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Neuroprotective effects exerted by activated microglia

Research Project

Project/Area Number 16390066
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionHIROSHIMA UNIVERSITY

Principal Investigator

NAKATA Yoshihiro  Hiroshima University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (40133152)

Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2004: ¥5,800,000 (Direct Cost: ¥5,800,000)
Keywordsmicroglia / neuroprotection / ATP / TNF / P2X_7 receptors / nicotine / LPS / 脳虚血モデル / α7受容体 / MAP2 / in vivo
Research Abstract

Microglia perform both neuroprotective and neurotoxic functions in the brain, with this depending on their state of activation and their release of mediators. Upon a brain insult, ATP is released from damaged cells and activates microglia. The microglia that are activated in this way then release a range of bioactive substances, one of which is tumor nectosis factor (TNF). The release of TNF appears to be dependent on the P2X_7 receptor. The inhibitors, U0126, SP600125 and SB203580, which target MEK, JNK and p38, respectively, all potently suppress the production of TNF in ATP-stimulated microglia, whereas the production of TNF mRNA from accumulating in the cytoplasm. The ATP-provoked activation of JNK and p38, but not ERK, could be inhibited by brilliant blue G, a P2X_7 receptor blocker, and by genistein and PP2, general and src-family specific tyrosine kinase inhibitors, respectively. The treatment of the microglia in neurone-microglia co-cultures with the P2X_7 agonist BzATP led to … More significant neuroprotective effects. On the other hand, LPS caused massive TNF release, but did not exert any protective effects on glutamate neurotoxity. In rat primary cultured microglia, α7 nicotinic acetylcholine receptor (α7 nAChR) is expressed, and the activation of this receptor by nicotine enhanced P2X_7 receptor-mediated TNF release, whilst suppressing LPS-induced TNF release. This response was independent of extracellular Ca^<2+> and blocked by U73122 and xestospongin C, inhibitors of phospholipase C and IP_3 receptor, respectively. In addition, nicotine-induced currents were not detected, suggesting that α7 nAChR may not function as conventional ion channels. This novel α7 nAChR signal may be involved in the nicotine modification of microglia activation towards a neuroprotective role by suppressing the inflammatory state and strengthening the protective function. Furthermore, intracerebroventricular injection of microglia protected neurodegeneration in brain ischemic model rats. Less

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (7 results)

All 2006 2004

All Journal Article (7 results)

  • [Journal Article] Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP_3 pathway and modulate the cell activation toward a neuroprotective role.2006

    • Author(s)
      Tomohisa Suzuki
    • Journal Title

      Journal of Neuroscience Research 83

      Pages: 1461-1470

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP_3 pathway and modulate the cell activation toward a neuroprotective role2006

    • Author(s)
      Tomohisa Suzuki, Izumi Hide, Akiyo Maysubara, Chihiro Hama, Kana Harada, Kanako Miyano, Matthias Andra, Hiroaki Matsubayashi, Norio Sakai, Shinichi Kohsaka, Kazuhide Inoue, Yoshihiro Nakata
    • Journal Title

      Journal of Neurosicence Research 83

      Pages: 1461-1470

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP_3 pathway and modulate the cell activation towards a neuroprotective role.2006

    • Author(s)
      T.Suzuki, I.Hide, A.Matsubara, C.Hama, K.Harada, K.Miyano, M.Andra, H.Matsubayashi, N.Sakai, S.Kohsaka, K.Inoue, Y.Nakata.
    • Journal Title

      Journal of Neuroscience Research (In press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] ミクログリアの活性制御と神経保護2004

    • Author(s)
      秀 和泉
    • Journal Title

      日本薬理学雑誌 124

      Pages: 123-124

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Regulation of microglia activation and neuroprotection.2004

    • Author(s)
      Izumi Hide, Yoshihiro Nakata
    • Journal Title

      Folic Pharmacogical Japonica 124

      Pages: 123-124

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Production and release of neuroprotective tumor necrosis factor by P2X_7 receptor-activated microglia.2004

    • Author(s)
      T.Suzuki, I.Hide, K.Ido, S.Kohsaka, K.Inoue, Y.Nakata
    • Journal Title

      JOURNAL OF NEUROSCIENCE 24

      Pages: 1-7

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ミクログリアの活性制御と神経保護2004

    • Author(s)
      秀 和泉, 仲田義啓
    • Journal Title

      日本薬理学雑誌 124

      Pages: 123-124

    • NAID

      10018622187

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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