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Microglial activation and blood-brain barrier function in ischemia-related neuronal death

Research Project

Project/Area Number 09670095
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

NIWA Masami  School of Medicine, Nagasaki University, Professor, 医学部, 教授 (20136641)

Co-Investigator(Kenkyū-buntansha) NAGAYAMA Yuji  School of Medicine, Nagasaki University, Lecturer, 医学部, 講師 (30274632)
SHIGEMATSU Kazuto  School of Medicine, Nagasaki University, Associate Professor, 医学部, 助教授 (20154205)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 1998: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
Keywordsischemia-related neuronal death / microglia / endothelin / endothelin receptor / blood-brain barrier / MCP-1 / vascular endothelial growth factor / hippocampus CA1 neurons / vascular endothelial growth factor / 脳血液関門
Research Abstract

We studied the pathophysiological significance of the blood-brain barrier function and microglial activation on our animal model of delayed neuronal death, based on the hypothesis that microglia across the damaged BBB is activated by monocyte chemotactic protein (MICP)-l produced by brain capillary endothelial cells, a main composer of the BBB, and the damaged BBB stimulates microglia with endothelin ET_B receptor to secrete vascular endothelial growth factor (VEGF) , a repair factor for the BBB.To test the hypothesis, we used our newly-developed method for analyzing the receptor dynamics ; the quantitative receptor-imaging system with three experimental techniques, 1) in vitro radioligand-binding technique for functional sites of receptors with ^1^2^51-MCP-I and ^1^2^5I-hVEGF.2) quantitative radioimmunohistochemical technique for sites of receptor proteins maturation with anti-MCP-1 and anti-hVEGF antibodies, and 3) in situ hybridization technique for production sites of receptors with ^3^5S-cRNA probes of MCP-l and VEGF receptors genes. At 7 days after transient forebrain ischemia, a time when neuronal death in the hippocampus CAl pyramidal cell layer occurred, the quantitative receptor autoradiographic method we used revealed a dramatic increase in number of ^1^2^5I-MCP-l binding sites. The de novo binding sites appeared in the area corresponding anatomically to the pyramidal cell layer with neuronal death and microglial aggregation. No changes were observed at 2 and 5 days after occlusion. Also, the de novo ^1^2^5I-hVEGF binding sites were detected in the area with a rich capillary in the CA I hippocampus area at 7 days after a transient forebrain ischemia. Taken together with the expression of MCP- I and VEGF receptor mRNA, we tentatively conclude that a dysfunction in the BBB occurs just before neuronal death and is closely related to microglial activation due to MCP-1.

Report

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

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Y.S-Yamashita: "Endothelin receptors in kainic acid-induced neural lesions of rat brain" Neuroscience. 81. 565-577 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yasuko S-Yamashita: "Expression of endothelin receptors and nitric oxide synthase activity in the brain of stroke-prone spontaneously hypertensive rats with cerebral apoplexy" Brain Research. 756. 61-67 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shigeki Shibata et al.: "Endothelin receptors in rat pituitary gland" Cellular and Molecular Neurobiology. 17. 89-100 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kazuhiko Shibata: "Up-regulation of angiotensin type 2mRNA by angiotensin II in rat cortical cells" Biochemical and Biophysical Research Communications. 239. 633-637 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山下樹三裕: "虚血性ニューロン死に関するグリアのエンドセリン-NO系" 日本薬理学雑誌. 111. 29-36 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ikuko Makino: "The increase in angiotensin type-2 receptor mRNA level by glutamate stimulation in cultured rat cortical cells" Brain Research. 804. 296-305 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Sakurai-Yamashita, M.Niwa, K.Yamashita, Y.Kataoka, A.Himeno, K.Shigematsu, K.Tsutsumi and K.Taniyama: "Endothelin receptors in kainic acid-induced neurallesions of rat brain" Neuroscience. 81. 565-577 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yasuko Sakurai-Yamashita, Kimihiro Yamashita, Yasufumi Kataoka, Akihiko Himeno, Masami Niwa and Kohtaro Taniyama: "Expression of endothelin receptors and nitric oxide synthase activity in the brain of stroke-prone spontaneously hypertensive rats with cerebral apoplexy." Brain Research. 756. 61-67 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shigeki Shibata, Akihiko Himeno, Kazuto Shigematsu, Keisuke Tsutsumi, Yasuko Sakurai-Yamashita and Kimihiro Yamashita: "Endothelin receptors in rat pituitary gland" Cellular and Molecular Neurobiology. 17. 89-100 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kazuhiko Shibata, Ikuko Makino, Hirotomo Shibaguchi, Masami Niwa, Takeshi Katsuragi and Tatsuo Furukawa: "Up-regulation of angiotensin type 2 mRNA by angiotensin II in rat cortical cells" Biochemical and Biophysical Research Communications. 239. 633-637 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kimihiro Yamashita, Yasuko Yamashita, Masami Niwa, Kohtaro Taniyama: "The glial endothelin-nitric oxide system in iscemia-related neuronal cell death" Folia Pharmacologica Japonica. 111. 29-36 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ikuko Makino, Kazuhiko Shibata, Hirotomo Shibaguchi, Masami Niwa, Takeshi Katsuragi, and Tatsuo Furukawa: "The increase in angiotensin type-2 receptor mRNA level by glutamate stimulation in cultured rat cortical cells" Brain Research. 804. 296-305 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 山下 樹三裕: "虚血性ニューロン死に関するグリアのエンドセリン-NO系" 日本薬理学雑誌. 111. 29-36 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Akihiko Himeno: "Ebdothelin-1 sinding to endothelin reaptons in the rat anterior pituiary gland:Interaction in the recognition of endothelin-1 between ET_A and ET_B receptors" Cellular and Molecular Neurobiology. 18. 459-464 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 重松和人: "脳内エンドセリンとその受容体" Clinical Neuroscience. 16. 1220-1221 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ikuko Makino: "The increase in angiotensintype-2 receptor mRNA level by glutamate stimulation in cultured rat cortical cells" Brain Research. 804. 296-305 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Carloss Manvel Diaz: "Glutathione related enzymeactivities in spontaneously hypertensive ratheart" Acta Medica Nagasakiensia. 43. 23-28 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shigeki Shibata ら: "The endothelin ET_A receptor existsin the caudal solitary tract nucleus of the rat brain" Cellular and Molecular Neurobiology. 17. 151-156 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yasuko Sakurai-Yamashita ら: "Expression of endothelin receptors and nitric oxide synthase autirty in the brain of stroke-pnere spontaneously hypertensue rats with cerebral apoplexy" Brain Research. 756. 61-67 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Sakurai-Yamashita ら: "Endothelin receptors in kainic acid-induced neural lesions of rat brain" Neuroscience. 81. 565-577 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kazuhiko Shibata ら: "Up-regulation of angiotenein type 2 mRNA by angiotensin II in rat cortical cells" Biochemical and Biophysical Research Iommunication. 299. 633-637 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 山下樹三裕 ら: "虚血性ニューロン死に関するグリアのエンドセリン-NO系" 日本薬理学雑誌. 111巻1号. 29-36 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] AKIHIKO HIMENO ら: "Endothelin-1 binding to endothelin receptors in the rat cnterior piluitery gland:Interaction in the recognition of endothdin-1 between ET_A and ET_B receptors" Cellular and Molecular Neurobiology. (印刷中). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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