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A possible new drug for Parkinson's disease regulating dopamine receptor genes.

Research Project

Project/Area Number 04557037
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionThe University of Tokyo

Principal Investigator

KANAZAWA Ichiro  Faculty of Medicine, The University of Tokyo, Professor, 医学部(病), 教授 (30110498)

Co-Investigator(Kenkyū-buntansha) KUSUNOKI Susumu  The University of Tokyo Faculty of Medicine, assistant professor, 医学部, 助手 (90195438)
Project Period (FY) 1992 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥16,200,000 (Direct Cost: ¥16,200,000)
Fiscal Year 1994: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1993: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1992: ¥9,200,000 (Direct Cost: ¥9,200,000)
Keywordslovodopa / dopamine receptor / promotor analysis / BDNF / POV family / cytochrome P-450 / Parkinson's disease / ドパミンレセプター / ヒトゲノミックDNA / 線条体細胞培養 / 黒質細胞培養 / 神経栄養因子 / L-DOPA
Research Abstract

The aims of the present study are to investigate the pharmacodynamics of levodopa, to elucidate the relationship between levodopa and neurotrophic factors, to analyze the gene for dopamine receptors and to clarify the genetic background of idiopathic Parkinson's disease. Summary of the results are as follows :
(1) In the long-term treatment of Parkinson's disease with levodopa, we often encountered with a loss of efficacy. In the study for elucidating the mechanism of this phenomenon, we found that the long-term oral administration of levodopa brought about an acceleration of absorption of levodopa from gut.
(2) In order to investigate the relationship between levodopa and the neurotrophic factors, we investigated the effect of orally administered levodopa on the amopunt of expressed mRNA level of brain-derived neurotrophic factos (BDNF) in the striatum of rat. mRNA for BDNF significantly increased from 2 hour through 16 hours after the administration of the final dose of levodopa. Interestingly, this increase was abolished by the co-administration of haloperidol.
(3) The gene for the human D1 dopamine receptor was cloned and investigated the expression dynamics in terms of the regulation mechanisms. Collaborated with Dr. Mouradian in NIH,we found that the Brn-4, a member of the POU family, bound to the D1 enhancer at 2 sites and suppressed the D1 gene expression.
(4) Sporadic Parkinson's disease could be caused by a toxic material coming from outside, and this material could be normally detoxicated and poorly metabolised in Parkinson's disease patient. We investigated the relationship between the detoxicating activity and the genetic polymorphism of cytochrome p-450 and found a positive relationship between them.

Report

(4 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • 1992 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Okazawa H., Murata M., Watanabe M., Kamei M.and Kanazawa I.: "Dopaminergic stimulation up-regulates the in vivo expression of brain-derived neurotrophic factor (BDNF) in the striatum." FEBS. 313. 138-142 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Murata M.and Kanazawa I.: "Repeated L-DOPA administration reduces the ability of dopamine storage and abolishes the supersensitivity of dopamine receptors in the striatum of intact rat." Neuroscience Research. 16. 15-23 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Okazawa H., Kamei M.and Kanazawa I.: "Molecular cloning and expression of a novel truncated form of chicken trkC." FEBS. 329. 171-177 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yokota H., Tamaru S., Furuya H., Kimura S., Watanabe M., Kanazawa I., Kondo I.and Gonzalez FJ.: "Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo rates of sparteine metabolism." Pharmacogenetics. 3. 256-263 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Imafuku I., Kamei M., Kanazawa I., Mouradian MM.and Okazawa H.: "POU Transcription Factors Differentially Regulate the D1A Dopamine Receptor Gene in Cultured Cells." Biochemical and Biophysical Research Communications. 222. 736-741 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Okazawa H., Imafuku I., Minowa MT., Kanazawa I., Hamada H.and Mouradian MM.: "Regulation of striatal D1A dopamine receptor gene transcription by Brn-4." Proc.Natl.Acad.Sci.USA,. 93. 11933-11938 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Okazawa H., Murata M., Watanabe M., Kamei M.and Kanazawa I.: "Dopaminergic stimulation up-regulates the in vivo expression of brain-derived neurotrophic factor(BDNF)in the striatum." FEBS. 313 (2). 138-142 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Murata M.and Kanazawa I.: "Repeated L-DOPA administration reduces the ability of dopamine storage and abolishes the supersensitivity of dopamine receptors in the striatum of intact rat." Neuroscience Research. 16. 15-23 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Okazawa H., Kamei M.and Kanazawa I.: "Molecular cloning and expression of a novel truncated form of chicken trkC." FEBS. 329 (1,2). 171-177 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Yokota H., Tamaru S., Furuya H., Kimura S., Watanabe M., Kanazawa I., Kondo I.and Gonzalez FJ.: "Evidence for a new variant CYP2D6 allele CYPD206J in Japanese population associated with lower in vivo rates of sparteine metabolism." Pharmacogenetics. 3. 256-263 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Imafuku I., Kamei M., Kanazawa I., Mouradian MM.and Okazawa H.: "POU Transcription Factors Differentially Regulate the D1A Dopamine Receptor Gene in Cultured Cells." Biochemical and Biophysical Research Communications. 222. 736-741 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Okazawa H., Imafuku I., Minowa MT., Kanazawa I., Hamada H.and Mouradian MM.: "Regulation of striatal D1A dopamine receptor gene transcription by Brn-4." Proc.Natl.Acad.Sci.USA. 93. 11933-11938 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 村田美穂,金澤一郎: "Dopamine receptorの分子生成物学と臨床的意義" Ammual Review 神経 1994. 12-20 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 金澤一郎: "Parkinson病の病態解明の現状" 内科. 73. 805-811 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Okazawa H.,Kamei M.,Imafuku I and Kanazawa I: "Gene reguration of trkB and trkC in the chick retina by Iight/darkness exposure." Oncogene. 9. 1813-1818 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kanazawa I: "Short review on monoamine oxidase and its inhibitors." Eur Neurol (suppI 3). 34. 36-39 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yanagisawa N,Kanazawa I,Goto I,Kowa H,kuno S,Mizuno Y,・・・・・: "Seven-year follow-up shudy of bromocriptine therapy for Parkinson′disease." Eur Neurol(supp1 3). 34. 29-35 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kondo I & Kanazawa I: "Debrosoquine hydroxylase and Parkinson's disease" Advances in Neurology. 60. 338-342 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Murata M & Kanazawa I: "Repeated L-DOPA administration reduces the ability of dopamine storage and abolishes the supersensitivity" Neuroscience Research. 16. 16-23 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Okazawa H,Nishiyama K,---Kanazawa I: "Trk immunoreactivity at neuronal dendrite & cell body" Biochemical Biophysical Research Communi.194. 683-690 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Okazawa H,Kamei M,& Kanazawa I: "Molecular cloning and expression of a novel truncated form of chicken trkC" FEBS Letters. 329. 171-177 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Yokota H,Tamura S,--Kanazawa I---: "Evidence for a new variant CYP2D6 allele CYP2D6J in a Japanese population associated with lower in vivo---" Pharmacokinetics. 3. 256-263 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Okazawa H,Murata M,Watanabe M,kamei M,Kanazawa I: "Dopaminergic stimulation up-regulates in vivo expression of brain derived neurotrophic factor(BDNF) in the striatum." FEBS Letters. 313. 138-142 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Murata M,Kanazawa I: "Repeated L-DOPA administration accelerates the dopamine metabolism and induces a loss of hypersensitivity of the dopamine receptor in the striatum of the intact rat." Neuroscience Res.

    • Related Report
      1992 Annual Research Report
  • [Publications] Okazawa H,Kamei M,Kanazawa I: "A non-catalytic form of chicken trk C expressed in the central nervous system." Oncogene.

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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