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Effects of calpain inhibitor on delayed neuronal death after global forebrain ischemia

Research Project

Project/Area Number 08671624
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Cerebral neurosurgery
Research InstitutionHyogo College of Medicine

Principal Investigator

YOKOTA Masayuki  Hyogo College of Medicine, Neurosurgery, Associate Professor, 医学部, 助教授 (40148648)

Co-Investigator(Kenkyū-buntansha) SAIDO Takaomi  Riken Brain Science Institute, Laboratory for Proteolytic Neuroscience, Team Lea, 神経蛋白制御部門, 研究員 (80205690)
Project Period (FY) 1996 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1996: ¥500,000 (Direct Cost: ¥500,000)
Keywordscerebral ischemia / calpain / calpain inhibitor / liposome / fodrin / calpastatin
Research Abstract

Transient forebrain ischemia induces activation of calpain and proteolysis of a neuronal cytoskeleton, fodrin, in gerbil hippocampus. This phenomenon precedes delayed neuronal death in hippocampal CAl neurons. We examined effects of a calpain inhibitor on delayed neuronal death after transient forebrain ischemia. In gerbils, a selective calpain inhibitor entrapped in liposome was given transvenously and 30 minutes later, 5-minute forebrain ischemia was produced by occlusion of both common carotid arteries. On day 7, CAl neuronal damage was examined in the hippocampal slices stained with cresyl-violet. Calpain-induced proteolysis of fodrin was also examined by immunohistochemistry and immunoblot. Additionally, to assure entrapment of the inhibitor by CAl neurons, the inhibitor-liposome complex was labeled with FITC and given to gerbils. Fluorescence in the hippocampal slices was examined by confocal laser scanning microscope. Selective CAl neuronal damage induced by forebrain ischemia w … More as prevented by administration of the inhibitor in a dose-dependent manner but not completely even in dose of 60mg/kg. Calpain-induced proteolysis of fodrin was also extinguished by the calpain inhibitor in a dose-dependent manner and completely abolished in dose of 60mg/kg. Bright fluorescence of the FITC-labeled inhibitor was observed in the CAl neurons. The data show an important role of calpain in development of the ischemic delayed neuronal death. Calpain seems to produce neuronal damage by degrading neuronal cytoskeleton. Our data also show a palliative effect of the calpain inhibitor on the neurotoxic damage. Although the calpain inhibitor does not completely block the ischemic neuronal damage, it offers a new and potent treatment of transient forebrain cerebral ischemia.
As an additional experimet, alteration of endogenous calpain inhibitor, calpastatin, in forebrain ischemia was examined by immunohistochemical and immunobloting methods. The immunoreactivity of calpastatin in hippocampal neurons increased 4 hours after the ischemic insult and then decreased. The result suggested that calpastatin may participate in the stress responses. Less

Report

(4 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • 1996 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] 横田正幸、他: "脳虚血における神経細胞障害メカニズム" 医学のあゆみ. 181. 258-259 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 横田正幸、他: "長期増強とプロテアーゼ" 実験医学. 15. 2074-2078 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 西道隆臣、他: "プロテアーゼ病としての神経変性疾患 : 脳虚血とアルツハイマー病" 蛋白質核酸酵素. 42. 2408-2417 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saido TC, et al: "Up-and down-regulation of calpain inhibitor polypeptide, calPastatin" Neuroscience Letters. 227. 75-78 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Masayuki Yokota, et al: "Calpain inhibitor entrapped in liposome rescues ischemic neuronal damage" Brain Research. 819. 8-14 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokota M,et al: "Mechanism of neuronal damage in cerebral ischemia" Journal of Clincal and Experimental Medicine. 181. 258-259 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokota M,et al: "The role of protease in LTP" Experimental Medicine. 15. 2074-2078 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saido TC,et al: "Neurodegenerative Diseases as Proteolytic Disorders : Brain Ischemia and Alzheimer's Disease" Protein, Nucleic Acid and Enzyme. 42. 2408-2417 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Saido TC,et al: "Up- and down-regulation of calpain inhibitor polypeptide, calpastatin" Neuroscience Letters. 227. 75-78 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yokota M,et al: "Calpain inhibitor entrapped in liposome rescues ischemic neuronal damage" Brain Research. 819. 8-14 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Masayuki Yokota,et al: "Calpain inhibitor entrapped in liposome rescues ischemic neuronal damage" Brain Research. 819. 8-14 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 横田正幸,西道隆臣: "長期増強とプロテアーゼ" 実験医学. 15. 2074-2078 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 西道隆臣,横田正幸: "プロテアーゼ病としての神経変性疾患:脳虚血とアルツハイマー病" 蛋白質核酸酵素. 42. 2408-2417 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Saido TC, Yokota M: "Up-and down-regulation of calpain inhibitor or polypeptide, calpastatin" Neuroscience Letters. 227. 75-78 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 横田正幸: "脳虚血における神経細胞障害メカニズム" 医学のあゆみ. 180(印刷中). (1997)

    • Related Report
      1996 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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