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Development of Huntington's model animals and protection of the symptom by antisense strategy

Research Project

Project/Area Number 09558104
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field 神経・脳内生理学
Research InstitutionNagoya City University

Principal Investigator

NISHINO Hitoo  Professor Department of Physiology, Nagoya City University Medical School, 医学部, 教授 (60073730)

Co-Investigator(Kenkyū-buntansha) TORII Kunio  Researcher (General manager) Ajinomoto company, 中央研究所, 部長
HIDA Hideki  Department of Physiology, Nagoya City University Medical School, 医学部, 助手 (00305525)
AGUI Takashi  Professor Institute of Animal Research, Nagoya City University Medical School, 医学部, 助教授 (00212457)
FUKUDA Atsuo  Professor Departmet of Physiology, Hamamatsu Medical School (50254272)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1997: ¥6,500,000 (Direct Cost: ¥6,500,000)
Keywordsmitochondrial toxin / cell death / necrosis / lateral striatal / NO / neural transplantation / NO / ミトコンドリア毒 / 3-ニトロプロピオン酸 / 外側線条体動脈 / [Ca^<++>]_i
Research Abstract

We first developed Huntington's model rats by systemic administration of 3-nitropropionic acid (3-NPA) and then tried to protect the symptoms using antisense strategy.
1. Acute intoxication with 3-NPA induced acute brain symptoms and resulted in the damage of the BBB and necrotic cell death of the striatum, while chronic intoxication resulted in hypotonic paralysis in lower extremities with motor disturbances.
2. The dysfunction of the BBB localized to the centrolateral striatum with the damage in endothelial cells and astrocytes of the lateral striatal artery.
3. The mechanism of the specific vulnerability of the lateral striatal artery (the dysfunction of the BBB) is summarized as follows
i) The angle of branching is sharp in this artery, thus easy to make turbulent flow at the bifurcation and make damage in endothelial cells.
ii) The metabolism of nitric oxide (NO) in this artery is set at a higher level : the expression of eNOS message and the production of NOx are extensive.
iii) Astrocytic end-feet uptake actively 3-NPA, having a similar structure as glutamate, through their glutamate-transporter, and the astrocytes fell into necrosis faster than neurons.
4. Co-injection of 3-NPA and an inhibitor of the glutamate-transporter reduced the astrocytic cell death in the striatum.
5. Application of the antisense of GLAST (glutamate-transporter) in the lateral ventricle increased the level of NOx in the striatum and worsened the motor symptoms.
6. More localized application of the antisense in the lateral striatum will improve the symptom or not should be investigated in future study.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] H. Nishino et al: "The striatum is the most vulnerable region in the brain to mitochondrial energy compromise : a hypothesis to explain the speciic bulnerability"17. (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] K. Nkajima et al: "Mitochondrial inhibitors and neurodegenerative disorders"The Human Press (P. R. Sanberg, H. Nishino and C. V. Borlongan). 121-127 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] M. Kumazaki et al: "Mitochondrial inhibitors and neurodegenerative disorders"the Human Press (P. R. Sanberg, H. Nishino and C. V. Borlongan). 157-165 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishino, H., nakajima, K, et al.: "Estrogen protects against while testosterone exacerbates vulnerability of the lateral striatal artery to chemical hypoxia by 3-nitropropionic acid."Neurosci. Res.. 30. 303-312 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fukuda, A., Nishinno, H. et al.: "Astrocytes are more vulnerable than neurons to cellular CaィイD12+ィエD1 overload induced by a mitochondrial toxin, 3-nitropropionic acid."Neuroscience. 87. 497-507 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kumazaki, M., Nishino, H. et al.: "Mechanisms of action of 3-NPA : dopamine overflow and vulnerability of the lateral striatal artery."Mitochondrial inhibitors and neurodegenerative disorders (P. R. Sanberg, H. Nishino & C. Borlonga, eds.) (The Humana Press). 157-165 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nakajima, K., Nishino, H. et al.: "Gender related difference of the effect of 3-NPA on stiatal artey."Mitochondrial inhibitors and neurodegenerative disorders (P. R. Sanber, H. Nishino & C. Borlonga, eds.) (The Humana Press). 121-127 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hida, H., Hishino, H. et al.: "Dopa-producing astrocytes generated by adenoviral trasduction of human tyrosine hydroxylase gene : in vitro study and transplantation to hemiparkinson model rats."Neurosci. Res.. 35. 101-112 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] H.Nishino et al: "The striatum is the most vulnerable region in the brain to mitochondrial energy compromise: a hypothesis to explain the specific vulnerability"J.Neurotrauma. 17. 255-264 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] K.Nakajima et al: "Mitochondrial inhibitors and neurodegenerative disorders"The Human Press(P.R.Sanberg,H.Nishino and C.V.Borlongan). 121-127 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] M.Kumazaki et al: "Mitochondrial inhibitors and neurodegenerative disorders"The Human Press(P.R.Sanberg,H.Nishino and C.V.Borlongan). 157-165 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] S.B.Deshpande: "In vitro protection of 3-nitropropionic acid-induced toxicity of astrocytes by basic fibroblast growth factor and thrombin." Brain Res.783. 28-36 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Nishino: "Estrogen protects against while testosterone exacerbates vunerability of the lateral striatal artery to chemical hypoxia by 3-nitropropionic acid." Neurosci.Res.30. 303-312 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Hashitani: "Dopamine metabolism in the striatum of hemiparkinsonian model rats with dopaminergic grafts." Neurosci.Res.30. 43-52 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] C.V.Borlongan: "Early assessment of motor dysfunctions aids in successful occlusion of the middle cerebral artery." NeuroReport.9. 3615-3621 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] H.Nishino: "The striatum is the most vulnerable region in the brain to mitochondrial energy compromise." J.Neurotrauma. (in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] C.V.Borlongan: "Cell transplantation for neurological disorders" T.B.Freeman and H.Widner, 20 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] M.Kumazaki: "Mitochondrial inhibitors as a tool for neurobiology" P.R.Sanberg,H.Nishino and C.V.Borlongan (in press), (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] S.B.Deshpande, A.Fukuda & H.Nishino: "3-Nitropropionic acid increases the intracellular Ca^<2+> in cultured astrocytes by reverse operation of Na-Ca exchanger." Exp.Neurol.145. 38-45 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Nishino, M.Kumazaki, et al.: "Acute 3-Nitropropionic acid intoxication induces striatal astrocytic cell death and dyslunction of the blood-brain barrier.involvement of dopamine toxicity." Neurosci.Res.27. 343-355 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] C.V.Borlongan, H.Nishino & PR Sanberg: "Systemic,but not intraparenchymal,administration of 3-nitropropionic acid mimics the neuropathology of Huntington's disease:a speculative explanation." Neurosci.Res.28. 185-189 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] S.B.Deshpande, & H.Nishino: "In vitro protection of 3-nitropropionic acid-induced toxicity of astrocytes by basic fibroblast growth factor and thrombin." Brain Res.783. 28-36 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] H.Nishino, K.Nakajima, et al.: "Estrogen protects against while testosterone exacerbates vunerability of the lateral striatal artery to chemical hypoxia by 3-nitropropionic acid." Neurosci.Rev.(in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Shimano, M.Kumazaki, et al.: "Spatio-temporal pattern of dysfunction of the blood-brain barrier in the striatum after systemic intoxication with 3-nitropropionic acid (a mitochondrial toxin)." J.Brain Sci.(in press). (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] M.Kumazaki, C.Ungsuparkorn: "Mitochondrial inhibitors as a tool for neurobiology" Landes Pub.Co, 7 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] K.Nakajima, Y.Shimano, et al.: "Mitochondrial inhibitors as a tool for neurobiology" Landes Pub.Co, 6 (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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