MODEL OF SLOWLY PROGRESSIVE PARKINSON'S DISEASE

缓慢进展的帕金森病模型

• 批准号: 6112679
• 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: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112679
• 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.

目前帕金森氏病(PD)的模型是不充分的，6- 羟基多巴胺剧烈破坏黑质纹状体通路，因此 与缓慢进展的神经变性几乎没有相似之处 是帕金森病的特征。同样，MPTP模型依赖于急性给药 虽然这种毒素可能会被反复注射。此外，MPTP 模型是高度可变的，一些动物变得如此严重，以至于 他们需要安乐死，其他动物永远不会达到足够的水平 帕金森症，还有一些人变成了理想的帕金森症患者。因此，有一个 需要一个可靠的模型来模拟帕金森病的缓慢进展。研究 我们实验室显示慢性、持续性、全身性 给予线粒体毒素鱼藤酮选择性破坏 纹状体和导联运动部的多巴胺能终末 长达数周或数月的多巴胺能神经退行性变 实质黑质的细胞。值得注意的是，系统鱼藤酮准确 重现帕金森病的多巴胺能病理：多巴胺能终末 纹状体丢失，伏隔核丢失相对较少； 嗅结节中的终末完全幸免于难； 黑质致密部实质变性，而邻近黑质致密部退化 腹侧被盖区幸存下来。在目前的提案中，我们将：(1)使用 鱼藤酮慢性静脉滴注大鼠模型的建立 黑质纹状体多巴胺能神经元缓慢进行性变性。 优化鱼藤酮用量和输液时间；(2)确定 沙门氏菌致多巴胺能神经变性的解剖学特异性 鱼藤酮注射；(3)研究与此相关的潜在机制 慢性神经退行性变的形式。具体来说，我们将寻找证据 氧化损伤，间接兴奋毒性，并确定细胞 死亡通过细胞凋亡或坏死发生；(4)检查行为 这种缓慢的多巴胺能神经变性的后果；和(5)修改 这种型号用于灵长类动物使用化疗输液泵。 这一模式的成功开发将使我们能够(I)可靠地调整 调节输注速度和剂量对多巴胺耗竭速度和严重程度的影响 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 在慢性阻塞性肺疾病体内模型中测试潜在的神经保护策略 与帕金森病高度相关的神经变性。