2003 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) 竹内有輔東北大学, 大学院・薬学研究科, 助教授 (90336214)
Keywords	Akt / バナジウム / 遅発性神経細胞死 / 脳保護薬 / 脳梗塞 / 虚血耐性 / 一酸化窒素 / 中大脳動脈閉塞モデル
Research Abstract	私達は蛋白質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Akt/protein kinase Bを活性化して虚血性脳障害に対して神経細胞保護作用を示すことを見いだした。しかしこれまでの、研究は虚血前投与での成績であり、臨床においては梗塞発症後投与の有効性が重要である。本研究ではよりヒトの脳梗塞モデルに近い、ラット中大脳動脈閉塞モデルを用いて、虚血後の末梢投与による神経保護作用を検討した。虚血後、および末梢投与で虚血周囲領域(ペナンブラ)で有意な梗塞サイズ縮小効果を示した。この脳保護作用にもAkt/protein kinase Bの活性化反応が関与していた。さらに、虚血後の血糖値の急激な上昇も抑制することが解った。これらの脳保護作用は梗塞後7日目のみならず、28日目においても同様の縮小効果が確認できた。神経細胞に対して致死的な虚血負荷を与える前に軽度の虚血を行うと神経細胞は虚血耐性を獲得する。私達はPI3キナーゼを介するAktシグナルがこの虚血耐性現象にも関わることをこれまでに明らかにした。本研究ではこれらのシグナルの下流標的蛋白質についてさらに検討した。その結果、この虚血耐性現象にはPI3キナーゼ系を介する内皮由来一酸化窒素合成酵素(eNOS)の誘導が関わっていることを明らかになった。以上の結果は、Aktシグナルを活性化するバナジウム酸ナトリウムが脳梗塞急性期治療薬として有効であることを示唆している。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] Kikukawa, K.: "Acute changes in the axonal cytoskeleton after mild stretching of the rat brachial plexus"J.Orthopaedic Res.. 21. 359-364 (2003)
[Publications] Nomura, K.: "Involvement of calcium/calmodulin-dependent protein kinase II in the induction of mPerl"J.Neurosci.Res.. 72. 384-392 (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.. 85. 729-739 (2003)
[Publications] Nishimura, H.: "Cloning, characterization, and expression of two alternatively splicing isoforms of Ca^<2+>/calmodulin-dependent protein kinase I_γ in the brain"J.Neurochem.. 85. 1216-1227 (2003)
[Publications] Takeuchi, Y.: "Differential subcellular localiztion of two dopamine D2 receptor isoforms in transfected NG108-15 cells"J.Neurochem.. 85. 1064-1074 (2003)
[Publications] Yunoue, S.: "Neurofibromatosis type I tumor suppressor neurofibromin regulates differentiation via its GAP function toward Ras"J.Biol.Chem.. 278. 26958-26969 (2003)
[Publications] 福永浩司: "最近の話題:心肥大形成とカルシウムシグナル"日薬理誌. 121. 287 (2003)
[Publications] Sakao, E: "Two-peaked synchronization in day/night expression rhythms of the fibrinogen gene cluster in the mouse liver"J.Biol.Chem.. 278. 30450-30457 (2003)
[Publications] Fukunaga, K.: "Akt is a molecular target for signal transduction therapy in brain ischemic insult"J.Pharmacol.Sci.. 92. 317-327 (2003)
[Publications] Hasegawa, Y.: "Neuroprotective effect of postischemic administration of sodium orthovanadate in rats with transient middle cerebral artery occlusion"J.Cereb.Blood Flow & Metab.. 23. 1040-1051 (2003)
[Publications] 福永浩司: "脳血管障害の新しい創薬ターゲット分子"医学のあゆみ. 207. 61-66 (2003)
[Publications] Jourdan, P.: "CaMKII contributes to activity-dependent filopodia growth and spine formation"J.Neurosci.. 23. 10645-10649 (2003)
[Publications] Takeuchi, Y.: "Different effects of five dopamine receptor subtypes on NF-κB activity in NG108-15 cells and mouse brain"J.Neurochem.. 88. 41-50 (2004)
[Publications] Hashiguchi, A.: "Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus"J.Cereb.Blood Flow & Metab.. 24. 271-279 (2004)
[Publications] Takeuchi, Y.: "Differential subcellular distributions of Ca^<2+>/Calmodulin-Dependent Protein kinase II subunits"J.Neurosci.Res.. (in press). (2003)
[Publications] Takeuchi, Y.: "Dopamine D2 receptor activates extracellular signal-regulated kianse through the specific region in the third cytoplasmic loop"J.Neurochem.. (in press). (2004)
[Publications] Takeuchi, Y.: "Different activation of NF-κB by stimulation of dopamine D2L and D2S receptors through calcineurin activation"J.Neurochem.. (in press). (2004)
[Publications] Iwahana, E.: "Effects of lithium on the circadian rhythms of locomotor activity and GSK-3 protein expression in the mouse suprachiasmatic nuclei"Eur.J.Neurosci. (in press). (2004)
[Publications] Miyazaki, K.: "Cell and Molecular Biology of Endometrial Carcinoma"Springer-Verlag Tokyo. 138 (2003)
[Publications] 大森始紀他: "神経回路の機能発現のメカニズム"共立出版. 500 (2004)

2003 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] Kikukawa, K.: "Acute changes in the axonal cytoskeleton after mild stretching of the rat brachial plexus"J.Orthopaedic Res.. 21. 359-364 (2003)

[Publications] Nomura, K.: "Involvement of calcium/calmodulin-dependent protein kinase II in the induction of mPerl"J.Neurosci.Res.. 72. 384-392 (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.. 85. 729-739 (2003)

[Publications] Nishimura, H.: "Cloning, characterization, and expression of two alternatively splicing isoforms of Ca^<2+>/calmodulin-dependent protein kinase I_γ in the brain"J.Neurochem.. 85. 1216-1227 (2003)

[Publications] Takeuchi, Y.: "Differential subcellular localiztion of two dopamine D2 receptor isoforms in transfected NG108-15 cells"J.Neurochem.. 85. 1064-1074 (2003)

[Publications] Yunoue, S.: "Neurofibromatosis type I tumor suppressor neurofibromin regulates differentiation via its GAP function toward Ras"J.Biol.Chem.. 278. 26958-26969 (2003)

[Publications] 福永 浩司: "最近の話題:心肥大形成とカルシウムシグナル"日薬理誌. 121. 287 (2003)

[Publications] Sakao, E: "Two-peaked synchronization in day/night expression rhythms of the fibrinogen gene cluster in the mouse liver"J.Biol.Chem.. 278. 30450-30457 (2003)

[Publications] Fukunaga, K.: "Akt is a molecular target for signal transduction therapy in brain ischemic insult"J.Pharmacol.Sci.. 92. 317-327 (2003)

[Publications] Hasegawa, Y.: "Neuroprotective effect of postischemic administration of sodium orthovanadate in rats with transient middle cerebral artery occlusion"J.Cereb.Blood Flow & Metab.. 23. 1040-1051 (2003)

[Publications] 福永 浩司: "脳血管障害の新しい創薬ターゲット分子"医学のあゆみ. 207. 61-66 (2003)

[Publications] Jourdan, P.: "CaMKII contributes to activity-dependent filopodia growth and spine formation"J.Neurosci.. 23. 10645-10649 (2003)

[Publications] Takeuchi, Y.: "Different effects of five dopamine receptor subtypes on NF-κB activity in NG108-15 cells and mouse brain"J.Neurochem.. 88. 41-50 (2004)

[Publications] Hashiguchi, A.: "Up-regulation of endothelial nitric oxide synthase via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus"J.Cereb.Blood Flow & Metab.. 24. 271-279 (2004)

[Publications] Takeuchi, Y.: "Differential subcellular distributions of Ca^<2+>/Calmodulin-Dependent Protein kinase II subunits"J.Neurosci.Res.. (in press). (2003)

[Publications] Takeuchi, Y.: "Dopamine D2 receptor activates extracellular signal-regulated kianse through the specific region in the third cytoplasmic loop"J.Neurochem.. (in press). (2004)

[Publications] Takeuchi, Y.: "Different activation of NF-κB by stimulation of dopamine D2L and D2S receptors through calcineurin activation"J.Neurochem.. (in press). (2004)

[Publications] Iwahana, E.: "Effects of lithium on the circadian rhythms of locomotor activity and GSK-3 protein expression in the mouse suprachiasmatic nuclei"Eur.J.Neurosci. (in press). (2004)

[Publications] Miyazaki, K.: "Cell and Molecular Biology of Endometrial Carcinoma"Springer-Verlag Tokyo. 138 (2003)

[Publications] 大森始紀 他: "神経回路の機能発現のメカニズム"共立出版. 500 (2004)

福永浩司東北大学, 大学院・薬学研究科, 教授 (90136721)

[Publications] 福永浩司: "最近の話題:心肥大形成とカルシウムシグナル"日薬理誌. 121. 287 (2003)

[Publications] 福永浩司: "脳血管障害の新しい創薬ターゲット分子"医学のあゆみ. 207. 61-66 (2003)

[Publications] 大森始紀他: "神経回路の機能発現のメカニズム"共立出版. 500 (2004)