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

亨廷顿舞蹈症模型动物的开发和反义策略对症状的保护

基本信息

批准号：
09558104
负责人：
NISHINO Hitoo
金额：
$ 8万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

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 followsi) 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.

我们首先通过全身给药3-硝基丙酸（3-NPA）建立亨廷顿病模型大鼠，然后尝试采用反义策略保护症状。3-NPA急性中毒可引起急性脑症状，导致血脑屏障损伤和纹状体坏死细胞死亡，而慢性中毒可导致下肢低张力瘫痪并伴有运动障碍。中央外侧纹状体血脑屏障功能障碍伴外侧纹状体动脉内皮细胞和星形胶质细胞损伤。侧纹状体动脉特异性易损（血脑屏障功能障碍）的机制总结如下：1)该动脉分支角度尖锐，易在分叉处产生湍流，对内皮细胞造成损伤。ii)该动脉中一氧化氮（NO）的代谢处于较高水平：eNOS信息的表达和NOx的产生广泛。iii)星形胶质细胞终足通过谷氨酸转运体积极摄取与谷氨酸结构相似的3-NPA，星形胶质细胞比神经元更快进入坏死状态。3-NPA与谷氨酸转运体抑制剂联合注射可降低纹状体星形细胞的死亡。侧脑室谷氨酸转运体（GLAST）反义蛋白的应用增加了纹状体中氮氧化物的水平，加重了运动症状。在侧纹状体更局部地应用反义是否会改善症状，有待于进一步的研究。