Fibroblast growth factor 20 is protective towards dopaminergic neurons in vivo in a paracrine manner


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Abstract

Neuroprotective strategies are an unmet medical need for Parkinson's disease. Fibroblast growth factor 20 (FGF20) enhances survival of cultured dopaminergic neurons but little is known about its in vivo potential. We set out to examine whether manipulation of the FGF20 system affected nigrostriatal tract integrity in rats, to identify which fibroblast growth factor receptors (FGFRs) might reside on dopaminergic neurons and to discover the source of endogenous FGF20 in the substantia nigra (SN). Male Sprague Dawley rats were subject to a partial 6-OHDA lesion alongside treatment with exogenous FGF20 or an FGFR antagonist. Behavioural readouts and tyrosine-hydroxylase (TH) immunohistochemistry were used to evaluate nigrostriatal tract integrity. Fluorescent immunohistochemistry was used to examine FGFR subtype expression on TH-positive dopamine neurons and FGF20 cellular localisation within the SN. FGF20 (2.5 μg/day) significantly protected TH-positive cells in the SN and terminals in the striatum, while reducing the development of motor asymmetry at 5, 8 and 11 days post lesion. Conversely, the FGFR antagonist PD173074 (2 mg/kg) significantly worsened both the 6-OHDA lesion and resultant motor asymmetry. Within the SN, TH-positive cells expressed FGFR1, 3 and 4 while FGF20 co-localised with GFAP-positive astrocytes. In conclusion, FGF20 protects dopaminergic neurons in vivo, an action likely mediated through activation of FGFRs1, 3 or 4 found on these neurons. Given FGF20 is localised to astrocytes in the adult SN, endogenous FGF20 provides its protection of dopamine neurons through a paracrine action. Boosting the endogenous FGF20 production might offer potential as a future therapeutic strategy in Parkinson's disease.HighlightsFGF20 infusion protects against a partial 6-OHDA nigrostriatal tract lesion in rats.Dopaminergic cells in the SNc express FGFR1, 3 and 4 upon which FGF20 can act.FGFR blockade exacerbates a partial 6-OHDA nigrostriatal tract lesion in rats.Endogenous FGF20 is expressed by astrocytes in the SN, not by dopaminergic neurons.Endogenous FGF20 most likely provides protection in a paracrine manner.

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