Role of Manganese in Neurodegenrative Disease

锰在神经退行性疾病中的作用

• 批准号: 6782504
• 负责人: DONALD R SMITH
• 金额: $ 32.5万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6782504
• 关键词: 6 hydroxydopamine; Parkinson' s disease; Rodentias; X ray spectrometry; basal ganglia; behavior test; behavioral /social science research tag; brain mapping; disease /disorder model; disease /disorder proneness /risk; dopamine; dosage; gamma aminobutyrate; manganese; metal poisoning; neural degeneration; neural transmission; neurochemistry; neuromuscular system; neurons; neuropsychology; neurotoxicology; neurotransmitters; pathologic process; tissue /cell culture

DESCRIPTION (provided by applicant): Recent studies have shown that chronic exposures to manganese (Mn) are associated with an increased risk for the development of neurodegenerative diseases, such as Parkinsonism. Concern over the potential neurotoxicity of low but chronic Mn exposure has increased in light of the incorporation of MMT into gasoline. The effects of Mn exposure in in vivo rodent models has focused on Mn-induced depletion of striatal dopamine, whereas non-human primate studies have more commonly shown gliosis in the globus pallidus. Also, most studies have utilized relatively high Mn exposures, while only a few have investigated the effects of chronic low-level Mn exposures. Here we are proposing that the locus of Mn toxicity may depend on the total cumulative Mn dose, such that more sensitive GABAergic systems of the globus pallidus are targeted at lower relative doses, while dopaminergic systems of the nigro-striatal pathway become involved at higher doses. To validate this, there is a need to investigate the effects of Mn on specific brain nuclei and neurotransmitter systems as a function of Mn exposure regimens in order to better characterize the overall susceptibility of the basal ganglia to Mn effects. Moreover, there is justified concern that increased chronic low-level Mn exposure may further undermine the functionality of the basal ganglia in susceptible populations in the early stages of neurodegenerative disease, and accelerate the emergence of neuromotor dysfunction. The specific aims of this study are to: (1) Determine the progression of Mn effects on brain regional Mn distribution, and neurochemical and neuromotor function, across different durations and low level doses of Mn exposures in a whole animal rodent model. And (2) Determine the effect(s) and underlying interaction(s) of Mn exposure on neurotoxicity and neuromotor performance in a rodent model of asymptomatic Parkinsonism, as a model of a susceptible population. These Aims will be pursued through several sub-aims focusing on the following major outcomes: (i) A Functional Observational Battery (FOB) of neuromotor performance; (ii) Particle induced X-ray emission (PIXE) analyses of in situ brain regional Mn levels; (iii) Neurochemical measures of GABAergic and dopaminergic metabolism/status in specific brain regions, and; (iv) Investigation of specific mechanisms underlying the Mn - GABAergic effect using cell culture models. These proposed studies will significantly extend our knowledge of chronic low level Mn neurotoxicity, by pursuing a unifying hypothesis of action of low-level chronic Mn exposure, and by investigating neurochemical and neuromotor outcomes of Mn exposure in conjunction with a moderate degree of sub-threshold Parkinsonism.

描述（由申请人提供）：最近的研究表明，慢性 接触锰 (Mn) 会增加罹患以下疾病的风险 神经退行性疾病的发展，例如帕金森症。关注 低水平但长期接触锰的潜在神经毒性在 鉴于将 MMT 掺入汽油中。锰暴露的影响 体内啮齿动物模型专注于锰诱导的纹状体多巴胺消耗， 而非人类灵长类动物的研究更常见地表明神经胶质细胞增生 苍白球。此外，大多数研究都采用了相对较高的锰暴露量， 而只有少数人研究了长期低水平锰的影响 曝光。在这里，我们提出锰毒性的轨迹可能取决于 总累积锰剂量，使得更敏感的 GABA 能系统 苍白球的目标剂量相对较低，而多巴胺能的 较高剂量时，黑质纹状体通路系统会参与其中。到 为了验证这一点，有必要研究 Mn 对特定的影响 脑核和神经递质系统与锰暴露方案的关系 为了更好地表征基底神经节的整体敏感性 对锰的影响。此外，人们有理由担心慢性病的增加 低水平的锰暴露可能会进一步破坏基础功能 神经退行性疾病早期易感人群的神经节 疾病，并加速神经运动功能障碍的出现。具体的 本研究的目的是：（1）确定锰对大脑影响的进展 区域锰分布以及神经化学和神经运动功能 整只动物不同持续时间和低水平的锰暴露剂量 啮齿动物模型。 (2) 确定影响和潜在的相互作用 锰暴露对啮齿动物模型神经毒性和神经运动性能的影响 无症状帕金森病，作为易感人群的模型。这些目标 将通过几个分目标来实现，重点关注以下主要目标 结果：（i）神经运动功能观察电池（FOB） 表现; (ii) 原位粒子诱导 X 射线发射 (PIXE) 分析 脑区域锰水平； (iii) GABAergic 的神经化学测量 特定大脑区域的多巴胺能代谢/状态； （四） 使用以下方法研究 Mn - GABA 能效应的具体机制 细胞培养模型。这些拟议的研究将显着扩展我们的 通过追求统一的方法，了解慢性低水平锰神经毒性的知识 低水平慢性锰暴露的作用假设，并通过调查 锰暴露与神经化学和神经运动结果相结合 中度亚阈值帕金森病。