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Involvement of glial nitric oxide in central adverse effects induced by immunosuppressants.

Research Project

Project/Area Number 12672218
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 InstitutionFukuoka University (2001)
Kyushu University (2000)

Principal Investigator

KATAOKA Yasufumi  Faculty of Pharm. Sci., Fukuoka University Professor, 薬学部, 教授 (70136513)

Co-Investigator(Kenkyū-buntansha) OISHI Ryouzo  Kyushu University, Fac. of Medical Sci., Prof., 医学部・付属病院, 教授 (90112325)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsImmunosuppressants / Cyclosporine A / nitric oxide (NO, nitrogen monooxide) / Neurotoxicity / Blood-brain barrier / Glia / Climacterium / 血液脳関門
Research Abstract

The present study was designed to clarify the mechanisms mediating cyclosporine A (CsA)-induced nausea, vomiting and convusions and to evaluate an involvement of glial nitric oxide (NO) in CsA neurotoxicity. (1) Subchronic treatment with CsA produced a dose- and time-dependent increase in kaolin intake in rats, this being blocked by H1 and muscarinic antagonist. Ovariectomy increased the susceptibility to CsA-induced convulsions by accelerating an inhibitory action of CsA on GABA neural activity in the rat hippocampus. This event was blocked by estrogen replacement. These findings suggest that scopolamine and diphenhydramine may be possible regimens to alleviate and avoid nausea/vomiting in patients.with CsA and that climacterium is included in the risk factors for CsA neurotoxicity and this risk is lowered by estrogen replacement therapy. (2) CsA failed to evoke NO production but increased phenylephrine-evoked NO production, this inhibited by IPS receptor blocker in C6 glioma cells. In the mouse brain endbthelial (MBEC4) cells, CsA stimulated NO production and increased histamine-evoked NO production. The effects of CsA were examined on the permeability of MBEC4 cells cocultured with C6 cells, each cell layer placed on the top and bottom of the insert membrane, respectively. The presence of C6 cells remarkably aggravated CsA-increased permeability of MBEC4 cells to sodium fluorescein. These findings suggest that asrocytes contribute to the occurrence of CsA-induced dysfunction of the blood-brain barrier (BBB) triggering neurotoxicity. The CsA-enhanced NO production in the brain endothelial and glial cells may be operative for the dysfunction of BBB. In light of the present findings, we raised the possible regimens to alleviate and avoid neurotoxicity in patients and patients with climacterium under CsA therapy. CsA-incresed glial and endothelial NO production in the brain may trigger the dysfunction of BBB and neurotoxicity.

Report

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

    (20 results)

All Other

All Publications (20 results)

  • [Publications] S.Dohgu, Y.Kataoka et al.: "Involvement of glial cells in cyclosporine-increased permeability of brain endothelial cells"Cellular and Molecular Neurobiology. 20. 781-786 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] H.Ikesue, Y.Kataoka et al.: "Cyclosporine enhances α_1-adrenoceptor-mediated nitric oxide production in C6 glioma cells"European Journal of Pharmacology. 407. 221-226 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Yamashita, Y.Kataoka et al.: "Involvement of glial endothelin/nitric oxide in delayed neuronal death of rat hippocampus after transient forebrain isehemia"Cellular and Molecular Neurobiology. 20. 541-551 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] H.Shibaguchi, Y.Kataoka et al.: "Transient Hypoxia/Hypoglycemia Upregulates Endothelin B Receptors in Cultured Rat Astrocytes"GLIA. 31. 91-94 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Tominaga, Y.Kataoka et al.: "Overiectomy aggravates convulsions and hippocampal γ-aminobutyric acid inhibition induced by cyclosporin A in rats"European Journal of Pharmacology. 430. 243-249 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Y.Fujisaki, Y.Kataoka et al.: "Pharmacological characterization of cyclosporine A-induced kaolin intake in rats"Pharmacology, Biochemistry and Behavior. 70. 267-271 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Dohgu S., Kataoka Y., et al.: "Involvement of glial cells in cyclosporine-increased permeability of brain endothelial cells"Cellular and Molecular Neurobiology. 20. 781-786 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ikesue H., Kataoka Y., et al.: "Cyclosporine enhances ai-adrenoceptor-mediated nitric oxide production in C6 glioma cell"European Journal of Pharmacology. 407. 221-226 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamashita K., Kataoka Y., et al.: "Involvement of glial endothelim/nitric oxide in delayed neuronal death of rat hippocampus after transient forebrain ischemia"Cellular and Molecular Neurobioloty. 20. 541-554 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shibaguchi H., Kataoka Y., et al.: "Transient Hypoxia/Hypoglycemia Upregulates Bndothelin B Receptors in Cultured Rat Astrocytes"GLIA. 31. 91-94 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tominaga K., Kataoka Y., et al.: "Overiectomy aggravates convulsions and hippocampal r-aminobutyric acid inhibition induced by cyclosporin A in rats"European Journal of Pharmacology. 430. 243-249 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujisaki Y., Kataoka Y., et al.: "Pharmacological characterization of cyclosporine A-induced kaolin intake in rats"Pharmacology, biochemistry and Behavior. 70. 267-271 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] S.Dohgu, Y.Kataoka et al.: "Involvement of glial cells in cyclosporine-increased permeability of brain endothelial cells"Cellular and Molecular Neurobiology. 20. 781-786 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] H.Ikesue, Y.Kataoka et al.: "Cyclosporine enhances α1-adrenoceptor-mediated nitric oxide production in C6 glioma cells"European Journal of Pharmacology. 407. 221-226 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Yamashita, Y.Kataoka et al.: "Involvement of glial endothelin/nitric oxide in delayed neuronal death of rat hippocampus after transient forebrain ischemia"Cellular and Molecular Neurobiology. 20. 541-551 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] H.Shibaguchi, Y.Kataoka et al.: "Transient Hypoxia/Hypoglycemia Upregulates Endothelin B Receptors in Cultured Rat Astrocytes"GLIA. 31. 91-94 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Tominaga, Y.Kataoka et al.: "Overiectomy aggravates convulsions and hippocampal γ-aminobutyric acid inhibition induced by cyclosporin A in rats"European Journal of Pharmacology. 430. 243-249 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Y.Fujisaki, Y.Kataoka et al.: "Pharmacological characterization of cyclosporine A-induced kaolin intake in rats"Pharmacology, Biochemistry and Behavior. 70. 267-271 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] S.Dohgu,Y.Kataoka et al.: "Involvement of glial cells in cyclosporine-increased permeability of brain endothelial cells"Cellular and Molecular Neurobiology. 20. 781-786 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Ikesue,Y.Kataoka et al.: "Cyclosporine enhances α1-adrenoceptoe-mediated nitric oxide production in C6 glioma cells"European Journal of Pharmacology. 407. 221-226 (2000)

    • Related Report
      2000 Annual Research Report

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

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