric oxide in dizocilpine-induced impairment of spontaneous alternation behavior in mice." J.Pharmacol.Exp.Ther.276. 460-466 (1996)
[Publications] 鍋島俊隆: "β-アミロイド蛋白によるアルツハイマー病動物モデル" 老年期痴呆研究会誌. 9. 34-38 (1996)
[Publications] 新田淳美、鍋島俊隆: "抗痴呆薬開発のための実験手技(10)β-アミロイド蛋白による痴呆動物モデル" 日本神経精神薬理学雑誌. 16. 85-90 (1996)
[Publications] Eguchi et al.: "MCI-225,a novel thienopyrimidine analog,enhances attentional eye tracking in midpontine pretrigeminal preparation." Pharmacol.Biochem.Behav.56. 229-234 (1997)
[Publications] Itoh et al.: "Effects of metrifonate on impairment of learning and dysfunction of cholinergic neuronal system in basal forebrain-lesioned rats." Behav.Brain Res.83. 165-167 (1997)
[Publications] Itoh et al.: "Effects of metrifonate on memory impairment and cholinergic dysfunction in rats." Eur.J.Pharmacol.322. 11-19 (1997)
[Publications] Miyagawa et al.: "Dissociation of impairment between spatial memory,and motor function and emotional behavior in aged rats." Behav.Brain.Res.1997(in press).
[Publications] Nabeshima and Itoh.: "Alzheimer's disease animal models induced by continuous infusion of Beta-amyloid protein and anti-nerve growth factor antibody." Rev.Heteroatom Chem.16. 229-255 (1997)
[Publications] Nitta et al.: "Oral administration of propentofylline,a stimulator of nerve growth factor(NGF)synthesis,recovers cholinergic neuronal dysfunction induced by the infusion of anti-NGF antibody into the rat septum." Behav.Brain Res.83. 201-204 (1997)
[Publications] Nitta et al.: "Continuous infusion of β-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration." Jpn.J.Pharmacol.73. 51-57 (1997)
[Publications] Noda et al.: "Role of nitric oxide in the effect of aging on spatial memory in rats." Behav.Brain Res.83. 153-158 (1997)
[Publications] Yamada et al.: "No changes in cerebrospinal fluid levels of nitrite,nitrate and cyclic GMP with aging." J.Neural Transm.104. 825-831 (1997)
[Publications] Yamada et al.: "Orally active NGF synthesis stimulators:potential therapeutic agents in Alzheimer's disease." Behav.Brain Res.83. 117-122 (1997)
[Publications] 鍋島俊隆: "特集『"アルツハイマー病"の分子生物学』β-アミロイド蛋白の複雑さ9)β-アミロイド蛋白脳内注入ラット" Brain Medical. 9. 383-388 (1997)
[Publications] 鍋島俊隆: "抗痴呆薬の現状の展望" Ther.Res.18. 3171-3177 (1997)
[Publications] 鍋島俊隆: "抗痴呆薬の開発と現状" ファルマシア. 33. 1228-1234 (1997)
[Publications] 野田幸裕、鍋島俊隆: "アルツハイマー病治療薬開発の現状" Geriat.Med.35. 61-66 (1997)
[Publications] 山田清文: "学習記憶過程における一酸化窒素の役割" Folia Pharmacol.Jpn.111. 87-96 (1998)
[Publications] Yamada et al.: "Propentofylline improves learning and memory deficits in rats induced by β-amyloid protein(1-40)" Eur.J.Pharmacol.(in press). (1998)
[Publications] Nabeshima and Itoh: "Alzheimer's Disease:Biology,Diagnosis and Therapeutics" Ed.by K.Iqbal B.Winblad T. Nishimura M.Takeda and H.M.Wisniewski,John Wiley & Sons Ltd, 7 (1997)

1997 Fiscal Year Annual Research Report

アルツハイマー型老年期痴呆動物モデルの作製

Principal Investigator

鍋島 俊隆 名古屋大学, 医学部, 教授 (70076751)

Research Products

[Publications] Eguchi et al.: "Effects of MCI-225 on memory and glucose utilization in basal forebrain-lesioned rats." Pharmacol.Biochem.Behav.51. 935-939 (1995)

[Publications] Yamada et al.: "Role of nitric oxide in learning and memory and in monoamine metabolism in the rat brain." Br.J.Pharmacol.115. 852-858 (1995)

[Publications] Yamada et al.: "Decresed interleukin-6 level in the cerebrospinal fluid of patients with Alzheimer-type dementia." Neurosci.Lett.186. 219-221 (1995)

[Publications] Yamada et al.: "Changes in ciliary neurotrophic factor content in the rat brain after continuous intracerebroventricular infusion of β-amyloid(1-40)protein." Neurosci.Lett.201. 155-158 (1995)

[Publications] 鍋島俊隆: "アルツハイマー型老年期痴呆に対する神成長因子戦略とモデル動物の作製" 薬学雑誌. 115. 499-512 (1995)

[Publications] 鍋島俊隆: "アルツハイマー型痴呆モデル動物" Bio.Clinica. 10. 688-691 (1995)

[Publications] 鍋島俊隆: "アルツハイマー病モデル動物作製の試み" 日本神経精神薬理学雑誌. 15. 411-418 (1995)

[Publications] 野田幸裕、鍋島俊隆: "抗痴呆薬の開発と今後" 臨床と研究. 72. 2746-2750 (1995)

[Publications] 吉田維志ら: "アルツハイマー型痴呆治療薬の開発状況" Dementia. 9. 233-245 (1995)

[Publications] Bessho et al.: "Effects of the novel high affinity choline uptake enhancer 2-(2-oxopyrrolidin-l-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-yl)'acetoamide on deficits of water maze learning in rats." Arzneim.-Forsch./Drug Res.46. 369-373 (1996)

[Publications] Itoh et al.: "Dysfunction of cholinergic and dopaminergic neuronal systems in β-amyloid protein-infused rats." J.Neurochem.66. 1113-1117 (1996)

[Publications] Nitta et al.: "Age-related changes in learning and memory and cholinergic neuronal function in senescence aceelerated mice(SAM)." Behav.Brain.Res.72. 49-55 (1996)

[Publications] Nitta et al.: "Propentofylline prevents neuronal dysfunction induced by infusion of anti-nerve growth factor antibody into the rat septum." Eur.J.Pharmacol.307. 1-6 (1996)

[Publications] Yamada et al.: "Reduction in the number of NADPH-diaphorase'-positive cells in the cerebral cortex and striatum in aged rats." Neurosci.Res.24. 393-402 (1996)

[Publications] Yamada et al.: "Role of nitric oxide and cyclic GMP in the dizocilpine-induced impairment of spontaneous alternation behavior in mice." Neuroscience. 74. 365-374 (1996)

[Publications] Yamada et al.: "The role of nitric oxide in dizocilpine-induced impairment of spontaneous alternation behavior in mice." J.Pharmacol.Exp.Ther.276. 460-466 (1996)

[Publications] 鍋島俊隆: "β-アミロイド蛋白によるアルツハイマー病動物モデル" 老年期痴呆研究会誌. 9. 34-38 (1996)

[Publications] 新田淳美、鍋島俊隆: "抗痴呆薬開発のための実験手技(10)β-アミロイド蛋白による痴呆動物モデル" 日本神経精神薬理学雑誌. 16. 85-90 (1996)

[Publications] Eguchi et al.: "MCI-225,a novel thienopyrimidine analog,enhances attentional eye tracking in midpontine pretrigeminal preparation." Pharmacol.Biochem.Behav.56. 229-234 (1997)

[Publications] Itoh et al.: "Effects of metrifonate on impairment of learning and dysfunction of cholinergic neuronal system in basal forebrain-lesioned rats." Behav.Brain Res.83. 165-167 (1997)

[Publications] Itoh et al.: "Effects of metrifonate on memory impairment and cholinergic dysfunction in rats." Eur.J.Pharmacol.322. 11-19 (1997)

[Publications] Miyagawa et al.: "Dissociation of impairment between spatial memory,and motor function and emotional behavior in aged rats." Behav.Brain.Res.1997(in press).

[Publications] Nabeshima and Itoh.: "Alzheimer's disease animal models induced by continuous infusion of Beta-amyloid protein and anti-nerve growth factor antibody." Rev.Heteroatom Chem.16. 229-255 (1997)

[Publications] Nitta et al.: "Oral administration of propentofylline,a stimulator of nerve growth factor(NGF)synthesis,recovers cholinergic neuronal dysfunction induced by the infusion of anti-NGF antibody into the rat septum." Behav.Brain Res.83. 201-204 (1997)

[Publications] Nitta et al.: "Continuous infusion of β-amyloid protein into the rat cerebral ventricle induces learning impairment and neuronal and morphological degeneration." Jpn.J.Pharmacol.73. 51-57 (1997)

[Publications] Noda et al.: "Role of nitric oxide in the effect of aging on spatial memory in rats." Behav.Brain Res.83. 153-158 (1997)

[Publications] Yamada et al.: "No changes in cerebrospinal fluid levels of nitrite,nitrate and cyclic GMP with aging." J.Neural Transm.104. 825-831 (1997)

[Publications] Yamada et al.: "Orally active NGF synthesis stimulators:potential therapeutic agents in Alzheimer's disease." Behav.Brain Res.83. 117-122 (1997)

[Publications] 鍋島俊隆: "特集『"アルツハイマー病"の分子生物学』β-アミロイド蛋白の複雑さ9)β-アミロイド蛋白脳内注入ラット" Brain Medical. 9. 383-388 (1997)

[Publications] 鍋島俊隆: "抗痴呆薬の現状の展望" Ther.Res.18. 3171-3177 (1997)

[Publications] 鍋島俊隆: "抗痴呆薬の開発と現状" ファルマシア. 33. 1228-1234 (1997)

[Publications] 野田幸裕、鍋島俊隆: "アルツハイマー病治療薬開発の現状" Geriat.Med.35. 61-66 (1997)

[Publications] 山田清文: "学習記憶過程における一酸化窒素の役割" Folia Pharmacol.Jpn.111. 87-96 (1998)

[Publications] Yamada et al.: "Propentofylline improves learning and memory deficits in rats induced by β-amyloid protein(1-40)" Eur.J.Pharmacol.(in press). (1998)

[Publications] Nabeshima and Itoh: "Alzheimer's Disease:Biology,Diagnosis and Therapeutics" Ed.by K.Iqbal B.Winblad T. Nishimura M.Takeda and H.M.Wisniewski,John Wiley & Sons Ltd, 7 (1997)

鍋島俊隆名古屋大学, 医学部, 教授 (70076751)