Grant-in-Aid for Scientific Research (B).
|Research Institution||Nagoya City University|
NISHINO Hitoo Professor Department of Physiology, Nagoya City University Medical School, 医学部, 教授 (60073730)
鳥居 邦夫 味の素株式会社, 中央研究所, 部長
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, 医学部, 助教授 (50254272)
HIDA Hideki Department of Physiology, Nagoya City University Medical School, 医学部, 助手 (00305525)
TORII Kunio Researcher (General manager) Ajinomoto company
|Project Fiscal Year
1997 – 1999
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)
|Keywords||mitochondrial toxin / cell death / necrosis / lateral striatal / NO / neural transplantation / ミトコンドリア / 虚血 / ラジカル / 細胞死 / ハンチントン病 / 線条体 / 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|
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.