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Experimental Studies with Animal Model for Menkes Disease Treatment

Research Project

Project/Area Number 02670421
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Pediatrics
Research InstitutionHIROSAKI UNIVERSITY

Principal Investigator

YOSHIMURA Noriaki  Hirosaki University School of Medicine, Associate Professor, 医学部, 助教授 (60018893)

Co-Investigator(Kenkyū-buntansha) SATO Tsuyoshi  Hirosaki University School of Allied Medical Sciences,Associate Professor, 医療技術短期大学, 助教授 (80003490)
Project Period (FY) 1990 – 1992
Project Status Completed (Fiscal Year 1992)
Budget Amount *help
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1992: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1991: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1990: ¥900,000 (Direct Cost: ¥900,000)
KeywordsMenkes disease / Brain degeneration / Animal model / Copper therapy / Histochemistry / Copper-dependent enzymes / Tissue copper content / Prolongation of life / 脳変性機序 / 銅依存酵素活性レベル / モノアミン・オキシダ-ゼ
Research Abstract

The following results were obtained.
(1) Unlike normal controls, brindled mouse hemizygotes(BMs) exhibit persistently low copper concentration and low activities of cytochrome oxidase(CyO) and superoxide dismutase(SOD) in brain tissue during the postnatal period. Neuronal degeneration due to progressive mitochondrial ballooning proceeds around after postnatal day 8, dopamine-beta-hydroxylase activity in the brain drops almost to zero at about 12 days of age, and BMs die usually around at 15 days old.
(2) By a single subcutaneous injection of 50mug of cupric chloride to BMs on postnatal day 7, activities of CyO and SOD in brain tissue elevate gradually and reach the normal level 6 month(about 170 days) later. Although there are no significant pathologic changes in the brain, the copper concentration shows only a slight elevation and the normal level is not reached; it shows about 60% of the normal level even in BMs surviving until 24 months old.
(3) Monoamine oxidase(MAO) activity in brain … More tissue of normal mice shows an agedependent increase and that of BMs elevates similarly without any decline. This implies that MAO activity is not significantly involved in brain degeneration in Menkes disease.
(4) A new modification from the original method for MAO activity staining by Kishimoto and Arai, has been established. Observations of normal adult mouse brains by this new method have demonstrated that staining of MAO positive neurons(MAO activity) is well preserved until 4 hours after sacrifice if the brain tissue is kept at 4゚C, and almost permanently when kept at -70゚C. The result indicates that this modification is applicable to human tissue biopsied or autopsied.
(5) Copper injection by any methods after postnatal day 7 cannot rescue BM life. Not only a single injection on postnatal day 7, but also divided injections on postnatal day 5(20 mug) and day 7(30 mug) with or without a booster injection(10 mug) on day 9 can success in prolonging the survival of BMs. However, it is difficult to say that there is a significant difference in macro- and microscopic changes as well as copper-dependent enzyme activity in brain tisse obtained from BMs survived by different therapeutic maneuvers described above. In the case of Menkes patient treatment, however, it is presumed that divided injections, which may prevent renal injuriy(intoxication)by copper-overdose, should bring about a better result. Less

Report

(4 results)
  • 1992 Annual Research Report   Final Research Report Summary
  • 1991 Annual Research Report
  • 1990 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] YOSHIMURA Noriaki: "Chronological observations of histological changes、cytochrome oxidase activity and copper level in the brain of the postnatal brindled mouse." Acta Pathol Jpn. 40. 383-390 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 吉村 教あき: "Menkes病マウス脳のモノアミンオキシダーゼ活性レベル組織化学的および生化学的検討" 脳と神経. 43. 939-944 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] 吉村 教あき: "Menkes病マウス脳におけるチトクロムオキシターゼおよびスーパーオキシドジスターゼの活性低下と銅治療の効果" 臨床環境医学. 1. 95-100 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] YOSHIMURA Noriaki: "Complete recovery of cytochrome oxidase and superoxide dismutase activities in the brain of brindled mice re-ceiving copper-therapy." J Intell Disad Res. (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] YOSHIMURA Noriaki: "Dopamine-β-hydroxylase activity in the brain of brindled mice before and after receiving copper-therapy." J Intell Disad Res.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] YOSHIMURA Noriaki: "Long-term observation of copper concentration in brain tissue of brindled mice receiving copper-therapy." Trace Elements in Med.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshimura, N., Asada, M., Kida, K., Usutani, S., and Nishimura, M.: "Chronological observations of histological changes, cytochrome oxidase activity and copper level in the brain of the postnatal brindled mouse." Acta Pathol. Jpn.40. 383-390 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshimura, N., Hatayama, I., Sato, K., and Nishimura, M.: "Complete recovery of cytochrome oxidase and superoxide dismutase activities in the brain of brindled mice receiving copper-therapy." J. Intellec. Disab. Res.(1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshimura, N., Kida, K., and Usutani, S.: "Long-term observation of tissue copper concentration in various organs of brindled mice receiving copper-therapy." Trace Elements in Medicine.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshimura, N., Hatayama, I., Sato, K., Kida, K., and Usutani, S.: "Neuronal degeneration in the brain of brindled mice: Histochemical and biochemichal studies." Am. J. Pathol.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshimura, N., Sato, T., Takahashi, A., Akanuma, J., and Nishimura, M.: "Histochemical and biochemical investigations of monoamine oxidase activity level in the brain of the brindled mouse." Brain and Nerve(Tokyo). 43. 939-944 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshimura, N., Hatayama, I., Sato, K., Kida, K., and Usutani, S.: "Decreased activity of cytochrome oxidase and superoxide dismutase in the brain of the brindled mouse and the efficacy of copper therapy." Jap. J. Clin. Ecol.1. 95-100 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1992 Final Research Report Summary
  • [Publications] Yoshimura Noriaki: "Chronological observations of histological changes,cytochrome oxidase activity and copper level in the brain of the postnatal brindled mouse." Acta Pathol Jpn. 40. 383-390 (1990)

    • Related Report
      1992 Annual Research Report
  • [Publications] 吉村 教あき: "Menkes病マウス脳のモノアミンオキシダーゼ活性レベルの組織化学的および生化学的検討" 脳と神経. 43. 939-944 (1991)

    • Related Report
      1992 Annual Research Report
  • [Publications] 吉村 教あき: "Menkes病マウス脳におけるチトクロムオキシダーゼおよびスーパーオキシドジスムターゼの活性低下と銅治療の効果" 臨床環境医学. 1. 95-100 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yoshimura Noriaki: "Complete recovery of cytochrome oxidase and superoxide dismutase activities in the brain of brindled mice receiving copper-therapy." J Intell Disab Res. in press. (1993)

    • Related Report
      1992 Annual Research Report
  • [Publications] Yoshimura Noriaki: "Dopamine--hydroxylase activity in the brain of brindled mice before and after receiving copper-therapy." J Intell Disab Res.

    • Related Report
      1992 Annual Research Report
  • [Publications] Yoshimura Noriaki: "Long-term observation of copper concentration in brain tissue of brindled mice receiving copper-therapy." Trace Elements in Med.

    • Related Report
      1992 Annual Research Report
  • [Publications] 吉村 教あき: "Menkes病マウス脳のモノアミン・オキシタ-ゼ(MAO)活性レベルの組織化学的及び生化学的検討" 脳と神経. 43. 939-944 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Noriaki Yoshimura: "Histochemical and biochemical demonstration of decreased cytochrome oxidase and superoxide dismutase activities in the brain of the brindled mouse and of its complete recovery by copper supplementation." American Journal of Mental Retardation. (1993)

    • Related Report
      1991 Annual Research Report
  • [Publications] Noriaki Yoshimura: "Histochemical demonstration of ageーdependency of monoamine oxidase (MAO) activity and the enzyme localization in MAO containing neurons in the mouse brain." Molecular and Chemical Neuropathol.

    • Related Report
      1991 Annual Research Report
  • [Publications] Noriaki Yoshimura: "Chronological observations of histological changes,cytochrome oxidase activity and copper level in the brain of the postnatal brindled mouse" Acta Pathol Jpn. 40. 383-390 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Noriaki Yoshimura: "Histochemical and biochemical demonstration of decreased cytochrome oxidase and superoxide dismutase activities in the brain of the brindled mouse and of its complete recovery by copper supplementation." Molecular and Chemical Neuropathol. (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] Noriaki Yoshimura: "Histochemical and biochemical demonstration of normal activity of monoamine oxidase in the brain of the postnatal brindled mouse" Acta Neuropathol(Berl). (1991)

    • Related Report
      1990 Annual Research Report
  • [Publications] 吉村 教〓: "Brindled mouse脳のモノアミン・オキシタ-ゼ(MAO)活性レベルの組織化学的及び生化学的検討" 弘前医学. (1991)

    • Related Report
      1990 Annual Research Report

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Published: 1990-04-01   Modified: 2016-04-21  

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