Role of Environment in Neuroprotection

环境在神经保护中的作用

• 批准号: 6858693
• 负责人: RICHARD J SMEYNE
• 金额: $ 17.34万
• 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/6858693
• 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)： 帕金森病是一种令人衰弱的神经疾病，每10万名50岁以上的人中就有20人患病。所有帕金森病患者中90%的病因不明。然而，副产物1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)的发现为帕金森病提供了一个有用的模型，似乎概括了人类疾病的病理。暴露于这种典型的“环境毒素”会导致黑质致密部(SNPC)多巴胺能神经元的选择性丧失。MPTP是一种脂溢性分子，它迅速进入大脑，并通过一系列中间产物被MAO-B酶代谢为MPP+。MPP+是多巴胺摄取机制的底物，它在神经细胞内蓄积并干扰电子传递链的复合体I。我们最近已经证明，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。由于帕金森病在细胞丢失和症状方面都是进行性的，如果有细胞生物学、药理学或非药理学的方法可以减轻细胞丢失，无论有没有疾病触发因素的中断，都将具有巨大的临床价值。或者，至少在出现症状时减缓细胞丢失的进展将是重要的。有一篇重要的文献可以追溯到1700年末的S，那就是改变动物的环境可以导致神经变化。这些变化表现为大脑大小增加，学习能力增强，最近有研究表明，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)中长大的小鼠可以免受MPTP毒性的保护。在本应用中，我们将研究并进一步建立EE模型。此外，我们将研究EE的组成部分(锻炼、环境复杂性的变化和/或社会互动)是否可以提供神经保护。此外，我们还将研究神经营养因子BDNF在EE依赖神经保护中的作用。申请中提出的工作和随后产生的结果将用作试点数据。我们认为，EE模型可能为预防PD症状和其他神经退行性疾病提供一种新的方法。

项目成果

Exercise protects against MPTP-induced neurotoxicity in mice.

• DOI: 10.1016/j.brainres.2010.01.053
• 发表时间: 2010-06-23
• 期刊: BRAIN RESEARCH
• 影响因子: 2.9
• 作者: Gerecke, Kimberly M.;Jiao, Yun;Pani, Amar;Pagala, Vishwajeeth;Smeyne, Richard J.
• 通讯作者: Smeyne, Richard J.