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新規カルモデュリン拮抗薬の抗アポトーシス作用の神経薬理学的研究

Research Project

Project/Area Number 11877018
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field General pharmacology
Research InstitutionKumamoto University

Principal Investigator

福永 浩司  熊本大学, 医学部, 助教授 (90136721)

Co-Investigator(Kenkyū-buntansha) 宮本 英七  熊本大学, 医学部, 教授 (50109659)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥1,400,000 (Direct Cost: ¥1,400,000)
Keywordsカルモデュリン / アポトーシス / 遅発性神経細胞死 / 脳虚血 / 一酸化窒素合成酵素 / 一酸化窒素 / 神経保護薬 / 海馬 / CaMキナーゼII / アストロサイト
Research Abstract

新規カルモデュリン拮抗薬であるDY-9760eはin vitroにおいて種々のカルモデュリン依存性酵素を阻害する。白崎ら(第一製薬)はラット中大脳動脈閉塞モデルにおいて虚血に伴う神経細胞死を有意に抑制することを報告した。本研究では新たな作用機構を有する新規脳保護薬、DY-9760eのin vivoにおける作用点を明らかにすることである。マウス神経芽腫細胞N1E-115細胞においてカルシウムイオノフォア、A23187によって誘発されるNO産生に対する効果を検討した。1μM以下の濃度で有意にNOの産生を抑制した。このNO産生抑制効果と同じ濃度でDY-9760eはA23187によるN1E-115細胞からのLDH(lactate dehydrogenase)の遊離を抑制し、細胞保護効果を示した。さらに、砂ネズミの前脳虚血モデルを用いて神経保護作用と、虚血による海馬でのNO産生に対する効果を検討した。ラット中大脳動脈閉塞モデルと同様に虚血負荷による遅発性神経細胞死をDY-9760eは有意に抑制した。また、マイクロダイアリシス法で海馬内のNO濃度を測定すると、虚血直後、海馬でNO濃度が有意に上昇することが解った。このNO濃度上昇に対してDY-9760eは抑制した。これらのin vitroとin vivoの結果からDY-9760eはカルモデュリン依存性NOSを阻害することによって神経保護作用を示すことが明らかとなった。さらに、神経型、内皮細胞型NOSに対する選択性について検討する必要がある。

Report

(2 results)
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] K.Fukunaga: "Decreased protein phosphatase 2A activity in hippocampal long-term potentiation."J.Neurochem.. 74. 807-817 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] J.Kasahara: "Activation of Ca^<2+>/calmodulin-dependent protein kinase IV in cultured rat hippocampal neurons."J.Neurosci.Res.. 59. 594-600 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Fukunaga: "Inhibition of neuronal nitric oxide synthase activity by 3-[2-[4-(3-chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3,5 hydrate (DY-9760e), a novel neuroprotective agent, in vitro and in cultured neuroblastoma cells in situ."Biochem.Pharmacol.. 60. 693-699 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Kanasaki: "Involvement of p38 mitogen-activated protein kinase activation in bromocriptine-induced apoptosis in rat pituitary GH3 cells."Biol.Reprod.. 62. 1486-1494 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Takeuchi: "Identification of the isoforms of Ca^<2+>/calmodulin-dependent protein kinase II in rat astrocytes and their subcellular localization."J.Neurochem.. 74. 2557-2567 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Tabuchi: "Regulation of insulin secretion by overexpression of Ca^<2+>/calmodulin-dependent protein kinase II in insulinoma MIN6 cells."Endocrinology. 141. 2350-2360 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] I.Munir: "Expression of cyclo-oxygenase 2 by prostaglandin E2 in human endometrial adenocarcinoma cell line HEC-1B."Biol.Reprod.. 63. 933-941 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Moriya: "Close linkage between calcium/calmodulin kinase II α/β and NMDA-2A receptors in the lateral amygdala and significance for retrieval of auditory fear conditioning."Eur.J.Neurosci.. 12. 3307-3314 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Q.Zhang: "Changes of free fatty acids and acyl-coas in rat brain hippocampal slice with tetraethy-lammonium-induced long-term potentiation."Biochem.Biophys.Res.Commun.. 267. 208-212 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] I.Munir: "Signaling pathways affecting cyclooxygenase 2 expression in endometrial epithelial cells."Recent Res.Devel.Endocrinol.. 1. 261-272 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] K.Fukunaga: "A working model of CaM kinase II activity in hippocampal long-term potentiation and memory."Neurosci.Res.. 38. 3-17 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 福永浩司: "海馬における神経活動依存性シナプス伝達効率の調節."蛋白質核酸酵素,増刊「神経回路形成と機能発達」. 45. 474-482 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.-I.Yokota: "Involvement of calcium-calmodulin protein kinase but not of mitogen-activated protein kinase in light-induced phase delay and per gene expression in the suprachiasmatic nucleus of hamster."J.Neurochem.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Yonehara: "Involvement of mitogen-activated protein kinase in cAMP-induced hormone gene expression in rat pituitary GH3 cells."Endocrinology. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] E.Miyamoto: "Involvement of CaM kinase II and mitogen-activated protein kinase in hippocampal long-term potentiation. Neuroscientific Basis of Dementia (eds.: C.Tanaka,P.L.McGeer,Y.Ihara)"Birkhauser Verlag, Basel, Switzerland. 9 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] M. Ohmitsu: "Phosphorylation of myristoylated alanine-rich protein kinase C substrate by mitogen-activated protein kinase in cultured rat hippocampal neurons following stmulation of glutamate receptors."J. Biol. Chem.. 274. 408-417 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K. Matsumoto: "Cloning from insulinoma cells of synapsin I associated with insulin secretory granules."J. Biol. Chem.. 274. 2053-2059 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] N. Masuko: "Interaction of NE-dlg/SPA90:A possible regulatory role in molecular clustering at synaptic sites."J. Biol. Chem.. 274. 5782-5790 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] J. Kasahara: "Differential effects of a calcineurin inhibitor on gultamate-induced phosphorylation of Ca^<2+>/calmodulin-dependent protein kinases in cultured rat hippocampal neurons."J. Biol. Chem.. 274. 9061-9067 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] H. Kuwahara: "A novel NE-dlg/SPA102-associated protein, P51-nedasin, related to the amidohydorlase superfamily, interferes with the association between NE-dlg/SAP102 and N-Methy1-D-aspartate receptor."J. Biol. Chem.. 274. 32204-32214 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] J. Liu: "Differential roles of Ca^<2+>/calmodulin-dependent protein kinases II and mitogen-activated protein dinase activation in hippocampal long-term potentiation."J. Neurosci.. 19. 8292-8299 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] M. Morioka: "Activities of calcineurin and phosphatase 2A in the hippocampus after transient forebrain ischemia."Brain Res.. 828. 135-144 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] H. Kanasaki: "Mitogen-activated protein kinase activation by stimulation with thyrotropin-releasing hormone in rat pituitary GH3 cells."Biol. of Reprod.. 61. 319-325 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] I. Munir: "Mitogen-activated protein kinase activation and regualtion of cycloxygenase 2 expression by platelet-actevating factor and hCG in human endometrial adenocarcinoma cell line HEC-1B"J. Reprod. Fertil.. 117. 49-59 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Q. Zhang: "Changes of free fatty acids and acyl-coas in rat brain hippocampal slice with tetraehylammonium-induced long-tem potentiation."Biochem. Biophys. Res. Commun.. 267. 208-212 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] K. Fukunaga: "Current studies on a working model of CaM kinase II in hippocampal long-term potentiation and memory."Jpn. J. Pharmacol.. 79. 7-15 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 福永浩司: "海馬における神経活動依存性シナプス伝達効率の調節"蛋白質核酸酵素、増刊「神経回路形成と機能発達」. 45. 474-482 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] J. Kasahara: "Activation of CA^<2+>/calmodulin-dependent protein kinase IV in cultured rat nippocampal neurons."J. Neurosci. Res.. 59. 594-600 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] K. Jukunaga: "Decreased protein phosphatase 2A activity n hippocampal long-teme potentiation."J. Neurochem.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] K. Fukunaga: "Ingibition of neuronal nitric oxide synthase activity by DY-9760e, anovel neuroprotective agent, in vitro and in cultured neuroblastoma cells in situ."Biochem. Pharmacol.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] H. Kanasaki: "Involvement of p38 mitogen-activated protein kinase activation in bromocriptine-induced apoptosis in rat pitutary GH3 cells."Biol. of Reprod.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 宮本英七: "脳と神経:分子神経生物科学入門(編集:金子章道、川村光毅、植村慶一)第3章 神経情報の統合、5.脳可塑性"共立出版. 7 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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