MODEL OF SLOWLY PROGRESSIVE PARKINSON'S DISEASE

缓慢进展的帕金森病模型

• 批准号: 6396020
• 负责人: J T GREENAMYRE
• 金额: $ 1.67万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6396020
• 关键词: Parkinson's disease; apoptosis; behavioral /social science research tag; corpus striatum; disease /disorder model; dopamine; intravenous administration; laboratory rat; model design /development; neurons; neurotoxicology; oxidative stress; plant insecticide

Current models of Parkinson's disease (PD) are inadequate, 6- Hydroxydopamine destroys the nigrostriatal pathway acutely and therefore bears little resemblance to the slowly progressive neurodegeneration that characterizes PD. Similarly, the MPTP model relies on acute administration of toxin although the toxin may be given repeatedly. In addition, the MPTP model is highly variable, with some animals becoming so severely ill that they require euthanasia, other animals never achieving an adequate level of parkinsonism, and some becoming ideally parkinsonian. Thus, there is a need for a reliable model that mimics the slow progression of PD. Studies in our laboratory indicate that chronic, continuous, systemic administration of the mitochondrial toxin, rotenone, selective destroys dopaminergic terminals in motor portions of striatum and leads over a period of weeks or months to retrograde degeneration of the dopaminergic cells of substantial nigra. Remarkably, systemic rotenone accurately reproduces the dopaminergic pathology of PD: dopaminergic terminals in striatum are lost while lose in nucleus accumbens are relatively spared; terminals in olfactory tubercle are completely spared; neurons in substantial nigra pars compacta degenerate while those in the adjacent ventral tegmental area survive. In the current proposal, we will: (1) use chronic intravenous infusion of rotenone to product in rats a model of slowly progressive degeneration of nigrostriatal dopaminergic neurons. Rotenone dosing and infusion duration will be optimized; (2) determine the anatomical specificity of dopaminergic neurodegeneration produced by rotenone infusion; (3) investigate potential mechanisms involved in this form of chronic neurodegeneration. Specifically, we will look for evidence of oxidative damage, indirect excitotoxicity, and determine whether cell death occurs via apoptosis or necrosis; (4) examine the behavioral consequence of this slow dopaminergic neurodegeneration; and (5) modify this model for use in primates using chemotherapy infusion pumps. Successful development of this model will allow us to (i) reliably adjust the rate and severity of dopamine depletion by adjusting infusion rate and duration; (ii) define the relevant mechanisms of neurodegeneration in an in vivo system that more accurately models the human disease; and (iii) test potential neuroprotective strategies in an in vivo model of chronic neurodegeneration that is highly relevant to PD.

目前的帕金森病（PD）模型是不够的，6- 羟多巴胺能迅速破坏黑质纹状体通路， 与慢性进行性神经退化 表征PD。类似地，MPTP模型依赖于急性给药 虽然毒素可以反复使用。此外，MPTP 模型是高度可变的，一些动物变得如此严重， 他们要求安乐死，其他动物从来没有达到足够的水平， 帕金森症，有些人会变成理想的帕金森症。由此可见，有一 需要一个可靠的模型来模拟PD的缓慢进展。研究 在我们的实验室表明，慢性，持续，系统 给予线粒体毒素鱼藤酮， 纹状体运动部分的多巴胺能末梢和a 多巴胺能神经元退行性变性的数周或数月的时间 黑质细胞。值得注意的是，系统鱼藤酮准确地 再现了PD的多巴胺能病理学： 纹状体丢失，而丘脑核丢失相对较少; 嗅结节中的终末完全保留; 黑质致密部退化，而邻近的黑质致密部退化 腹侧被盖区存活。在目前的建议中，我们将：（1）使用 慢性静脉输注鱼藤酮，以产生大鼠模型 黑质纹状体多巴胺能神经元缓慢进行性变性。 鱼藤酮的剂量和输注时间将得到优化;（2）确定 多巴胺能神经变性的解剖学特异性 鱼藤酮输注;（3）研究参与这一过程的潜在机制 一种慢性神经退化具体来说，我们会寻找证据 氧化损伤，间接兴奋毒性，并确定是否细胞 通过凋亡或坏死发生死亡;（4）检查行为学 这种缓慢的多巴胺能神经变性的后果;和（5）改变 该模型用于使用化疗输注泵的灵长类动物。 该模型的成功开发将使我们能够（i）可靠地调整 通过调整输注速率和 持续时间;（ii）定义神经变性的相关机制， 更准确地模拟人类疾病的体内系统;以及（iii） 在体内慢性脑缺血模型中测试潜在的神经保护策略 与PD高度相关的神经变性。