Abstract
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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterised by motor symptoms such as tremor, bradykinesia and postural instability[1]
Of the top 50 ranking drugs identified through interrogation of the Connectivity Map database (CMap) database to increase Fibroblast growth factor 20 (FGF20) gene transcription, a number were eliminated due to low blood-brain barrier (BBB) penetration probability
Other drugs were eliminated owing to contraindications for use in PD or known toxicity associated with chronic use
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterised by motor symptoms such as tremor, bradykinesia and postural instability[1]. We interrogated the transcriptional profiles of more than a thousand Food and Drug Administration (FDA)-approved drugs from the Broad Institute’s connectivity mapping database[17] to identify drugs that increase FGF20 gene transcription We selected those that cross the blood-brain barrier and have no contra-indication for use in PD, and screened for their ability to boost endogenous FGF20 protein production in vitro. We explored the protective efficacy of the best two drugs in a preliminary study in the partial 6-OHDA lesion rat model of PD, to generate proof of concept for our targeted repositioning approach. This approach revealed salbutamol and triflusal as the two most promising drugs of interest
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