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イムノフィリンリガンドが示す神経保護作用におけるニューロイムノフィリンの役割

Research Project

Project/Area Number 13780617
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Neurochemistry/Neuropharmacology
Research InstitutionOkayama University

Principal Investigator

田中 健一  岡山大学, 大学院・医歯学総合研究科, 助手 (20281313)

Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Keywordsイムノフィリンリガンド / 非免疫抑制性 / ニューロイムノフィリン / 神経保護作用 / グルタチオン / 抗酸化作用 / 神経栄養因子 / パーキンソン病
Research Abstract

[1]非免疫抑制性イムノフィリンリガンドの薬理作用
(2)抗酸化作用以外の薬理作用の検索;イムノフィリンリガンドの神経保護作用の分子機序を明らかにする目的で,(2)タンパク質品質管理機構に関する作用に着目した.ウエスタンブロット法にて,HSP60,HSP70,HSP90のタンパクならびに遺伝子発現におよぼす影響を評価したが,顕著な効果を見いだせなかった.
(3)各種ストレスに基づく神経細胞死に対する保護作用の分子機序解析;α-シヌクレイン過剰発現株を用いて検討した結果,FK506,GPI1046,V10367,rapamycinの4つのFKBP-bindingイムノフィリンリガンドは何れもα-シヌクレイン過剰発現によって認められる細胞生存率の低下を抑制できなかった.
[2]ニューロイムノフィリンの機能解析
(1)ニューロイムノフィリンの神経保護作用への関与;FKBP12,FKBP25,FKBP38,FKBP51,FKBP52/59,FKBP65の内在性の遺伝子発現をSH-SY5Y細胞とU251細胞を用いてRT-PCR法で検討したところ,U251細胞はFKBP12の遺伝子発現を確認できなかった.そこで,過酸化水素による実験系での細胞生存率と,それぞれの正常細胞を用いたグルタチオン増加作用を指標に検討したところ,どちらの細胞でもFK506,GPI1046共に同様の効果を示した.したがって,少なくともこの実験系において,FKBP12はイムノフィリンリガンドの神経保護作用に寄与しないことを明らかにした.
[3]ニューロイムノフィリンに関連する神経保護薬の新規候補物質の探索
(1)新規候補物質の作成とスクリーニング;ニューロイムノフィリン結合性候補物質を22種類作成し,神経栄養因子活性化作用を指標に検討した結果,12種類の化合物で何らかの効果を示した.

Report

(2 results)
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] Tanaka, K.: "Effects of immunophilin ligands on hydrogen peroxide-induced apoptosis in C6 glioma cells"Synapse. 43. 219-222 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka, K.: "Neuroprotective and antioxidant properties of FKBP-binding immunophilin ligands are independent on the FKBP12 pathway in human cells"Neurosci.Lett.. 330. 147-150 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka, K.: "Chronic cerebral hyperfusion induces striatal alterations due to the transient increase of NO production and the continuous depression of glutathione content"Neurochem.Res. 27. 331-336 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshioka, M.: "The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavengnig free radicals"Neurosci.Res.. 43. 259-267 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Higashi, Y.: "The p53-activated gene, PAG608, requires a zinc finger domain for nuclear localization and oxidative stress-induced apoptosis"J.Biol.Chem.. 277. 42224-42232 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Asanuma, M.: "Aggravation of 6-hydroxydopamine-induced dopaminergic lesions in metallothionein-I and-II knock-out mouse brain"Neurosci.lett.. 327. 61-65 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka, K.: "Immunosuppressant Analogs in Neuroprotection"Humana Press, Inc.. 424 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka K: "GPI1046 prevents dopaminergic dysfunction by activating glutathione system in the mouse striatum"Neuroscience Letter. 321. 45-48 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka K: "Immunosuppressive and non-immunosuppressive immunophilin ligands improve H_2O_2-induced cell damage by increasing glutathione levels in NG108-15 cells"Brain Research. 889. 236-239 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka K: "FK506 ameliorates the discrimination learning impairment due to preventing the rarefaction of white matter induced by chronic cerebral hypoperfusion in rats"Brain Research. 906. 184-189 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka K: "Molecular mechanism in activation of glutathione system by ropinirole, a selective dopamine D2 agonist"Neurachemical Research. 26. 31-36 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hironaka N: "Memory related acetylcholine release from the rat prefrontal cortex and hippocampus : A microdialysis study"Brain Research. 901. 143-150 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kondo F: "Progressive cortical atrophy after forebrain ischemia in diabetic rats"Neuroscience Research. 39. 339-346 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ogawa N: "Molecular Mechanism and Therapeutics of Amyotrophic Lateral Sclerosis"Elsevier. 382 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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