Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
Center for Computation and Visualization, Brown University, Providence, Rhode Island, USA.
Sci Rep. 2022 Apr 21;12(1):6120. doi: 10.1038/s41598-022-10133-y.
Repurposing FDA-approved drugs is an efficient and cost-effective approach in the development of therapeutics for a broad range of diseases. However, prediction of function can be challenging, especially in the brain. We screened a small-molecule library with FDA-approved drugs for effects on behavior. The studies were carried out using zebrafish larvae, imaged in a 384-well format. We found that various drugs affect activity, habituation, startle responses, excitability, and optomotor responses. The changes in behavior were organized in behavioral profiles, which were examined by hierarchical cluster analysis. One of the identified clusters includes the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506), which are immunosuppressants and potential therapeutics in the prevention of Alzheimer's disease. The calcineurin inhibitors form a functional cluster with seemingly unrelated drugs, including bromocriptine, tetrabenazine, rosiglitazone, nebivolol, sorafenib, cabozantinib, tamoxifen, meclizine, and salmeterol. We propose that drugs with 'CsA-type' behavioral profiles are promising candidates for the prevention and treatment of Alzheimer's disease.
重新利用已获美国食品和药物管理局批准的药物是开发治疗广泛疾病的治疗方法的一种高效且经济有效的方法。然而，功能预测可能具有挑战性，特别是在大脑中。我们用美国食品和药物管理局批准的药物对小分子文库进行了筛选，以研究其对行为的影响。这些研究是使用斑马鱼幼虫进行的，以 384 孔格式进行成像。我们发现，各种药物会影响活动、习惯化、惊跳反应、兴奋性和光感受器反应。行为变化被组织成行为图谱，通过层次聚类分析进行检查。其中一个确定的集群包括钙调神经磷酸酶抑制剂环孢素（CsA）和他克莫司（FK506），它们是免疫抑制剂，也是预防阿尔茨海默病的潜在治疗药物。钙调神经磷酸酶抑制剂与看似无关的药物（包括溴隐亭、四苯嗪、罗格列酮、奈必洛尔、索拉非尼、卡博替尼、他莫昔芬、美克洛嗪和沙美特罗）形成了一个功能集群。我们提出，具有“CsA 型”行为特征的药物是预防和治疗阿尔茨海默病的有前途的候选药物。
