2002 Fiscal Year Annual Research Report

虚血性脳障害におけるシグナル伝達セラピーの創薬科学研究

Research Project

Project/Area Number	14370035
Research Institution	Tohoku University
Principal Investigator	福永浩司東北大学, 大学院・薬学研究科, 教授 (90136721)
Co-Investigator(Kenkyū-buntansha)	矢野茂敏熊本大学, 医学部附属病院, 助手 (60332871) 森岡基浩熊本大学, 医学部附属病院, 助手 (20295140) 比佐博彰東北大学, 大学院・薬学研究科, 助教授 (60192712)
Keywords	プロテインキナーゼ / 脳虚血 / 遅発性神経細胞死 / Fasリガンド / Forkhead transcription factor / カルモデュリン阻害剤 / 一酸化窒素 / ニトロチロシン
Research Abstract	砂ネズミ海馬神経細胞における一過性前脳虚血に伴う遅発性神経細胞死にはprotein kinase B (Akt)の不活性化反応が関与している。私達はホスホチロシンホスファターゼ阻害剤であるバナジウム酸ナトリウムが虚血直後に起こるAktの不活性化反応を抑制することによって、神経保護効果を示すことを報告した。本研究ではAktの不活性化反応に伴ってForkhead transcription factorファミリーの一つであるFKHRの脱燐酸化反応がin vivoで起こることを見出した。FKHRはSer-256がAktによりリン酸化されることによって、転写活性が抑制されている。FKHRの脱燐酸化反応によって、核内に移行して、その後標的遺伝子であるFasリガンドが誘導されことを砂ネズミ海馬で確認した。このFasリガンドの誘導は遅発性神経細胞死に関わっていると考えられる。これらのアポトーシスシグナルの活性化反応はバナジウム酸ナトリウムの投与で完全に抑制された。次に新規脳保護薬であるカルモデュリン阻害剤DY-9760eの作用機構について解析した。マイクロダイアリシス法で海馬内一酸化窒素(NO)濃度を虚血再灌流後にリアルタイムで測定したところ、海馬においてNOが持続的に上昇することが解った。DY-9760eの前投与はNO上昇を完全に抑制した。NOと活性酸素種との反応で産生されるパーオキシナイトライトの作用である、蛋白質のニトロチロシン化が虚血後、著しく上昇した。この蛋白質のニトロチロシン化もDY-9760e投与によって完全に抑制された。ニトロチロシン化が神経細胞障害にどのように関わるのか今後さらに追究する。以上の結果から、新しい作用メカニズムを有する脳保護薬としてバナジウム酸ナトリウムとDY-9760eが有効であることが示唆された。

Research Products

(16 results)

All Other

All Publications (16 results)

[Publications] Kanasaki, H.: "Differential regulation of pituitary hormone secretion and gene expression by thyrotropin-releasing hormone. A role for mitogen-activated protein kinase signaling cascade in rat pituitary GH3 cells"Biol. Reproduction. 67. 107-113 (2002)
[Publications] 福永浩司: "長期増強とCaMキナーゼ"Clinical Neuroscience. 20. 618-619 (2002)
[Publications] Takeuchi, Y.: "Activation of Ca^<2+>/calmodulin-dependent protein kinase II and brain-derived neurotrophic factor gene expression by stimulation of dopamine D2 receptor in transfected NG108-15 cells"J. Neurochem.. 82. 316-328 (2002)
[Publications] Kawano, T.: "Decreased Akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus"J. Cereb. Blood Flow Metab.. 22. 926-934 (2002)
[Publications] Uezu, A.: "Activation of Ca^<2+>/calmodulin-dependent protein kinase I in cultured rat hippocampal neurons"J. Neurochem.. 82. 585-593 (2002)
[Publications] Osuka, K.: "Phosphorylation of neuronal nitric oxide synthase at Ser^<847> by CaM-KII in the hippocampus of rat brain after transient forebrain ischemia"J. Cereb. Blood Flow Metab.. 22. 1098-1106 (2002)
[Publications] Sakurada, K.: "Synapsin I is phosphorylated at Ser^<603> by p21-activated kinases (PAKs) in vitro and in PC12 cells stimulated with bradykinin"J. Biol. Chem.. 277. 45473-45479 (2002)
[Publications] Takeuchi, Y.: "Activation of the rat dopamine D2 receptor promoter by mitogen-activated protein kinase and Ca^<2+>/calmodulin-dependent protein kinase II pathways"J. Neurochem.. 83. 784-796 (2002)
[Publications] Fukunaga, K.: "Ca^<2+>/calmodulin-dependent protein kinase II-dependent long-term potentiation in the rat suprachiasmatic nucleus and its inhibition by melatonin"J. Neurosci. Res.. 70. 799-807 (2002)
[Publications] Kanasaki, H.: "Regulation of gonadotropin a subunit gene expression by dopamine D_2 receptor agonist in clonal mouse gonadotroph αT3-1 cells"Biol. Reproduction. 67. 1218-1224 (2002)
[Publications] Li, X.-L.: "Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents"Neuroscience. 113. 607-615 (2002)
[Publications] Fueta, Y.: "Hyperexcitability and changes in activities of Ca^<2+>/calmodulin-dependent kinase II and mitogen-activated protein kinase in the hippocampus of rats exposed to 1-bromopropane"Life Science. 72. 521-529 (2002)
[Publications] Nomura, K.: "Involvement of calcium/calmodulin-dependent protein kinase II in the induction of mPer1"J. Neurosci. Res.. (in press). (2003)
[Publications] Takeuchi, Y.: "Differential regulation of NF-_κB, SRE and CRE by dopamine D1 and D2 receptors in transfected NG108-15 cells"J. Neurochem.. (in press). (2003)
[Publications] Takeuchi, Y.: "Differential subcellular localization of two dopamine D2 receptor isoforms in transfected NG108-15 cells"J. Neurochem.. (in press). (2003)
[Publications] Fukunaga, K.: "Recent Research Developments in Neurochemistry (ed. : S.G. Pandalai), Differential role of CaM kinases II and IV activities in neuronal plasticity and memory"Research Signpost, Kerala, India. 16 (2002)

2002 Fiscal Year Annual Research Report

虚血性脳障害におけるシグナル伝達セラピーの創薬科学研究

Principal Investigator

福永 浩司 東北大学, 大学院・薬学研究科, 教授 (90136721)

Research Products

[Publications] Kanasaki, H.: "Differential regulation of pituitary hormone secretion and gene expression by thyrotropin-releasing hormone. A role for mitogen-activated protein kinase signaling cascade in rat pituitary GH3 cells"Biol. Reproduction. 67. 107-113 (2002)

[Publications] 福永浩司: "長期増強とCaMキナーゼ"Clinical Neuroscience. 20. 618-619 (2002)

[Publications] Takeuchi, Y.: "Activation of Ca^<2+>/calmodulin-dependent protein kinase II and brain-derived neurotrophic factor gene expression by stimulation of dopamine D2 receptor in transfected NG108-15 cells"J. Neurochem.. 82. 316-328 (2002)

[Publications] Kawano, T.: "Decreased Akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus"J. Cereb. Blood Flow Metab.. 22. 926-934 (2002)

[Publications] Uezu, A.: "Activation of Ca^<2+>/calmodulin-dependent protein kinase I in cultured rat hippocampal neurons"J. Neurochem.. 82. 585-593 (2002)

[Publications] Osuka, K.: "Phosphorylation of neuronal nitric oxide synthase at Ser^<847> by CaM-KII in the hippocampus of rat brain after transient forebrain ischemia"J. Cereb. Blood Flow Metab.. 22. 1098-1106 (2002)

[Publications] Sakurada, K.: "Synapsin I is phosphorylated at Ser^<603> by p21-activated kinases (PAKs) in vitro and in PC12 cells stimulated with bradykinin"J. Biol. Chem.. 277. 45473-45479 (2002)

[Publications] Takeuchi, Y.: "Activation of the rat dopamine D2 receptor promoter by mitogen-activated protein kinase and Ca^<2+>/calmodulin-dependent protein kinase II pathways"J. Neurochem.. 83. 784-796 (2002)

[Publications] Fukunaga, K.: "Ca^<2+>/calmodulin-dependent protein kinase II-dependent long-term potentiation in the rat suprachiasmatic nucleus and its inhibition by melatonin"J. Neurosci. Res.. 70. 799-807 (2002)

[Publications] Kanasaki, H.: "Regulation of gonadotropin a subunit gene expression by dopamine D_2 receptor agonist in clonal mouse gonadotroph αT3-1 cells"Biol. Reproduction. 67. 1218-1224 (2002)

[Publications] Li, X.-L.: "Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents"Neuroscience. 113. 607-615 (2002)

[Publications] Fueta, Y.: "Hyperexcitability and changes in activities of Ca^<2+>/calmodulin-dependent kinase II and mitogen-activated protein kinase in the hippocampus of rats exposed to 1-bromopropane"Life Science. 72. 521-529 (2002)

[Publications] Nomura, K.: "Involvement of calcium/calmodulin-dependent protein kinase II in the induction of mPer1"J. Neurosci. Res.. (in press). (2003)

[Publications] Takeuchi, Y.: "Differential regulation of NF-_κB, SRE and CRE by dopamine D1 and D2 receptors in transfected NG108-15 cells"J. Neurochem.. (in press). (2003)

[Publications] Takeuchi, Y.: "Differential subcellular localization of two dopamine D2 receptor isoforms in transfected NG108-15 cells"J. Neurochem.. (in press). (2003)

[Publications] Fukunaga, K.: "Recent Research Developments in Neurochemistry (ed. : S.G. Pandalai), Differential role of CaM kinases II and IV activities in neuronal plasticity and memory"Research Signpost, Kerala, India. 16 (2002)

福永浩司東北大学, 大学院・薬学研究科, 教授 (90136721)