Role of Environment in Neuroprotection

环境在神经保护中的作用

• 批准号: 6783811
• 负责人: RICHARD J SMEYNE
• 金额: $ 19.47万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6783811
• 关键词: Parkinson' s disease; behavioral /social science research tag; brain derived neurotrophic factor; disease /disorder model; disease /disorder prevention /control; exercise; laboratory mouse; methylphenyltetrahydropyridine; neurotoxins; socioenvironment

DESCRIPTION (provided by applicant): PD is a debilitating neurological disorder that strikes 20 per 100,000 persons greater than 50 years of age. The cause of >90% of all PD cases are unknown. However, the discovery of the meperidine by-product 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has provided a useful model of Parkinsonism that appears to recapitulate the pathology of the disease seen in man. Exposure to this prototypical "environmental toxin" causes a selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). MPTP is a lipophillic molecule that rapidly enters the brain and is metabolized to MPP+ through a series of intermediates to MPP+ by the enzyme MAO-B. MPP + is a substrate for dopamine uptake mechanisms and it accumulates intraneuronally and interferes with complex I of the electron transport chain. We have recently shown that the glial cell is the critical cell for conferring protection or susceptibility to this toxin. Since PD is progressive, both in terms of cell loss and symptomotology, it would be of tremendous clinical value if there were cell biological, pharmacological or non-pharmacological methods that could attenuate cell loss; with or without interruption of the disease triggers. Alternatively, at the least, it would be important to slow the progression of cell loss once symptoms arose. There is a significant literature, dating back to the late 1700's that altering an animals' environment can lead to neurological changes. These changes are manifested as increased brain size, increased learning, and recently it has been shown that environment can increase neurogenesis. Recently, we have preliminary data to suggest that mice raised in an "Enriched Environment" (EE) are protected from MPTP toxicity. In this application, we will study and further establish the EE model. In addition, we will examine if the components (exercise, alterations in environmental complexity and/or social interactions) of the EE can confer neuroprotection. In addition, we will examine the role of the neurotrophin BDNF in EE-dependent neuroprotection. The work proposed and subsequent results generated in the application will be used as pilot data. We believe that the EE model may provide a new approach to prevention of PD symptomatology as well as other neurodegenerative disorders.

描述（由申请人提供）： PD 是一种使人衰弱的神经系统疾病，每 10 万名 50 岁以上的人中就有 20 人患有帕金森病。超过 90% 的帕金森病病例的病因尚不清楚。然而，哌替啶副产物 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 的发现提供了一个有用的帕金森病模型，它似乎概括了人类疾病的病理学。暴露于这种典型的“环境毒素”会导致黑质致密部（SNpc）中的多巴胺能神经元选择性丧失。 MPTP是一种亲脂性分子，快速进入大脑，并通过MAO-B酶通过一系列MPP+中间体代谢为MPP+。 MPP + 是多巴胺摄取机制的底物，它在神经元内积聚并干扰电子传递链的复合物 I。我们最近表明，神经胶质细胞是对这种毒素提供保护或易感性的关键细胞。由于帕金森病无论是在细胞损失还是症状学方面都是进行性的，如果有细胞生物学、药理学或非药理学方法可以减轻细胞损失，将具有巨大的临床价值；有或没有疾病触发因素的中断。或者，至少，一旦症状出现，减缓细胞损失的进程就很重要。有一篇重要的文献可以追溯到 1700 年代末，表明改变动物的环境可以导致神经系统的变化。这些变化表现为大脑尺寸增大、学习能力增强，最近研究表明环境可以增加神经发生。最近，我们有初步数据表明，在“丰富环境”(EE) 中饲养的小鼠可以免受 MPTP 毒性的影响。在本应用中，我们将研究并进一步建立EE模型。此外，我们将检查 EE 的组成部分（锻炼、环境复杂性的改变和/或社交互动）是否可以赋予神经保护作用。此外，我们将研究神经营养蛋白 BDNF 在 EE 依赖性神经保护中的作用。提议的工作和应用程序中生成的后续结果将用作试点数据。我们相信 EE 模型可能为预防 PD 症状以及其他神经退行性疾病提供一种新方法。