In Vivo Screen for Neuroprotective Agents

描述（由申请人提供）：神经元凋亡已被证明参与多种神经退行性疾病的发病机制，包括帕金森病（PD）、阿尔茨海默病（AD）、肌萎缩性侧索硬化症（ALS）和中风。目前，还没有简单的方法来评估脊椎动物体内的神经元凋亡或神经保护。此外，传统的脊椎动物试验，这是漫长和费力的，是不切实际的筛选化合物文库。在进行昂贵的哺乳动物试验之前，经过验证的体内试验将有助于预先筛选候选药物。本研究的总体目标是开发一种快速、定量的斑马鱼体内检测方法，以识别潜在的神经保护剂。第一阶段的研究建立了可重复的脑细胞凋亡模型，并开发了体内筛选神经保护剂的方法。II期研究将自动化分析以增加筛选通量，使用化合物库进行试点筛选，并使用传统的哺乳动物模型确认“命中”化合物的神经保护作用。在进行昂贵的哺乳动物试验之前，通过提供快速的体内试验来预筛选候选药物，拟议的斑马鱼试验将促进神经退行性疾病和中风的药物开发。

DESCRIPTION (provided by applicant): Neuronal apoptosis has been shown to be involved in pathogenesis of several neurodegenerative disorders including Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotophic Lateral Sclerosis (ALS) and stroke. Currently, there is no simple method to assess neuronal apoptosis or neuroprotection in vivo in vertebrates. Furthermore, conventional vertebrate assays, which are lengthy and laborious, are impractical for screening compound libraries. A validated in vivo assay will be useful for prescreening drug candidates prior to performing expensive mammalian testing. The overall aim of this research is to develop a rapid, quantitative in vivo zebrafish assay to identify potential neuroprotectants. Phase I research established a reproducible model for generating apoptosis in the brain and developed methods for screening neuroprotectants in vivo. Phase II research will automate the assay to increase screening throughput, perform a pilot screen using a compound library and confirm neuroprotective effects of "hit" compounds using a conventional mammalian model. By providing a rapid in vivo assay for prescreening drug candidates prior to performing expensive mammalian testing, the proposed zebrafish assay will facilitate drug development for neurodegenerative disorders and stroke.