Novel use of FDA-approved drugs identified by cluster analysis of behavioral profiles.
Novel use of FDA-approved drugs identified by cluster analysis of behavioral profiles.
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DOI：
10.1038/s41598-022-10133-y
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发表时间：
2022-04-21
影响因子：
4.6
通讯作者：
Creton, Robbert
中科院分区：
文献类型：
--
作者：
Edmister, Sara Tucker;Hernandez, Thais Del Rosario;Ibrahim, Rahma;Brown, Cameron A.;Gore, Sayali, V;Kakodkar, Rohit;Kreiling, Jill A.;Creton, Robbert
重新利用FDA批准的药物是一种有效且具有成本效益的方法，用于开发各种疾病的治疗方法。然而，预测功能可能具有挑战性，特别是在大脑中。我们用FDA批准的药物筛选了一个小分子文库，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孔格式成像。我们发现，各种药物影响活动，习惯化，惊吓反应，兴奋性和视动反应。行为的变化被组织在行为配置文件，这是由层次聚类分析。其中一个确定的集群包括钙调磷酸酶抑制剂环孢素（CsA）和他克莫司（FK 506），这是免疫抑制剂和潜在的治疗，在预防阿尔茨海默氏病。钙调磷酸酶抑制剂与看似无关的药物形成功能簇，包括溴隐亭、丁苯那嗪、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。我们认为，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希望的候选药物。
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.
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影响因子：
4
作者：
Liew WC;Orbán L
通讯作者：
Orbán L
影响因子：
14.8
作者：
Bruni G;Rennekamp AJ;Velenich A;McCarroll M;Gendelev L;Fertsch E;Taylor J;Lakhani P;Lensen D;Evron T;Lorello PJ;Huang XP;Kolczewski S;Carey G;Caldarone BJ;Prinssen E;Roth BL;Keiser MJ;Peterson RT;Kokel D
通讯作者：
Kokel D
影响因子：
64.8
作者：
Arron, Joseph R.;Winslow, Monte M.;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
8.8
作者：
Kondo, Takayuki;Imamura, Keiko;Inoue, Haruhisa
通讯作者：
Inoue, Haruhisa
影响因子：
2.7
作者：
Tucker Edmister S;Ibrahim R;Kakodkar R;Kreiling JA;Creton R
通讯作者：
Creton R