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| 144P London, UK Pharmacology 2017 |
Identifying FDA-approved drugs that boost endogenous FGF-20 for targeted repurposing in Parkinson’s disease
Introduction: Parkinson’s disease (PD) is characterised by impaired movement resulting from degeneration of the dopaminergic neurones in the substantia nigra pars compacta and reduced striatal dopaminergic innervation. Current treatments only provide symptomatic relief, highlighting the need for new disease-modifying therapies. We previously showed that brain infusions of exogenous fibroblast growth factor-20 (FGF-20) protected dopaminergic neurones in the 6-hydroxydopamine lesion rat model of PD (1). Identifying systemically active drugs that increase endogenous levels of FGF-20 would be favourable therapeutically as it would be far less invasive. The aim of this study was to identify FDA-approved drugs that could boost FGF-20 production, using a combination of bioinformatics, in vitro and in vivo studies.
Methods: Using in-house designed SPIED software (2), we interrogated the Broad Institute’s connectivity mapping database (3) of transcriptional profiles of 1,300 FDA-approved drugs to shortlist those that increased FGF-20 gene transcription (≥2 fold) in MCF-7 cells. To investigate whether shortlisted drugs increased FGF-20 protein production, MCF-7 cells were exposed to each drug (10μM) or vehicle for 24h (n=5 per drug). ELISA was performed on cell lysates obtained following 3 freeze/thaw cycles and centrifugation (10,000 rpm for 5 min). For one positive hit, salbutamol, the ability to boost endogenous FGF-20 protein production was assessed in mouse brain. Briefly, CD-1 mice (Charles River, UK) were treated with either salbutamol (50mg/kg; P.O.; n=4) or saline (n=4) twice-daily for 7 days. Levels of FGF-20 were measured in homogenates of striatum and mid-brain by Western blot and ELISA.
Results: Of the 20 candidate drugs short-listed following bioinformatics screening, nine increased the concentration of FGF-20 (3-4 fold) in MCF-7 cell lysates when compared to controls (propranolol: p<0.001, salbutamol: p=0.015, atenolol: p=0.02, dimethadione: p<0.001, trazodone: p=0.004, harmine: p=0.039, torsemide: p=0.043, ethaverine: p=0.015, triflusal: p=0.009; one-way ANOVA with Dunnett’s post-hoc). Following oral dosing, salbutamol significantly increased FGF-20 levels in mouse striatum (1.5 fold increase in ELISA; p=0.029, two-tailed t-test) but not in the mid-brain.
Conclusions: This study identified a number of promising FDA-approved drugs that increase FGF-20 production in vitro, at least one of which, salbutamol, also boosts FGF-20 production in the striatum of systemically-treated mice. Further in vivo studies are currently underway with the remaining compounds to identify those that boost FGF-20 production in the brain before examining their neuroprotective potential in the 6-OHDA lesion rat model of PD.
References:
1. Sleeman I.J. et al., (2012) Neuropharmacology 63:1268-77
2. Williams G. (2013). BMC Genomics 14: 765.