King's College London, Institute of Psychiatry, Psychology & Neuroscience, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK.
King's College London, Institute of Psychiatry, Psychology & Neuroscience, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK.
Neuropharmacology. 2018 Jul 15;137:156-163. doi: 10.1016/j.neuropharm.2018.04.017. Epub 2018 Apr 23.
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.
神经保护策略是帕金森病未满足的医学需求。成纤维细胞生长因子 20（FGF20）可增强培养的多巴胺能神经元的存活率，但对其体内潜力知之甚少。我们着手研究 FGF20 系统的操作是否会影响大鼠黑质纹状体束的完整性，以确定哪些成纤维细胞生长因子受体（FGFR）可能存在于多巴胺能神经元上，并发现黑质（SN）中内源性 FGF20 的来源。雄性 Sprague Dawley 大鼠在接受 6-羟基多巴胺（6-OHDA）部分损伤的同时接受外源性 FGF20 或 FGFR 拮抗剂治疗。行为读数和酪氨酸羟化酶（TH）免疫组织化学用于评估黑质纹状体束的完整性。荧光免疫组织化学用于检查 TH 阳性多巴胺神经元上 FGFR 亚型的表达以及 SN 内 FGF20 的细胞定位。FGF20（2.5μg/天）显著保护 SN 中的 TH 阳性细胞和纹状体中的终末，同时减少损伤后 5、8 和 11 天的运动不对称发展。相反，FGFR 拮抗剂 PD173074（2mg/kg）显著加重 6-OHDA 损伤和由此产生的运动不对称。在 SN 中，TH 阳性细胞表达 FGFR1、3 和 4，而 FGF20 与 GFAP 阳性星形胶质细胞共定位。总之，FGF20 在体内保护多巴胺能神经元，其作用可能通过激活这些神经元上的 FGFR1、3 或 4 介导。鉴于 FGF20 在成年 SN 中的星形胶质细胞中定位，内源性 FGF20 通过旁分泌作用为多巴胺能神经元提供保护。增强内源性 FGF20 的产生可能为帕金森病的未来治疗策略提供潜力。
