Targeted repositioning identifies drugs that increase fibroblast growth factor 20 production and protect against 6-hydroxydopamine-induced nigral cell loss in rats
Targeted repositioning identifies drugs that increase fibroblast growth factor 20 production and protect against 6-hydroxydopamine-induced nigral cell loss in rats
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DOI：
10.1038/s41598-019-44803-1
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发表时间：
2019-06-06
影响因子：
4.6
通讯作者：
Duty, Susan
中科院分区：
文献类型：
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作者：
Fletcher, Edward J. R.;Jamieson, Aran D.;Duty, Susan
内源性成纤维细胞生长因子20 （FGF20）支持维持黑质纹状体通路内的多巴胺能神经元。此外，在帕金森病6-羟多巴胺损伤大鼠模型中，直接脑内灌注FGF20可防止黑质纹状体束损失。增加内源性FGF20的产生可能提供一种侵入性更小、更具转译性的方式来提供这种保护。因此，我们采用了一种靶向重新定位的方法来筛选fda批准的候选药物，这些药物有可能增强大脑内源性FGF20的产生。对Broad研究所的连接图谱数据库（CMap）进行的计算机分析显示，预计有50种候选药物可以增加FGF20的转录，其中16种具有有利于治疗帕金森病的特征。在这些药物中，有11种药物可以显著提高MCF-7细胞中FGF20蛋白的产量，提高幅度在2到4倍之间。选择4种药物进行体内试验。大鼠口服沙丁胺醇和三氟醚7天后，黑质纹状体束FGF20水平显著升高，而非二甲二酮或曲唑酮。对单侧6-羟多巴胺损伤大鼠的初步检查显示，这两种药物对神经细胞损失具有适度但显著的保护作用。我们的数据表明，靶向重新定位作为一种识别现有药物的方法，可以通过提高FGF20水平来对抗帕金森病的疾病进展。
Endogenous fibroblast growth factor 20 (FGF20) supports maintenance of dopaminergic neurones within the nigrostriatal pathway. Moreover, direct intracerebral infusion of FGF20 protects against nigrostriatal tract loss in the 6-hydroxydopamine lesion rat model of Parkinson's disease. Increasing endogenous FGF20 production might provide a less-invasive, more translational way of providing such protection. Accordingly, we adopted a targeted repositioning approach to screen for candidate FDA-approved drugs with potential to enhance endogenous FGF20 production in brain. In silico interrogation of the Broad Institute's Connectivity Map database (CMap), revealed 50 candidate drugs predicted to increase FGF20 transcription, 16 of which had profiles favourable for use in Parkinson's disease. Of these, 11 drugs were found to significantly elevate FGF20 protein production in MCF-7 cells, between two- and four-fold. Four drugs were selected for examination in vivo. Following oral dosing in rats for 7 days, salbutamol and triflusal, but not dimethadione or trazodone, significantly elevated FGF20 levels in the nigrostriatal tract. Preliminary examination in the unilateral 6-hydroxydopamine-lesioned rat revealed a modest but significant protection against nigral cell loss with both drugs. Our data demonstrate the power of targeted repositioning as a method to identify existing drugs that may combat disease progression in Parkinson's by boosting FGF20 levels.