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Development of endothelin antagonists protecting against ischemic neuronal degeneration

Research Project

Project/Area Number 07672463
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionFaculty of Medicine, Kyushu University

Principal Investigator

KATAOKA Yasufumi  Kyushu University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (70136513)

Co-Investigator(Kenkyū-buntansha) NIWA Masami  Nagasaki University, Faculty of Medicine, Professor, 医学部, 教授 (20136641)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1996: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1995: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsEndothelin / Endothelin receptors / Endothelin antagonists / brain ischemia / brain damage / striatum / dopamine / nitric oxide
Research Abstract

The present study was aimed at elucidating a neuroprotective action of endothelin (ET) antagonists on ischemic neuronal degeneration with the in vitro and in vivo rat model for brain ischemia. (1) RES-701-1 (ETB antagonist) but not BQ-123 (ETA antagonist) inhibited the release of dopamine from rat striatal slices. (2) Striatal response to the test stimulation remained impaired up to 2 hr after the pulse exposure of ET-1 under conditions of hypoglycemia/hypoxia. We termed this event striatal dopaminergic dysfunction'. RES-701-1 but not BQ-123 led to a recovery from this striatal dysfunction. An inhibitor of nitric oxide synthase closely associated with ETB function improved ET-1 neurotoxicity. (3) The delayd neuronal death occurred in the hippocampus CA1 pyramidal cell layr of rats at 7 days after a 20-min bilateral carotid occlusion according to Pulsinelli's method. RES-701-1 and T-0201 (ETA/ETB antagonist) injected into the lateral ventricle 10 min after reperfusion protected against ischemic neuronal death. (4) The quantitative receptor autoradiographic method we used revealed a dramatic increase in 125-I-ET-1 binding sites in the hippocampus CA1 pyramidal cell layr with neuronal death. The de novo 125-I-ET-1 binding sites were characteristically the ETB receptor.
The present findings provide evidence that ETB antagonists could be operative for the treatment of ischemic brain damage.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] K.Yamashita: "Glial endothelin/nitric oxide system participates in hippocampus CA1 neuronal death of stroke-prone spontaneously hypertensive rats following transient forebrain ischemia" Clin.Exp.Pharmacol.Physiol.22. S277-S278 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H.Shibaguchi: "Nitri oxide contributes to endothelin-induced stimulation and neurotoxicity of dopaminergic function in rat striatal slices" Cell.Mol.Neurobiol.(in press). (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] K.Yamashita: "Glial endothelin/nitric oxide system participates in hippocampus CA1 neuronal death of stroke-prone spontaneously hypertensive rats following transient forebrain ischemia" Clin.Exp.Pharmacol.Physiol.22. S277-S278 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] H.Shibaguchi: "Nitri oxide contributes to endothelin-induced stimulation and neurotoxicity of dopaminergic function in rat striatal slices" Cell.Mol.Neurobiol.(in press). (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] K.Yamashita: "Glial endothelin/nitric oxide system participates in hippocampus CA1 neuronal death of stroke-prone spontaneously hypertensive rats following transient forebrain ischemia" Clin.Exp.Pharmacol.Physiol.22. S277-S278 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] H.Shibaguchi: "Nitri oxide contributes to endothelin-induced stimulation and neurotoxicity of dopaminergic function in rat striatal slices" Cell.Mol.Neurobiol.(in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] S. Koizumi, Y. Kataoka, K. Inoue et al.: "Contribution of L-type Ca2_+ channels to long-term enhancement of high K_+-evoked release of dopamine from rat striatal slices" Neuroscience Letters. 187. 123-126 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Y. Kataoka, S. Koizumi, M. Kohzuma et al.: "NMDA receptor involvement in endotheline neurotoxicity in rat striatal slices" European Journal of Pharmacology. 273. 285-289 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] M. N. Nakashima, K. Yamashita, Y. Kataoka et al.: "Time course of nitric oxide synthase activity in neuronal, glial and endothelial cells of rat striatum following focal cerebral ischemia" Cellular and Molecular Neurociology. 15. 341-349 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] K. Yamashita, Y. Kataoka, Y. S. Yamashita et al.: "Glial endothelin/nitric oxide system participates in hippocampus CA1 neuronal death of stroke-prone spontaneously hypertensive rats following transient forebrain ischemia" Clinical and Experimental Pharmacology and Physiology. (in press). (1996)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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