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Immunosuppressants neurotoxicity : The mechanism of immunosuppressants-induced neurotoxicity and the prediction of its risk with gene polymorphisms.

Research Project

Project/Area Number 14370789
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionFukuoka University

Principal Investigator

KATAOKA Yasufumi  Fukuoka University, Faculty of Pharmaoeutical Sciences, Professor, 薬学部, 教授 (70136513)

Co-Investigator(Kenkyū-buntansha) TAKAHASHI Mitsuo  Fukuoka Univ., Faculty of Pharmaceutical Sciences, Prof., 薬学部, 教授 (70299543)
YAMAUCHI Atsushi  Fukuoka Univ., Faculty of Pharmaceutical Sciences, Assist.Prof., 薬学部, 助手 (90341453)
NIWA Masami  Nagasaki Univ., Graduate School of Medicine, Dept.of Pharmacology 1, Professor, 大学院・医歯学総合研究科, 教授 (20136641)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥13,800,000 (Direct Cost: ¥13,800,000)
Fiscal Year 2004: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2003: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2002: ¥8,400,000 (Direct Cost: ¥8,400,000)
KeywordsImmunosuppressants / cyclosporin A / tacrolimus / neurotoxicity / BBB / NO / TGF-β / genetic polymorphism / 一酸化窒素 / ペリサイト / 時間治療 / GABA受容体 / 肝移植患者 / P-糖蛋白質関連遺伝子
Research Abstract

Cyclosporin A(CsA) and tacrolimus(TCL), are widely used as a potent immunosuppressant to prevent allograft rejection in solid organ transplantation and to treat various autoimmune diseases including rheumatoid arthritis. Despite its high efficacy, theses immunosuppressants have adverse effects including renal dysfunction, cardiovascular disorders, gastrointestinal disorders and neurological complications. These events occur with a relatively high frequency (20-40%) in organ-transplanted patients. The entry of CsA and TCL into the brain is prevented by the tight junctions and P-glycoprotein(P-gp), a multi-drug efflux pump, of the brain microvascular endothelial cells. But the adverse neurolocical effects of CsA and TCL, including tremors, seizures and encephalopathy, strongly suggest the possibility of CsA and TCL transport across the blood-brain barrier(BBB). The objective of this study is to clarify the mechanism of immunosuppressants-induced neurotoxicity and the prediction of its ri … More sk with gene polymorphisms.
1.Potentially positive correlations between mutation in the multidrug resistant 1 gene(ABCB1) and neurotoxic events were detected. Mutation at position 2677 in exon 21 of ABCB1 gene may be an useful probe to predict TCL-induced neurotoxicity.
2.The BBB is a highly organized multicellular complex consisting of an endothelium, brain pericytes and astrocytes. Brain pericyte and astrocyte induce and maintain BBB function. The presence of pericytes and astrocytes markedly aggravated CsA-induced hyperpermeability and P-gp dysfunction in brain microvascular endothelial cells. This aggravation appears to occur due to the inhibition of transforming growth factor- □(TGF-□) production in brain pericytes and the enhancement of NO production in astrocytes.
3.The administration of TCL in the light phase produced a significantly greater increase than that in the dark phase in the duration of harmine-induced tremors in rats. This finding suggests that TCL neurotoxicity may be ameliorated by administration in the active phase of the diurnal cycle.
We tentatively conclude that the polymorphism in the ABCB1 gene and the pathological conditions accompanied with the inhibition of TGF-β production and/or the enhancement of NO production in the brain are included in the risk factors for immunosuppressants-induced neurotoxicity. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (21 results)

All 2005 2004 2002 Other

All Journal Article (15 results) Publications (6 results)

  • [Journal Article] Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-β production.2005

    • Author(s)
      Dohgu S.et al.
    • Journal Title

      Brain Res. 1038(2)

      Pages: 208-215

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-β production.2005

    • Author(s)
      Dohgu S. et al.
    • Journal Title

      Brain Res. 1038(2)

      Pages: 208-215

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production.2005

    • Author(s)
      Shinya Dohgu et al.
    • Journal Title

      Brain Research 1038・2

      Pages: 208-215

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Transforming growth factor-β1 upregulates the tight junction and p-glycoprotein of brain microvascular endothelial cells.2004

    • Author(s)
      Dohgu S.et al.
    • Journal Title

      Cell.Mol.Neurobiol. 24(3)

      Pages: 491-497

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tacrolimus-induced neurotoxicity and nephrotoxicity is ameliorated by the administration in the dark phase in rats.2004

    • Author(s)
      Yamauchi A.et al.
    • Journal Title

      Cell.Mol.Neurobiol. 24(5)

      Pages: 695-704

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in coculture of mouse brain endothelial cells and rat astrocytes.2004

    • Author(s)
      Dohgu S.et al.
    • Journal Title

      Eur.J.Pharmacol. 505(1-3)

      Pages: 51-59

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transforming growth factor-β1 upregulates the tight junction and p-glycoprotein of brain microvascular endothelial cells.2004

    • Author(s)
      Dohgu S. et al.
    • Journal Title

      Cell.Mol.Neurobiol. 24(3)

      Pages: 491-497

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Tacrolimus-induced neurotokicity and nephrotoxicity is ameliorated by the administration in the dark phase in rats.2004

    • Author(s)
      Yamauchi A. et al.
    • Journal Title

      Cell.Mol.Neurobiol. 24(5)

      Pages: 695-704

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in coculture of mouse brain endothelial cells and rat astrocytes.2004

    • Author(s)
      Dohgu S. et al.
    • Journal Title

      Eur.J.Pharmacol. 505(1-3)

      Pages: 51-59

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transforming growth factor-beta1 upregulates the tight junction and P-glycoprotein of brain microvascular endothelial cells.2004

    • Author(s)
      Shinya Dohgu et al.
    • Journal Title

      Cellular and Moleculer Neurobiology 24・3

      Pages: 491-497

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in cocultures of mouse brain endothelial cells and rat astrocytes.2004

    • Author(s)
      Shinya Dohgu et al.
    • Journal Title

      European Journal of Pharmacology 505・1-3

      Pages: 51-59

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Neurotoxicity induced by tacrolimus after liver transplantation : relation to genetic polymorphisms of the ABCB1 (MDR1) gene.2002

    • Author(s)
      Yamauchi A.et al.
    • Journal Title

      Transplantation 74(4)

      Pages: 571-573

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Neurotoxicity induced by tacrolimus after liver transplantation : relation to genetic polymorphisms of the ABCB1(MDR1)gene.2002

    • Author(s)
      Yamauchi A. et al.
    • Journal Title

      Transplantation 74(4)

      Pages: 571-573

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nitric oxide lowers the function of tight junction and P-glycoprotein at the blood-brain barrier.

    • Author(s)
      Yamauchi A.et al.
    • Journal Title

      Cell.Mol.Neurobiol. (In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Nitric oxide lowers the function of tight junction and P-glycoprotein at the blood brain barrier.

    • Author(s)
      Yamauchi A. et al.
    • Journal Title

      Cell.Mol.Neurobiol. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Shinya Dohgu et al.: "Uptake and efflux of quinacrine, a candidate for the treatment of prion diseases, at the blood-brain barrier."Cellular and Molecular Neurobiology. 24(2). 205-217 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shinya Dohgu et al.: "Transforming growth factor-β1 upregulates the tight junction and p-glycoprotein of brain microvascular endothelial cells."Cellular and Molecular Neurobiology. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Atsushi Yamauchi et al.: "Tacrolimus-induced neurotoxicity and nephrotoxicity is ameliorated by administration in the dark phase in rats."Cellular and Molecular Neurobiology. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Atsushi Yamauchi et al.: "Neurotoxicity induced by tacrolimus after liver transplantation : relation to genetic polymorphisms of the ABCB1 (MDR1) gene"Transplantation. 74・4. 571-573 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Koji Tominaga et al.: "Subchronic treatment with cyclosporin A decreases the binding properties of the GABA_A receptor in ovariectomized rats"Life Sciences. 72. 425-430 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yuko Fujisaki et al.: "Cyclosporine A-increased nitric oxide production in the rat dorsal hippocampus mediates convulsions"Life Sciences. 72. 549-556 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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