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Basic investigation of hypothermia for a treatment of stroke : ischemic neuronal damage by the disruption of blood-brain barrier and microglial activation

Research Project

Project/Area Number 12557131
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Anesthesiology/Resuscitation studies
Research InstitutionEhime University

Principal Investigator

OHNISHI Katsuyuki  Ehime University, Faculty of Medicine, Assistant Professor, 医学部・附属病院, 講師 (90127887)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Youichi  Kanazawa University, School of Pharmacy, Associate Professor, 薬学部, 助教授 (90180413)
FUKUHARA Toshiyuki  Ehime University, Faculty of Medicine, Instructor, 医学部, 助手 (00228925)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥9,400,000 (Direct Cost: ¥9,400,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2000: ¥7,500,000 (Direct Cost: ¥7,500,000)
Keywordshypothermia / blood brain barrier / brain ischemia / microglia / albumin / theanine
Research Abstract

Blood-brain barrier (BBB) breakdown was evaluated by examining extravasation of intravenously injected Evans Blue dye in forebrain ischemic gerbils. Dye extravasation was estimated by the fluorometric method. Slight extravasation was observed in the forebrain 1 days after ischemia, and was most severe 4 days after ischemia. Extravasation decreased in whole of brain in the hypothermic gerbils. When serum were administered through the lateral ventricle after forebrain ischemia under hypothermic conditions, neuronal death was detected in CA1 neurons of the hippocampus. Infarction volume 24 h after 1 h MCA occlusion decreased in none-albumin rats compared with normal rats. These results suggest that infiltration of serum factors into brain parenchyma may play a key role in ischemic neuronal death.
We examined the effect of serum on the production of super oxide (O_2^-), nitric oxide (NO) and tumor necrosis factor-α (TNF-α) in rat cultured microglia. We found that a serum factor, albumin, in … More creased phorbol ester (PMA)-induced O_2^- production and that serum also enhanced lipopolysaccharide (LPS)-induced production of NO and TNF-α. We identified the active site of this enhancement within the albumin molecule. The activated of a series of synthesized peptides conclusely indicated that the minimum active sequences was Leu-His-Thr-Leu. Activated microglia can release various neurotoxic mediators. Such neurotoxic mediators have been proposed to exert neuronal damage under brain ischemia. Therefore, suppression of microglial activation will open a new window for treatment of ischemic stroke.
We examined the protective effect of short-duration and mild hypothermia in combination with daily γ-glutamylethylamide (theanine) treatment on delayed neuronal death in transient forebrain ischemia of gerbils. Theanine was administered daily 5 mg/kg alter ischemia for 30 days. After survival of 30 days, the extent of CA1 neuronal damage in the hippocampus was assessed histologically. Short-duration and mild postischemic hypothermia combined with theanine treatment led to significant increase (67% and 72%, respectively) in viable CA1 neurons, compared to the control group (8% survival). These findings indicate that short-duration and mild hypothermia in combination with theanine has a beneficial effect on ischemic neuronal damage consistently. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Si Q: "A serum factor enhances production of nitric oxide and tumor necrosis factor-a from cultured microglia"Exp Neurol. 162. 89-97 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 柳瀬尚人: "グルタミン酸毒性と虚血神経細胞死"Brain Medical. 12. 176-180 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kataoka Y: "Neovascularization with blood-brain barrier breakdown in delayed neuronal death"Biochem Biophys Res Com. 273. 637-641 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kakuda T: "Protective effect of γ-glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils"Neurosci Lett. 289. 189-192 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Schubert P: "Cascading glia reactions : a common pathomechanism and its differenciated control by cyclic nucleotide signaling"Ann N Y Acad Sci. 903. 24-33 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakamura Y: "Identification of a peptide sequence in albumin that potentiates superoxide production by microglia"J Neurochem. 75. 2309-2315 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakamura Y: "Diferential regulation of microglial NO production by protein kinase C inhibitors"Neurochem Int. 38. 1-7 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirai T: "Potentiation of nuclear activator protein-1 DNA binding following brief exposure to N-methyl-D-aspartate in immature cultured rat hippocampal neurons"J Neurosci Res. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yanase H: "Brain Hypothermia"Springer-Verlag. 14 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Si Q., Nakamura Y., Kataoka K.: "A serum factor enhances production of nitric oxide and tumor necrosis factor-α from cultured microglia"Exp Neurol. 162. 89-97 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yanase H., Nakamura Y.: "Glutamate neurotoxicity and ischemic neuronal death"Brain Medical. 12. 176-180 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kataoka Y., Cui Y., Yamada H., Tsunomiya H., Niiya H., Yanase H., Nakamura Y., Mitani A., Kataoka K., Watanabe Y.: "Neovascularization with blood-brain barrier breakdown in delayed neuronal death"Biochem Biophys Res Com. 273. 637-641 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kakuda T., Yanase H., Utsunomiya K., Nozasa A., Unno T., Kataoka K.: "Protective effect of γ-glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils"Neurosci Lett. 289. 189-192 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Schubert P., Morino T., Miyazaki H., Ogata T., Nakamura Y., Marchini C., Ferroni S.: "Cascading glia reactions: a common pathomechanism and its differentiated control by cyclic nucleotide signaling"Ann NY Acad Sci. 903. 24-33 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakamura Y., Si Q.-S., Takaku T., Kataoka K.: "Identification of a peptide sequence in albumin that potentiates superoxide production by microglia"J Neurochem. 75. 2309-2315 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yanase H., Kataoka K.: "Neuroprotective effect of mild hypothermia in experimental brain ischemia"Hayashi N (Ed), Brain Hypothermia Springer-Verlag, Tokyo. 69-82 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakamura Y., Si Q.-S., Kataoka K.: "Diferential regulation of microglial NO production by protein kinase C inhibitors"Neurochem In. 38. 1-7 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hirai T., Kuramoto N., Maruyama H., Balcar V.J., Nakamura Y., Yoneda Y.: "Potentiation ot nuclear activator protein-1 DNAX binding following brief exposure to N-methyl-D-aspartate in immature cultured rat hippocampal neurons"J Neurosci Res. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakamura Y: "Differential regulation of microglial NO production by protein kinase C inhibitors"Neurochem Int.. 38. 1-7 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hirai T: "Potentiation of nuclear activator protein-1 DNA binding following brief exposure to N-methyl-D-aspartate in immature cultured rat hippocampal neutrons"J Neurosci Res.. (in press). (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Si Q: "A serum factor enhances production of nitric oxide and tumor necrosis factor-a from cultured microglia"Exp Neurol. 162. 89-97 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 柳瀬尚人: "グルタミン酸毒性と虚血神経細胞死"Brain Medical. 12. 176-180 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kataoka Y: "Neovascularization with blood-brain barrier breakdown in delayed neuronal death"Biochem Biophys Res Com. 273. 637-641 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kakuda T: "Protective effect of γ-glutamylethylamide (theanine) on ischemic delayed neuronal death in gerbils"Neurosci Lett. 289. 189-192 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yanase H: "Brain Hypothermia"Springer-Verlag. 14 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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