In Vivo Screen for Neuroprotective Agents

描述（由申请人提供）：已显示神经元凋亡涉及几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神经元凋亡或神经保护。此外，常规的脊椎动物测定法冗长且费力，对于筛选化合物文库是不切实际的。一个有效的体内试验将是有用的预筛选候选药物之前进行昂贵的哺乳动物试验。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，以鉴定潜在的神经保护剂。第一阶段研究建立了一个可重复的模型，在大脑中产生细胞凋亡，并开发了体内筛选神经保护剂的方法。第二阶段的研究将自动化检测，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。通过在进行昂贵的哺乳动物测试之前提供用于预筛选候选药物的快速体内测定，所提出的斑马鱼测定将促进用于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.