2000 Fiscal Year Annual Research Report

筋萎縮性側索硬化症の分子病態機序に関する研究

Research Project

Project/Area Number	11470145
Research Institution	KYOTO UNIVERSITY
Principal Investigator	下濱俊京都大学, 医学研究科, 講師 (60235687)
Co-Investigator(Kenkyū-buntansha)	赤池昭紀京都大学, 薬学研究科, 教授 (80135558)
Keywords	筋萎縮性側索硬化症 / ALS / ホスホジエステラーゼ(PPE) / CGMP / 運動ニューロン / グルタミン酸 / アミノフィリン / アイソザイム
Research Abstract	筋萎縮性側索硬化症(ALS)に対する有効な治療法が切望されている。本研究では、ラット脊髄初代培養系を用いてホスホジエステラーゼ(PDE)阻害剤の運動ニューロン保護効果を解析し、ALSに対する新たな治療法の可能性について検討した。我々は、すでにcGMPアナログが急性ラジカル毒性から運動ニューロンを保護することを見出していたが、今回、PDE阻害剤であるアミノフィリンまたはジピリダモール投与で細胞内のcGMP濃度を持続的に上昇させることにより、低濃度(30μM)のグルタミン酸とグルタミン酸トランスポーター阻害薬を24時間曝露することにより選択的運動ニューロン死をきたす慢性グルタミン酸毒性からも運動ニューロンを保護することができた。 PDEには多数のアイソザイムが存在し、一大スーパーファミリーを形成している。現在知られているだけでPDE1〜11のファミリーが存在する。各ファミリーに1から数個の遺伝子が存在し、そのそれぞれについて複数のsplice variantが存在する。このうち、cGMPを分解するのはPDE1,2,5,6,9,10,11の7つのファミリーである。アミノフィリンは非選択的なPDE阻害剤であるが、ジピリダモールはPDE5,6,7,8,10,11の選択的阻害剤である。これらのうち、PDE6は網膜に特異的に発現する酵素でありPDE7,8はcAMP特異的な酵素であることから、運動ニューロン保護効果にはPDE5,10,11もしくは未同定の(新規の)アイソザイムが関与していることが示唆される。今後、このアイソザイム、さらにはsplice variantを決定し、これに特異的な阻害剤を開発することで、ALSに対する新しい治療法につながることが期待される。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] Kume T,Nishikawaff et al.: "PQS-mediated neuroprotection by NGF against glutamate cytotanicity in cortical cultures"Brain Research. 852. 279-289 (2000)
[Publications] Kageyama T,Oeda T et al: "Coexistence of expanded CAG raptats in the MJDla and DRPLA genes"Neurology. 54. 265-266 (2000)
[Publications] Yawamoto K,Hashimoto K et al: "An IPs-assisted form of Ca^<2+>-induced Ca^<2+> release in aeocartical neurons"Neuroreport. 11. 535-539 (2000)
[Publications] Sawada H,Ib,M et al: "Neuroprotective mechanism of glical cell line-derived neurotrophic tactor in mesurcephalis neurons"Journal of Neurochemistry. 74. 1175-1184 (2000)
[Publications] Honda K,Sawada H et al: "Phosphatidy linosital 3-kinase mediates neuroprotection by estrogew in cultured cortical neurons"Journal of Neuroscience Research. 60. 321-327 (2000)
[Publications] Sawada H,Ibi M et al: "Mechanisms of antiapoptotic effects of estrogen in nigral dopaminergic neurons"FASEB Journal. 14. 1202-1214 (2000)
[Publications] Tanino H,shimohama S et al: "Increase in phospholipase C-J_1 protein levels in aluminum-treated rat brains"Biochem Biophys Res Commun. 271. 620-625 (2000)
[Publications] Shimohama S,Tanino H et al: "Activatioon of NADPH oxidase in Alzhetwers disease brains"Biochem Biophys Res Commun. 273. 5-9 (2000)
[Publications] Urushituai M,Inoeu R et al: "Neuroprotective effect of cyclis GMP against radical-induced toxicity in cultured spinal motor neurous"Journal of Neuro science Research. 61. 443-448 (2000)
[Publications] Kogeyama T,Nakamura M et al: "The 4F2hc/LATI complex transports L-Dopa across the blood-brain barrer"Brain Research. 879. 115-121 (2000)
[Publications] Imura T,Shimohama S: "Opposing effects of adenosure on the survival of glial cells exposed to chemical ischemia"Journal of Neuroscience Research. 62. 539-546 (2000)
[Publications] Nakanizo T,Urushitani M et al: "Protection of motor neurons by estradial"Neuro Report. 11. 3493-3497 (2000)
[Publications] Kakimura J Kitamura et al: "Big/GRP-induced protectioon of cytokines and uptake of amyloid-β(1-42) peptide in microglia"Biochem Biophys Res Commun. 281. 6-10 (2001)
[Publications] Kageyama T,Imura T et al: "Distribution of the 4F2 light chain, LATI, in the mouse brain"Neuroreport. 11. 3663-3666 (2000)
[Publications] Urashitani M.Nakamizo T et al: "NMDA receptor-mediated mitocheudrial Ca^<2+> overload in acute excitotoxic motor neurons death : a distinct mechanism from chronic neuro toxicityafter Ca^<2+> influx"Journal of Neuroscience Research. 63. 377-387 (2001)
[Publications] Shimohama S,Kihara T: "Nicotinic receptor-mediated protection against beta amyloid neurotoxicity"Biolopgical Psychiatry. (in press). (2001)
[Publications] Kihara T,Shimohama S et al: "Alpha 7 nicotinic receptor transduces signals to P3 kinase to block Aβ-induced neurotoxicity"Journal of Biological Chemistry. (in press). (2001)
[Publications] Honda K,Shimohama S et al: "Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons"Journal of Neuroscience Research. (in press). (2001)

2000 Fiscal Year Annual Research Report

筋萎縮性側索硬化症の分子病態機序に関する研究

Principal Investigator

下濱 俊 京都大学, 医学研究科, 講師 (60235687)

Research Products

[Publications] Kume T,Nishikawaff et al.: "PQS-mediated neuroprotection by NGF against glutamate cytotanicity in cortical cultures"Brain Research. 852. 279-289 (2000)

[Publications] Kageyama T,Oeda T et al: "Coexistence of expanded CAG raptats in the MJDla and DRPLA genes"Neurology. 54. 265-266 (2000)

[Publications] Yawamoto K,Hashimoto K et al: "An IPs-assisted form of Ca^<2+>-induced Ca^<2+> release in aeocartical neurons"Neuroreport. 11. 535-539 (2000)

[Publications] Sawada H,Ib,M et al: "Neuroprotective mechanism of glical cell line-derived neurotrophic tactor in mesurcephalis neurons"Journal of Neurochemistry. 74. 1175-1184 (2000)

[Publications] Honda K,Sawada H et al: "Phosphatidy linosital 3-kinase mediates neuroprotection by estrogew in cultured cortical neurons"Journal of Neuroscience Research. 60. 321-327 (2000)

[Publications] Sawada H,Ibi M et al: "Mechanisms of antiapoptotic effects of estrogen in nigral dopaminergic neurons"FASEB Journal. 14. 1202-1214 (2000)

[Publications] Tanino H,shimohama S et al: "Increase in phospholipase C-J_1 protein levels in aluminum-treated rat brains"Biochem Biophys Res Commun. 271. 620-625 (2000)

[Publications] Shimohama S,Tanino H et al: "Activatioon of NADPH oxidase in Alzhetwers disease brains"Biochem Biophys Res Commun. 273. 5-9 (2000)

[Publications] Urushituai M,Inoeu R et al: "Neuroprotective effect of cyclis GMP against radical-induced toxicity in cultured spinal motor neurous"Journal of Neuro science Research. 61. 443-448 (2000)

[Publications] Kogeyama T,Nakamura M et al: "The 4F2hc/LATI complex transports L-Dopa across the blood-brain barrer"Brain Research. 879. 115-121 (2000)

[Publications] Imura T,Shimohama S: "Opposing effects of adenosure on the survival of glial cells exposed to chemical ischemia"Journal of Neuroscience Research. 62. 539-546 (2000)

[Publications] Nakanizo T,Urushitani M et al: "Protection of motor neurons by estradial"Neuro Report. 11. 3493-3497 (2000)

[Publications] Kakimura J Kitamura et al: "Big/GRP-induced protectioon of cytokines and uptake of amyloid-β(1-42) peptide in microglia"Biochem Biophys Res Commun. 281. 6-10 (2001)

[Publications] Kageyama T,Imura T et al: "Distribution of the 4F2 light chain, LATI, in the mouse brain"Neuroreport. 11. 3663-3666 (2000)

[Publications] Urashitani M.Nakamizo T et al: "NMDA receptor-mediated mitocheudrial Ca^<2+> overload in acute excitotoxic motor neurons death : a distinct mechanism from chronic neuro toxicityafter Ca^<2+> influx"Journal of Neuroscience Research. 63. 377-387 (2001)

[Publications] Shimohama S,Kihara T: "Nicotinic receptor-mediated protection against beta amyloid neurotoxicity"Biolopgical Psychiatry. (in press). (2001)

[Publications] Kihara T,Shimohama S et al: "Alpha 7 nicotinic receptor transduces signals to P3 kinase to block Aβ-induced neurotoxicity"Journal of Biological Chemistry. (in press). (2001)

[Publications] Honda K,Shimohama S et al: "Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons"Journal of Neuroscience Research. (in press). (2001)

下濱俊京都大学, 医学研究科, 講師 (60235687)