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Basic research for cerebral ischemia therapy based on ischemic tolerance

Research Project

Project/Area Number 15390437
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

NOZAKI Kazuhiko  Kyoto Univ., Neurosurgery, Associate Prof, 医学研究科, 助教授 (90252452)

Co-Investigator(Kenkyū-buntansha) HASHIMOTO Nobuo  Kyoto Univ., Neurosurgery, Prof, 医学研究科, 教授 (40135570)
TAKAGI Yasushi  Kyoto Univ., Neurosurgery, Assistant Prof, 医学研究科, 助手 (40312227)
NISHIDA Eisuke  Kyoto Univ., Biophysics, Prof, 理学研究科, 教授 (60143369)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2004: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2003: ¥9,600,000 (Direct Cost: ¥9,600,000)
KeywordsMARK / Cerebral ischemia / Ischemic tolerance / STAT / 脳梗塞
Research Abstract

It has been reported that prior sublethal ischemia in brain tissue induces the phenomenon of ischemic tolerance to subsequent lethal ischemic stress in the hippocampal CA1 region. We recently reported the activation of MAPK cascades after the administration of 3-NP, which is a mitochondrial succinate dehydrogenase inhibitor, at a dose that induced ischemic tolerance in the gerbil hippocampus, but it remains to be shown whether or not the activations of MAPK cascades may affect the ischemic tolerance phenomenon induced by sublethal ischemia. In previous studies, we obtained evidence suggesting that p38 was activated in the gerbil hippocampus after 5-minute transient forebrain ischemia in vivo and that the inhibition of the activity of p38 protected against delayed neuronal death in CA1 pyramidal cells. We investigated the activation of p38 mitogen-activated protein kinase in the gerbil hippocampus by Western blotting and immunohistochemistry to clarify the role of p38 kinase in ischemic tolerance. Immunoblot analysis indicated the activation of p38 in the hippocampus after 2 minutes of global sublethal ischemia. After this 2-minute global ischemia, immunoreactivity indicating active p38 was enhanced at 6 hours of reperfusion and continuously demonstrated 72 hours after ischemia in CA1 and CA3 neurons. Pretreatment with SB203580, an inhibitor of active p38, 30 minutes before the 2-minute ischemia reduced the ischemic tolerance effect in a dose-dependent manner. Genetic disruption of STAT1, a targeted molecule of p38, reduced ischemic damage in a mice ischemic model. These findings suggest that p38 may contribute to both ischemic damage and tolerance in CA1 neurons of the hippocampus and that components of the p38 cascade can be target molecules to modify neuronal survival after ischemia.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (8 results)

All 2004 2003 Other

All Journal Article (6 results) Publications (2 results)

  • [Journal Article] Intravenous administration of thioredoxin decreases brain damage following transient focal cerebral ischemia in mice2004

    • Author(s)
      Hattori I, et al.
    • Journal Title

      Antioxidants & Redox Signaling 6

      Pages: 81-87

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Control of axon elongation via an SDF-1a/Rho/mDia pathway in cultured cerebellar granule neurons2003

    • Author(s)
      Arakawa Y, et al.
    • Journal Title

      J Cell Biol 161

      Pages: 381-391

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Activation of p38 kinase in the gerbil hippocampus showing ischemic tolerance2003

    • Author(s)
      Nishimura M, et al.
    • Journal Title

      J Cereb Blood Flow Metab 23

      Pages: 1052-1059

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Adenovirus-mediated gene transfer of fibroblast growth factor-2 increases BrdU-positive cells after forebrain ischemia2003

    • Author(s)
      Matsuoka N, et al.
    • Journal Title

      Stroke 34

      Pages: 1519-1525

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Adenovirus-mediated gene transfer of fibroblast growth factor-2 increases BrdU-positie cells after forebrain ischemia2003

    • Author(s)
      Matsuoka N, et al.
    • Journal Title

      Stroke 34

      Pages: 1519-1525

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Adenovirus-mediated gene transfer of fiblo blast growth factor-2 increases Brd-U-positive cells after forebrain ischemia2003

    • Author(s)
      Matsuoka N, et al.
    • Journal Title

      Stroke 34

      Pages: 1519-1525

    • Related Report
      2004 Annual Research Report
  • [Publications] Nishimura M. et al.: "Activation of p38 kinase in the gerbil hippocampus showing ischemic tolerance"J Cereb Blood Flow & Matabol. 23. 1052-1059 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hattori I. et al.: "Intravenous Administration of Thioredoxin Decreases Brain Damage Following Transient Focal Cerebral Ischemia in Mice"Antioxidants & Redox Signaling. 6. 81-87 (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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