MPTP INDUCED ANIMAL MODEL OF PARKINSON'S DISEASE

MPTP诱导的帕金森病动物模型

• 批准号: 3476668
• 负责人: MADHU GUPTA
• 金额: $ 9.37万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3476668
• 关键词: MAO inhibitors; Parkinson's disease; aging; animal age group; corpus striatum; disease /disorder model; dopamine receptor; dorsal raphe nucleus; fluorescence; high performance liquid chromatography; histochemistry /cytochemistry; immunocytochemistry; laboratory mouse; locus coeruleus; methylphenyltetrahydropyridine; model design /development; neural degeneration; neuroanatomy; neurochemistry; neuromuscular disorder chemotherapy; neuropharmacology; neurotoxins; nicotinic receptors; substantia nigra

Parkinson's disease is an idiopathic degenerative disorder affecting one in 1000 of the general population. This disorder affects the dopaminergic nigrostriatal system, as well as other monoaminergic systems, but does not become apparent clinically until the degenerative process is quite advanced. Although various approaches in search of an animal model of Parkinson's disease have been undertaken, none has proven to be a close parallel to human Parkinson's disease. Recently, human administration of MPTP, a potent neurotoxin, inadvertently injected as an illicit synthetic heroin produced Parkinsonian symptoms and nigrostriatal degeneration in humans. Injection of MPTP in non-human primates and rodents results in some motor disorder characteristic of Parkinsonism, and results in nigrostriatal degeneration. Thus MPTP may provide a model for some aspects of Parkinson's disease. These proposed studies will examine the effects of MPTP on the nigrostriatal and non-nigrostriatal monoaminergic systems in C57BL/6 mice at different ages. We will test the hypothesis that MPTP alters the meso-limbic dopaminergic and the locus coeruleus noradrenergic system, in addition to the nigrostriatal dopaminergic system. Based on our preliminary studies, we will further test the hypothesis that MPTP effects in aging mice, in which degeneration of the monoaminergic systems, has already begun as an age-related phenomenon, will be more severe than in young adult mice. We will treat mice at 3, 12, and 24 months of age with MPTP, and will examine the monoaminergic systems with fluorescence histochemistry for localization of cells and fibers, with micropunch neurochemistry for levels of monoamines and their metabolites, and with immunocytochemistry for tyrosine hydroxylase, dopamine-B-hydroxylase, 5-HT for morphometric analysis and cell counts in the substantia nigra, the ventral tegmental area, locus coeruleus, and raphe nuclei. Finally, we will pretreat mice with monoamine oxidase inhibitor, deprenil, prior to MPTP treatment to see if damage to the nigrostriatal dopaminergic and other monominergic systems can be prevented by pretreatment with MAO inhibitor. With this approach, we will establish the extent to which MPTP administration in young and aging mice can be used as a model for anatomical and neurochemical characteristics of Parkinson's disease.

帕金森氏病是一种特发性退行性疾病，影响 占总人口的1000。这种紊乱会影响多巴胺能 黑质纹状体系统以及其他单胺能系统，但不 在临床上变得明显，直到退变过程相当 高级。尽管各种方法都在寻找一种动物模型 帕金森氏症已经发生过，没有一例被证明是接近成功的 类似于人类的帕金森氏症。最近，人类对 MPTP，一种强有力的神经毒素，无意中作为非法合成药物注射 海洛因引起帕金森症状和黑质纹状体变性 人类。在非人灵长类和啮齿动物体内注射MPTP可导致 帕金森氏症的一些运动障碍特征，并导致 黑质纹状体变性。因此，MPTP可以为某些方面提供一个模型 帕金森氏症。这些拟议的研究将检验 MPTP对大鼠黑质纹状体和非黑质纹状体单胺能系统的影响 不同月龄C57BL/6小鼠。我们将测试MPTP的假设 改变中脑边缘多巴胺能区和蓝斑去甲肾上腺素能区 除了黑质纹状体的多巴胺能系统。基于我们的 初步研究后，我们将进一步检验MPTP效应的假设 在衰老的小鼠中，单胺类系统的退化 已经开始作为一种与年龄相关的现象，将比#年更严重 幼年成年小鼠。我们将在3个月、12个月和24个月大的时候用 MPTP，并将用荧光检测单胺能系统 细胞和纤维定位的组织化学，用微穿孔机 单胺及其代谢物水平的神经化学，以及 酪氨酸羟基酶、多巴胺B羟基酶、5-羟色胺的免疫细胞化学 为了对黑质进行形态计量分析和细胞计数， 腹侧被盖区、蓝斑和中缝核团。最后，我们 将用单胺氧化酶抑制剂Deprenil预处理小鼠，然后 MPTP治疗观察黑质纹状体多巴胺能等是否受损 单胺类神经系统可被MAO抑制剂预处理。 通过这种方法，我们将确定MPTP在多大程度上 幼龄和老年小鼠给药可作为一种模型 帕金森病的解剖和神经化学特征。