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2004 Fiscal Year Annual Research Report

シナプス蛋白のチロシンニトロ化による脳機能障害

Research Project

Project/Area Number 14370031
Research InstitutionNagoya University

Principal Investigator

鍋島 俊隆  名古屋大学, 医学部附属病院, 教授 (70076751)

Co-Investigator(Kenkyū-buntansha) 新田 淳美  名古屋大学, 医学部附属病院, 助教授 (20275093)
山田 清文  金沢大学, 大学院・自然科学研究科, 教授 (30303639)
Keywordsβアミロイド / アルツハイマー病 / 一酸化窒素 / 誘導型NO合成酵素 / チロシンニトロ化 / シナプトフィジン / インターロイキン-1β / 腫瘍壊死因子
Research Abstract

本研究課題では、アルツハイマー病の原因物質と考えられるβアミロイドを脳室内へ持続注入したラットにおける脳機能障害のメカニズムを検討した。本年度は、βアミロイドを注入したラットの海馬切片における長期増強(LTP)の障害とニコチン受容体機能との関係を検討した。その結果、(1)βアミロイドを注入したラットの海馬ではα7ニコチン性アセチルコリン受容体(α7-nAChR)アゴニストに対する反応性が低下した。(2)α7-nAChRアンタゴニストは正常動物の海馬LTPを障害した。(3)α7-nAChRアゴニストの前処置はβアミロイド注入ラットのLTPの障害を改善した。したがって、βアミロイドにより誘発されるLTPの障害にはα7-nAChRの機能障害が関係しており、このニコチン受容体サブユニットがアルツハイマー病治療薬の標的分子となることが示唆された。さらに、βアミロイドを海馬内に注入したラットの短期記憶障害に対するアルツハイマー病治療薬ドネペジルとメマンチンの効果について、delayed matching to position (DMTP)課題を用いて調べた。その結果、(4)βアミロイド注入ラットは遅発性で持続性の短期記憶障害を示した。(5)弱いNMDA受容体アンタゴニスト作用を有するメマンチンはβアミロイドによる短期記憶障害の形成を抑制し、(6)アセチルコリンエステラーゼ阻害薬であるドネペジルは短期記憶障害を一時的に改善した。以上の結果より、βアミロイドにより誘発される記憶障害に対するNMDA受容体アンタゴニストの有効性が示唆された。

  • Research Products

    (42 results)

All 2005 2004 Other

All Journal Article (39 results) Book (1 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Role of tumor necrosis factor-α in down-regulation of hepatic cytochrome P450 and P-glycoprotein by endotoxin.2005

    • Author(s)
      Miyoshi M et al.
    • Journal Title

      Eur J Pharmacol. 507

      Pages: 229-237

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages.2005

    • Author(s)
      Hashimoto M et al.
    • Journal Title

      J Neurosci Res. 79

      Pages: 476-487

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor.2005

    • Author(s)
      Miyamoto, Y. et al.
    • Journal Title

      J.Neurosci. 25(7)

      Pages: 1826-1835

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The role of tissue plasminogen activator in methamphetamine-related reward and sensitization.2005

    • Author(s)
      Nagai T et al.
    • Journal Title

      J Neurochem. 92(3)

      Pages: 660-667

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Molecular mechanism of amyloid β-peptide-induced impairment of neurotransmission and memory in relation to oxidative stress.2005

    • Author(s)
      Yamada, K. et al.
    • Journal Title

      Progress in Alzheimer's and Parkinson's Disease (in press)

  • [Journal Article] Amyloid pathology and protein kinase C(PKC) : possible therapeutic effects of PKC activators.2005

    • Author(s)
      Olariu A et al.
    • Journal Title

      J Pharmacol Sci. 97

      Pages: 1-5

  • [Journal Article] Behavioural adaptations to addictive drugs in mice lacking the NMDA receptor ε1 subunit.2004

    • Author(s)
      Miyamoto Y. et al.
    • Journal Title

      Eur J Neurosci. 19

      Pages: 151-158

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Enhanced antidepressant efficacy of σ1 receptor agonists in rats after chronic intracerebroventricular infusion of β-amyloid-(1-40) protein.2004

    • Author(s)
      Urani A. et al.
    • Journal Title

      Eur J Pharmacol. 486

      Pages: 151-161

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The modulator role of the hypothalamic paraventricular nucleus on immune responsiveness.2004

    • Author(s)
      Hefco V. et al.
    • Journal Title

      Brain Behav Immun. 18

      Pages: 158-165

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Role of tumor necrosis factor-α in methamphetamine-induced drug dependence and neurotoxicity.2004

    • Author(s)
      Nakajima A. et al.
    • Journal Title

      J Neurosci. 24

      Pages: 2212-2225

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release.2004

    • Author(s)
      Nagai T et al.
    • Journal Title

      Proc Natl Acad Sci USA. 101

      Pages: 3650-3655

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Insulin-like growth factor 1 prevents neuronal cell death induced by corticosterone through activation of the PI3k/Akt pathway.2004

    • Author(s)
      Nitta A et al.
    • Journal Title

      J Neurosci Res. 76

      Pages: 98-103

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Axonal regrowth downregulates the synthesis of glial cell line-derived neurotrophic factor in the lesioned rat sciatic nerve.2004

    • Author(s)
      Yamada Y et al.
    • Journal Title

      Neurosci Lett. 364

      Pages: 11-15

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Molecular mechanisms in dizocilpine-induced attenuation of development of morphine dependence : an association with cortical Ca^<2+>/calmodurin-dependent signal cascade.2004

    • Author(s)
      Hamdy.M.et al.
    • Journal Title

      Behav.Brain.Res. 152(2)

      Pages: 263-270

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Effects of nicotine on stress response in mice.2004

    • Author(s)
      Zeng, N. et al.
    • Journal Title

      Jpn.J.Neuropsychopharmacol. 24

      Pages: 313

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Tissue plasminogen activator (t-PA) is involved in morphine-induced rewarding effects.2004

    • Author(s)
      Yan, Y.et al.
    • Journal Title

      Jpn.J.Neuropsychopharmacol. 24

      Pages: 314

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cyclic AMP/protein kinase a signal attenuates Ca(2+)-induced fibroblast growth factor-1 synthesis in rat cortical neurons.2004

    • Author(s)
      Kinukawa H. et al.
    • Journal Title

      J Neurosci Res. 77

      Pages: 487-497

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Anatomical substrates for the discriminative stimulus effects of methamphetamine in rats.2004

    • Author(s)
      Nakajima, A. et al.
    • Journal Title

      J.Neurochem. 91(2)

      Pages: 308-317

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Hydrophobic dipeptide Leu-Ile protects against neuronal death by inducing brain-delivered neurotrophic factor and glial cell line-derived neurotrophic factor synthesis.2004

    • Author(s)
      Nitta A. et al.
    • Journal Title

      J Neurosci Res. 78

      Pages: 250-258

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The interaction between the cholinergic and dopaminergic system in learning and memory process in rats.2004

    • Author(s)
      Hefco V. et al.
    • Journal Title

      Rom J Physiol. 41

      Pages: 21-30

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] β-Amyloid(1-42)-induced learning and memory deficits in mice : involvement of oxidative burdens in the hippocampus and cerebral cortex.2004

    • Author(s)
      Jhoo.J.H.et al.
    • Journal Title

      Behav Brain Res. 155

      Pages: 185-196

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Role for brain-derived neurotrophic factor in learning and memory.2004

    • Author(s)
      Yamada, K. et al.
    • Journal Title

      Life Sci.Minireview 70

      Pages: 735-744

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Interaction of BDNF/TRKB signaling NMDA receptors in Learning and Memory.2004

    • Author(s)
      Yamada, K. et al.
    • Journal Title

      Drug News Perspect 17

      Pages: 435-438

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] 気分障害治療の新規ターゲットタンパク質2004

    • Author(s)
      野田幸裕 ほか
    • Journal Title

      Bioベンチャー別刷 11-12月号

      Pages: 31-35

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors.2004

    • Author(s)
      Mizoguchi, H. et al.
    • Journal Title

      Mol.Pharmacol. 65(5)

      Pages: 1293-1301

  • [Journal Article] N-Propargyl-1 (R)-aminoindan, rasagiline, increases glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma SH-SY5Y cells through activation of NF-κB transcription factor.2004

    • Author(s)
      Maruyama, W. et al.
    • Journal Title

      Neurochem.Int. 44(6)

      Pages: 393-400

  • [Journal Article] A neuroactive steroid dehydroepiandrosterone sulfate prevents the development of morphine dependence and tolerance linked to the extracellular signal-regulated protein kinase.2004

    • Author(s)
      Ren, X.et al.
    • Journal Title

      Behav.Brain.Res. 152(2)

      Pages: 243-250

  • [Journal Article] Nitric oxide in learning and memory.2004

    • Author(s)
      Yamada, K et al.
    • Journal Title

      Memories are made of These : From Messengers to Molecules

      Pages: 480-491

  • [Journal Article] Oxidative Stress Mechanism of Amyloid β-Peptide-Induced Impairment of Neurotransmission and Memory.2004

    • Author(s)
      Nabeshima T. et al.
    • Journal Title

      Methods Find Exp Clin Pharmacol. (supple.2)

      Pages: 29-31

  • [Journal Article] Learning and Memory Alzheimer's Disease and Dementia.2004

    • Author(s)
      Yamada, K. et al.
    • Journal Title

      Methods Find Exp Clin Pharmacol. (supple.2)

      Pages: 55-64

  • [Journal Article] Continuous infusion of GDNF can recover the functional damaged following the spinal cord transaction.2004

    • Author(s)
      Nitta A. et al.
    • Journal Title

      Methods Find Exp Clin Pharmacol. (supple.2)

      Pages: 83

  • [Journal Article] Nootropic nefiracetam inhibits proconvulsant action of peripheral-type benzodiazepines in epileptic mutant EL mice.2004

    • Author(s)
      Nakamoto, Y. et al.
    • Journal Title

      Current Status of Drug Dependence/Abuse Studies 1025

      Pages: 135-139

  • [Journal Article] α7-type nicotine acetylcholine receptor and prodynorphin mRNA expression after administration of (-)-nicotine and U-50, 488H in β-amyloid peptide (25-35)-treated mice.2004

    • Author(s)
      Hiramatsu, M. et al.
    • Journal Title

      Current Status of Drug Dependence/Abuse Studies 1025

      Pages: 508-514

  • [Journal Article] Opiate physical dependence and N-methyl-D-aspartate2004

    • Author(s)
      Noda Y et al.
    • Journal Title

      EJP Special Celebratory 500

      Pages: 121-128

  • [Journal Article] フェンシクリジンによるNMDA受容体機能障害と統合失調症モデル2004

    • Author(s)
      毛利彰宏 ほか
    • Journal Title

      分子精神医学 Vol.4

      Pages: 52-56

  • [Journal Article] 神経栄養因子産生誘導化合物の糖尿病誘発神経変性疾患などの治療薬としての可能性2004

    • Author(s)
      新田淳美 ほか
    • Journal Title

      日薬理誌 124

      Pages: 119-120

  • [Journal Article] Molecular mechanism of amyloid β-peptide-induced impairment of neurotransmission and memory in relation to oxidative stress.

    • Author(s)
      Yamada, K. et al.
    • Journal Title

      Progress in Alzheimer's and Parkinson's Disease (in press)

  • [Journal Article] Age-related expression of O_1 receptor and antidepressant efficacy of a selective agonist in the senescence-accelerated (SAM) mouse.

    • Author(s)
      Phan V-L et al.
    • Journal Title

      J Neurosci Res. (in press)

  • [Journal Article] Effects of memantine and donepezil on amyloid β-induced memory impairment in a delayed-matching to position task in rats.

    • Author(s)
      Yamada K et al.
    • Journal Title

      Behav Brain Res. (in press)

  • [Book] 脳と心に効く薬を創る2004

    • Author(s)
      鍋島俊隆
    • Total Pages
      110
    • Publisher
      岩波書店(東京)
    • Description
      「研究成果報告書概要(和文)」より
  • [Patent(Industrial Property Rights)] Akt刺激薬2005

    • Inventor(s)
      新田淳美, 鍋島俊隆
    • Industrial Property Rights Holder
      新田淳美
    • Industrial Property Number
      特願2005-51829
    • Filing Date
      2005-02-25
  • [Patent(Industrial Property Rights)] 薬物依存関連遺伝子2005

    • Inventor(s)
      新田淳美, 鍋島俊隆
    • Industrial Property Rights Holder
      新田淳美
    • Industrial Property Number
      特願2005-59518
    • Filing Date
      2005-03-03

URL: 

Published: 2006-07-12   Modified: 2016-04-21  

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