MPTP INDUCED MODEL OF PARKINSON'S DISEASE

MPTP 诱发的帕金森病模型

• 批准号: 3476665
• 负责人: MADHU GUPTA
• 金额: $ 9.17万
• 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/3476665
• 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.

帕金森病是一种原发性退行性疾病， 总人口的1000人。 这种疾病影响多巴胺能神经元， 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，直到退行性过程相当 先进 虽然各种方法在寻找动物模型， 帕金森氏症已经进行，没有一个被证明是一个关闭 与人类帕金森病相似。 最近，人类管理 MPTP，一种强效神经毒素，无意中作为非法合成物注射 海洛因引起帕金森病症状和黑质纹状体变性， 人类 在非人灵长类动物和啮齿类动物中注射MPTP导致 帕金森综合征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模型 帕金森氏症 这些拟议的研究将审查 MPTP对黑质纹状体和非黑质纹状体单胺能系统的作用 C57 BL/6小鼠在不同的年龄。 我们将检验MPTP 改变中脑边缘多巴胺能和蓝斑去甲肾上腺素能 系统，除了黑质纹状体多巴胺系统。 基于我们 初步研究，我们将进一步测试的假设，MPTP的影响 在衰老的小鼠中，单胺能系统的退化， 已经开始作为一个与年龄有关的现象，将更加严重， 年轻的成年小鼠。 我们将在3、12和24个月大时用以下药物治疗小鼠： MPTP，并将检查单胺能系统与荧光 组织化学用于细胞和纤维定位，使用微穿孔 神经化学单胺及其代谢物的水平，并与 酪氨酸羟化酶、多巴胺-B-羟化酶、5-HT免疫细胞化学 对于黑质中的形态测定分析和细胞计数， 腹侧被盖区、蓝斑和中缝核。 最后我们 将用单胺氧化酶抑制剂Deprenil预处理小鼠， MPTP治疗，看看是否损害黑质纹状体多巴胺能和其他 单能系统可以通过用MAO抑制剂预处理来防止。 通过这种方法，我们将确定MPTP 年轻和衰老小鼠的给药可以用作模型， 帕金森病的解剖学和神经化学特征。