Targeted repositioning identifies drugs that increase fibroblast growth factor 20 production and protect against 6-hydroxydopamine-induced nigral cell loss in rats

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.

FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response

“…Reports about the therapeutic effects of FGF20 on CNS conditions, except for PD and Alzheimer's disease (AD), are limited. FGF20 exerted a protective effect on dopamine neurons in a rat model of 6-hydroxydopamine-induced PD ( Boshoff et al, 2018 ; Fletcher et al, 2019 ). However, the role of FGF20 in the BBB after TBI is unknown.…”

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

“…To establish whether antipsychotic gene expression signatures were associated with gene expression of conditions representing known side-effects, we first conducted a high throughput in-silico screen against gene expression data from 415,252 human samples from 11,305 experimental series in the NCBI GEO repository using the Searchable Platform Independent Expression Database (SPIED, www.spied.org.uk) [18,19]. The SPIED tool facilitates querying of publicly available gene expression data from NCBI GEO with user-defined transcriptional signatures [8,9,11]. A major barrier to high throughput in-silico interrogation of human disease gene expression samples is that in many NCBI GEO series the case/control assignment of individual samples is not clear without manually curating the data (thus it is not practical to determine relative expression change across many hundreds or thousands of series).…”

FGF, Mechanism of Action, Role in Parkinson’s Disease, and Therapeutics

“…The effects of existing drugs on endogenous FGF 20 production in substantia nigra and striatum were studied. It was finally determined that salbutamol and trifluorofloxacin could be used to increase the FGF-20 level to resist the progression of Parkinson's disease ( Fletcher et al, 2019 ).…”