2000 Fiscal Year Annual Research Report

ステロイド受容体ファミリーを介するドーパミンニューロン死の防御機構

Research Project

Project/Area Number	12031209
Research Institution	Kyoto University
Principal Investigator	下濱俊京都大学, 医学研究科, 講師 (60235687)
Keywords	パーキンソン病 / ドーパミンニェーロン / 細胞死 / エストロゲン / アポトーシス / エストロゲンレセプター / AP-1 site / カスペース
Research Abstract	ラット腹側中脳の初代培養を用いてBleomycin sulfate(BLM)あるいはButhionine sulfoximine(BSO)によるアポトーシスに対し、17β-estradiolが抗アポトーシス作用を有するか否かを検討した。BLMおよびBSOによる神経細胞死はDNA断片化、核クロマチンの凝集をともない、caspase-3阻害薬や、JNK/AP-1活性化抑制薬であるcurcuminによって拮抗された。curminはcaspase-3活性化を抑制しなかったが、caspase-3拮抗薬はJNK2の増大を抑制したことより、caspase-3の活性化とその下流でのJNK2活性化を介していることが示された。17β-estradiolは1〜10nMでBSOあるいはBLM誘発アポトーシスを抑制し、この抑制作用は、エストロゲン受容体拮抗薬によって遮断された。また、17β-estradiolはBLM,BSO刺激によるcaspase-3活性化やJNK2増大に影響を与えなかった。これらの点から、17β-estradiolはERβを介し、caspase-3やJNKの活性化の下流で抗アポトーシス作用を呈すると考えられた。ERはEREを介した転写調節ではダイマー形成を必要とするが、AP-1 consensus elementを介し転写調節をする際には二量体を形成しないことから、ERのダイマー形成を合成ペブチドで抑制してその影響を調べた。その結果、抗アポトーシス作用はダイマー阻害薬によっては抑制されず、AP-1 siteを介した転写調節である可能性が示された。また、BSO刺激によってAP-1産物であるTNF-αが増大したが、17β-estradiolはこれを抑制した。17β-estradiolはERβに結合し、AP-1 siteを介した抑制的転写調節により抗アポトーシス作用を示すものと考えられた。

Research Products
(18 results)

All Other

All Publications (18 results)

[Publications] Kume T,Nishikawa H et al.: "P75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures"Brain Research. 852. 279-289 (2000)
[Publications] Kageyama T,Oeda.T. et al: "Coexistence of expanded CAG repeats in the MSDla and DRPLA genes"Neurology. 54. 265-266 (2000)
[Publications] Yamamoto K,Hashimoto K et al: "An IPs-assisted form of Ca^<2+>-induced Ca^<2+>release in neocortical neurons"Neuroreport. 11. 535-539 (2000)
[Publications] Sawada H,Ibi M et al: "Neuroprotective mechanism of glial cell line-derived neurotrophic tactor in mesencephalic neurons"Journal of Neurochemistry. 74. 1175-1184 (2000)
[Publications] Houda K,Sawada H et al: "Phosphatidy linositol 3-kinase mediates neuroprotection by estrogen 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 dopaminorgic neuron"FASEB Journal. 14. 1202-1214 (2000)
[Publications] Tanino H,Shimohama S et al: "Incease in phospholipase C-δ_1, protein levels in aluminum-treated rat brains"Biochem Biophys Res Commun. 271. 620-625 (2000)
[Publications] Shimohama S,tanino H et al: "Activation of NADPH oxidase in Alzheimers disease brains"Biochem Biophys Res Commun. 273. 5-9 (2000)
[Publications] Urushitani M,Inoeu R et al: "Neuroprotective effect of cyclio GMP against radical-induced toxicity in cultured spinal motor neurons "Jounal of Neuroscience Research. 61. 443-448 (2000)
[Publications] Kageyama T,Nakamura M et al: "The 4F2hc/GATl complex transports L-Dopa across the blood-brain barrier"Brain Research. 879. 115-121 (2000)
[Publications] Imura T,Shimohama S: "Opposing effects of adenosine on the survival of glial cells exposed to chemical ischemia"Joural of Neuroscience research. 62. 539-546 (2000)
[Publications] Nakanizo T.Urushitani M et al.: "Protection of motor neurous by estradiol"Neuro report. 11. 3493-3497 (2000)
[Publications] Kakimura J.Kitamura Y et al: "Bip/GRP78-induced protection 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, LATl, in the mouse brain"Neuroreport. 11. 3663-3666 (2000)
[Publications] Urashitani M,Nakamizo T et al: "NMDA receptor-mediated mitochoudrial Ca^<2+> overload in acute excitotoxic motor neurons death : a distinct mechanism from chronic neurotoxicity after Ca^<2+> influx"Journal of Neuroscience Research . 63. 377-387 (2001)
[Publications] Shimohama S,Kihara T: "Nicotinic receptor-mediated protection against beta amyloid neurotoxicity"Biological Psychiatry. (in press). (2001)
[Publications] Kihara T.Shimohama S et al: "Alpha 7 nicotinic receptor transduces signals to PI3 kinase to block Aβ-induced neurotoxicity"Journal of Biological Chemistry. (in press). (2001)
[Publications] Honda K,Shimohama S et al: "Nongenomic autiapoptotic signal transduction by estrogen in cultured cortical neurons"Journal of Neuroscience Research. (in press). (2001)

2000 Fiscal Year Annual Research Report

ステロイド受容体ファミリーを介するドーパミンニューロン死の防御機構

Principal Investigator

下濱 俊 京都大学, 医学研究科, 講師 (60235687)

Research Products

[Publications] Kume T,Nishikawa H et al.: "P75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures"Brain Research. 852. 279-289 (2000)

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

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

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

[Publications] Houda K,Sawada H et al: "Phosphatidy linositol 3-kinase mediates neuroprotection by estrogen 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 dopaminorgic neuron"FASEB Journal. 14. 1202-1214 (2000)

[Publications] Tanino H,Shimohama S et al: "Incease in phospholipase C-δ_1, protein levels in aluminum-treated rat brains"Biochem Biophys Res Commun. 271. 620-625 (2000)

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

[Publications] Urushitani M,Inoeu R et al: "Neuroprotective effect of cyclio GMP against radical-induced toxicity in cultured spinal motor neurons "Jounal of Neuroscience Research. 61. 443-448 (2000)

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

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

[Publications] Nakanizo T.Urushitani M et al.: "Protection of motor neurous by estradiol"Neuro report. 11. 3493-3497 (2000)

[Publications] Kakimura J.Kitamura Y et al: "Bip/GRP78-induced protection 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, LATl, in the mouse brain"Neuroreport. 11. 3663-3666 (2000)

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

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

[Publications] Kihara T.Shimohama S et al: "Alpha 7 nicotinic receptor transduces signals to PI3 kinase to block Aβ-induced neurotoxicity"Journal of Biological Chemistry. (in press). (2001)

[Publications] Honda K,Shimohama S et al: "Nongenomic autiapoptotic 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)