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

我们首先通过全身注射3-硝基丙酸(3-NPA)建立亨廷顿病大鼠模型，然后尝试使用反义策略来保护症状。结果：1.急性3-NPA中毒可引起急性脑部症状，导致血脑屏障受损和纹状体坏死细胞死亡；慢性中毒可导致肢体低张性瘫痪并伴有运动障碍。血脑屏障功能障碍定位于中央外侧纹状体，纹状体外侧动脉内皮细胞和星形胶质细胞受损。纹状外侧动脉的特异性易损性(血脑屏障功能障碍)的机制概括如下：1)纹状外侧动脉分支角度陡峭，容易在分叉处形成湍流，损伤内皮细胞；ii)纹状外侧动脉一氧化氮(NO)的代谢处于较高水平：eNOS信息的表达和NOx的产生广泛存在；3)星形胶质细胞末端足部通过谷氨酸转运体主动摄取结构类似谷氨酸的3-NPA，星形胶质细胞比神经元更快地进入坏死。联合注射3-NPA和谷氨酸转运蛋白抑制剂可减少纹状体星形胶质细胞的死亡。侧脑室应用GLAST(谷氨酸转运体)反义基因可增加纹状体NOx水平，加重运动症状。更多地在侧纹状体局部应用反义寡核苷酸是否会改善症状，有待进一步研究。

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.