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Development of novel therapeutic drugs for Alzheimer disease

Research Project

Project/Area Number 14572081
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionMeijo University

Principal Investigator

UKAI Makoto  Meijo University, Faculty of Pharmacy, Department of Chemical Pharmacology, Professor, 薬学部, 教授 (80131209)

Co-Investigator(Kenkyū-buntansha) MAMIYA Takayoshi  Meijo University, Faculty of Pharmacy, Department of Chemical Pharmacology, Assistant Professor, 薬学部, 助手 (70340297)
Project Period (FY) 2002 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,100,000 (Direct Cost: ¥1,100,000)
KeywordsOpioid peptides / Learning and memory / Alzheimer disease / mutant mice / phenylpropanoids / 植物由来 / 抗認知症薬 / Aβ誘発学習記憶障害モデル / κ-オピオイド受容体作動薬 / 新奇物質認知試験 / CaMKIIαサブユニット / タンパクリン酸化 / 記憶 / 痴呆 / 迷路 / オピオイド受容体 / オープンフィールド / 自発的交替行動 / 遺伝子改変動物 / 移所運動 / 神経ペプチド / アルツハイマー型痴呆 / エンドモルフィン / オピオイドペプチド / スコポラミン / 学習 / モノアミン
Research Abstract

1.The effects of naloxonazine, a mu(1)-opioid receptor antagonist, and physostigmine, a cholinesterase inhibitor, on the endomorphins-induced impairment of passive avoidance learning were investigated in mice. Endomorphin-1(10 microg) and endomorphin-2(10 microg) significantly impaired passive avoidance learning, while naloxonazine (35 mg/kg, s.c.), a mu(1)-opioid receptor antagonist, which alone failed to influence passive avoidance learning significantly inhibited the endomorphin-1(10 microg)- but not endomorphin-2(10 microg)-induced disturbance of such learning. A rather nonselective higher dose (50 mg/kg, s.c.) of naloxonazine almost completely antagonized the endomorphin-1(10 microg)- and endomorphin-2(10 microg)-induced impairment of passive avoidance learning. In contrast, physostigmine (0.025 and 0.05 mg/kg, i.p.) significantly reversed the endomorphin-1(10 microg)- and endomorphin-2(10 microg)-induced disturbance of passive avoidance learning, whereas physostigmine (0.025 and 0.05 mg/kg, i.p.) alone did not influence such learning. These results suggest that endomorphin-1 but not endomorphin-2 impairs learning and memory resulting from cholinergic dysfunction, and from activation of mu(1)-opioid receptors.
2.We investigated the effects of U-50,488H, a kappa-opioid receptor agonist, on the learned helplessness model of depression in mice. Mice pre-exposed to inescapable electric footshock were treated with U-50,488H. Stimulation of the kappa-opioid receptor by U-50,488H (10 mg/kg/day, i.p.) attenuated the escape failure induced by pre-exposure to shock. This attenuation by U-50,488H was blocked by MR2266 (10 mg/kg/day, s.c.), an opioid receptor antagonist. These results suggest that the kappa-opioid system plays an important role in the learned helplessness depression in mice.

Report

(5 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (37 results)

All 2005 2004 2003 2002 Other

All Journal Article (22 results) Book (2 results) Publications (13 results)

  • [Journal Article] Involvement of dopamine D3 and D4 receptor in the discriminative stimulus properties of cocaine in the rat.2005

    • Author(s)
      Ukai M, Mitsunaga H.
    • Journal Title

      Methods Find Exp Clin Pharmacol. 27(9)

      Pages: 645-649

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Behavioral characterization of mouse strains in learning and memory tests.2005

    • Author(s)
      亀山 勉, 間宮隆吉(他3名)
    • Journal Title

      日本神経精神薬理学会誌 25(3)

      Pages: 153-157

    • NAID

      10016667923

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Enhanced learning of normal adult rodents by repeated oral administration of soybean transphosphatidylated phosphatidylserine.2005

    • Author(s)
      Kataka-Kato A, Ukai M, (他3名)
    • Journal Title

      J Pharmacol A, Ukai M.(他3名) 98(3)

      Pages: 307-14

    • NAID

      10025729143

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Behavioral characterization of mouse strains in learning and memory tests2005

    • Author(s)
      Kameyama T, et al.
    • Journal Title

      Nihon Shinkei Seishin Yakurigaku Zasshi. 25(3)

      Pages: 153-157

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Enhanced learning of normal adult rodents by repeated oral administration of soybean transphosphatidylated phosphatidylserine.2005

    • Author(s)
      Kataoka-Kato A, et al.
    • Journal Title

      J Pharmacol Sci. 98(3)

      Pages: 307-314

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Involvement of dopamine D3 and D4 receptors in the discriminative stimulus properties of cocaine in the rat.2005

    • Author(s)
      Ukai M, Mitsuimaga H.
    • Journal Title

      Methods Find Exp Clin Pharmacol. 27(9)

      Pages: 645-649

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Involvement of dopamine D3 and D4 receptors in the discriminative stimulus properties of cocaine in the rat.2005

    • Author(s)
      Ukai M, Mitsunaga H.
    • Journal Title

      Methods Find Exp Clin Pharmacol. 27(9)

      Pages: 645-649

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Enhanced learning of normal adult rodents by repeated oral adminis tration of soybean transphosphatidylated phosphatidylserine.2005

    • Author(s)
      Kataoka-Kato A, Ukai M, (他3名)
    • Journal Title

      J Pharmacol Sci. 98(3)

      Pages: 307-314

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition in mice.2004

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

      Eur J Pharmacol. 492(2-3)

      Pages: 183-187

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Effects of pre-germinated brown rice on beta-amyloid prote in-2004

    • Author(s)
      Mamiya et al.
    • Journal Title

      Biol Pharm Bull. 27(7)

      Pages: 1041-1045

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of L-745,870, a dopamine D4 receptor antagonist, on naloxone-induced morphine dependence in mice.2004

    • Author(s)
      Mamiya et al.
    • Journal Title

      Ann N Y Acad Sci. 1025

      Pages: 424-429

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of pre-germinated brown rice on beta-amyloid protein-induced learning and memory deficits in mice.2004

    • Author(s)
      Mamiya T, et al.
    • Journal Title

      Biol Pharm Bull. 27(7)

      Pages: 1041-1045

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of L-745,870, a dopamine D4 receptor antagonist, on naloxone-induced morphine dependence in mice.2004

    • Author(s)
      Mamiya T, et al.
    • Journal Title

      Ann N Y Acad Sci. 1025

      Pages: 424-429

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of pre-germinated brown rice on beta-amyloid protein-induced learning and memory deficits in mice.2004

    • Author(s)
      Mamiya et al.
    • Journal Title

      Biol Pharm Bull. 27(7)

      Pages: 1041-1045

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Effects of L-745, 870, a dopamine D4 receptor antagonist, on naloxone-induced morphine dependence in mice.2004

    • Author(s)
      Mamiya et al.
    • Journal Title

      Ann N Y Acad Sci. 1025

      Pages: 424-429

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Endomorphin-1,an endogenous mu-opioid receptor agonist, improves apomorphine-induced impairment of prepulse inhibition in mice.2003

    • Author(s)
      Ukai M, Okuda A.
    • Journal Title

      Peptides. 24(5)

      Pages: 741-744

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tail-swing behavior : a novel animal model for anxiety.2003

    • Author(s)
      Ukai M, Mitsunaga H.
    • Journal Title

      Methods Find Exp Clin Pharmacol. 25(5)

      Pages: 355-359

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects of anticholinergic drugs selective for muscarinic receptor subtypes on prepulse inhibition in mice.2003

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

      Eur J Pharmacol. 492(2-3)

      Pages: 183-187

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Involvement of mu(1)-opioid receptors and cholinergic neurotransmission in the endomorphins-induced impairment of passive avoidance learning in mice.2002

    • Author(s)
      Ukai M, Lin HP
    • Journal Title

      Behav Brain Res. 129(1-2)

      Pages: 197-201

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Endomorphins 1 and 2 induce amnesia via selective modulation of dopamine receptors in mice.2002

    • Author(s)
      Ukai M, Lin HP
    • Journal Title

      Eur J Pharmacol. 446(1-3)

      Pages: 97-101

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Psychological stress, but not physical stress, causes increase in diazepam binding inhibitor (DBI) mRNA expression in mouse brains.2002

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

      Brain Res Mol Brain Res. 104(1)

      Pages: 103-109

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Effects ofU-50,488H, a kappa-opioid receptor agonist, on the learned helplessness model of depression in mice.2002

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

      J Neural Transm. 109(9)

      Pages: 1221-1225

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] オピオイド神経系と認知機能 -内在性オピオイドペプチドによる調節作用- オピオイド研究の進歩と展望2004

    • Author(s)
      間宮 隆吉, 鵜飼 良
    • Total Pages
      222
    • Publisher
      鎮痛薬・オピオイドペプチド研究会(編)ネオメディカル(2004)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] オピオイド神経系と認知機能-内在性オピオイドペプチドによる調節作用-オピオイド研究の進歩と展望(鎮痛薬・オピオイドペプチド研究会(編))(2004)2004

    • Author(s)
      間宮 隆吉, 鵜飼 良
    • Total Pages
      222
    • Publisher
      ネオメディカル
    • Related Report
      2004 Annual Research Report
  • [Publications] Makoto Ukai: "Tail-swing behavior : a novel animal model for anxiety"Methods and Findings in Experimental and Clinical Pharmacology. 25・5. 355-359 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Makoto Ukai: "Endomorphin-1,an endogenous μ-opioid receptor agonist improves apomorphine-induced impairment of prepulse inhibition in mice"Peptides. 24. 741-744 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 鵜飼 良: "Methamphetamineの弁別刺激効果に対するオピオイド受容体の関与"日本神経精神薬理学雑誌. 23. 319 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Makoto Ukai: "Memories Are Made of These"Landes Bioscience. 10 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 鵜飼 良: "痛み臨床における鎮痛薬・オピオイドの選択"メディカル・パブリケーションズ. 9 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 鵜飼 良: "ペインクリニシャンのためのオピオイドの基礎と臨床"真興交易(株)医書出版部(印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 鵜飼 良: "オピオイド研究の進歩と展望"ネオメディカル(印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Makoto Ukai: "Involvement of μ_1-opioid receptors and cholinergic neurotransmission in the endomorphins-induced impairment of passive avoidance learning in mice"Behavioural Brain Research. 129・1-2. 197-201 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Makoto Ukai: "Endomorphins 1 and 2 induce amnesia via selective modulation of dopamine receptors in mice"European Journal of Pharmacology. 446・1-3. 97-101 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Makoto Ukai: "Psychological stress, but not physical stress, causes increase in diazepam binding inhibitor (DBI) mRNA expression in mouse brains"Molecular Brain Research. 104・1. 103-109 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Makoto Ukai: "Effects of U-50,488H, a κ -opioid receptor agonist, on the learned helplessness model of depression in mice"Journal of Neural Transmission. 109・9. 1221-1225 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 鵜飼 良: "鎮痛作用以外の薬理作用-学習・記憶-"ペインクリニック. 23・7. 945-951 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 鵜飼 良: "Morris型水迷路学習に及ぼすendomorphin-1の作用"名城大学総合研究所紀要. 8(印刷中). (2003)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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