Role of Environment in Neuroprotection

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岁以上的人中有20人患有PD。>90%的PD病例的原因不明。然而，哌替啶副产物1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的发现提供了一种有用的帕金森病模型，其似乎概括了在人类中所见的疾病的病理学。暴露于这种典型的“环境毒素”导致黑质丘脑部（SNpc）中多巴胺能神经元的选择性丧失。MPTP是一种亲脂性分子，可迅速进入大脑，并通过一系列中间产物被酶MAO-B代谢为MPP+。MPP +是多巴胺摄取机制的底物，它在神经元内积累并干扰电子传递链的复合物I。我们最近已经表明，神经胶质细胞是关键的细胞，赋予保护或易感性，这种毒素。由于PD在细胞损失和细胞学方面都是进行性的，如果存在可以减弱细胞损失的细胞生物学、药理学或非药理学方法，无论是否中断疾病触发因素，都将具有巨大的临床价值。或者，至少，一旦出现症状，减缓细胞损失的进展是很重要的。有一个重要的文献，可以追溯到1700年代后期，改变动物的环境会导致神经系统的变化。这些变化表现为大脑体积的增加，学习能力的提高，最近已经表明环境可以增加神经发生。最近，我们有初步数据表明，在“富集环境”（EE）中饲养的小鼠可以免受MPTP毒性的影响。在此应用中，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（运动，环境复杂性和/或社会互动的改变）是否可以提供神经保护。此外，我们将研究神经营养因子BDNF在EE依赖性神经保护中的作用。拟议的工作和应用程序中产生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的方法。

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.