Fibroblast growth factor 20 is protective towards dopaminergic neurons in vivo in a paracrine manner.
Fibroblast growth factor 20 is protective towards dopaminergic neurons in vivo in a paracrine manner.
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成纤维细胞生长因子20在体内以旁分泌方式对多巴胺能神经元具有保护作用。
DOI：
10.1016/j.neuropharm.2018.04.017
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发表时间：
2018-07-15
影响因子：
4.7
通讯作者：
Duty S
中科院分区：
文献类型：
--
作者：
Boshoff EL;Fletcher EJR;Duty S
神经保护策略是帕金森病未满足的医疗需求。成纤维细胞生长因子20（FGF 20）可增强培养的多巴胺能神经元的存活，但对其在体内的潜力知之甚少。我们着手研究是否操纵FGF 20系统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）可能驻留在多巴胺能神经元，并发现内源性FGF 20的来源在黑质（SN）。雄性Sprague道利大鼠在用外源性FGF 20或FGFR拮抗剂治疗的同时经受部分6-OHDA损伤。行为读数和酪氨酸羟化酶（TH）免疫组化被用来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的FGFR亚型表达和SN内的FGF 20细胞定位。FGF 20（2.5 μg/天）显著保护SN中的TH阳性细胞和纹状体中的终末，同时在损伤后5、8和11天减少运动不对称的发展。相反，FGFR拮抗剂PD 173074（2 mg/kg）显著恶化了6-OHDA损伤和由此产生的运动不对称。在SN内，TH阳性细胞表达FGFR 1、3和4，而FGF 20与GFAP阳性星形胶质细胞共定位。总之，FGF 20在体内保护多巴胺能神经元，这种作用可能是通过激活这些神经元上发现的FGF 1、3或4介导的。鉴于FGF 20定位于成年SN中的星形胶质细胞，内源性FGF 20通过旁分泌作用提供其对多巴胺神经元的保护。促进内源性FGF 20的产生可能为帕金森病的未来治疗策略提供潜力。FGF 20输注保护大鼠免受部分6-OHDA黑质纹状体束损伤。SNc中的多巴胺能细胞表达FGFR 1、3和4，FGF 20可对其起作用。FGFR阻断加重大鼠中的部分6-OHDA黑质纹状体束病变。内源性FGF 20由SN中的星形胶质细胞表达，而不是由多巴胺能神经元表达。内源性FGF 20最可能以旁分泌方式提供保护。
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. FGF20 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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影响因子：
5.3
作者：
Ong, SH;Guy, GR;Lax, I
通讯作者：
Lax, I
DOI：
10.1006/bbrc.2000.3675
发表时间：
2000-10-22
影响因子：
3.1
作者：
Ohmachi, S;Watanabe, Y;Itoh, N
通讯作者：
Itoh, N
影响因子：
4.2
作者：
Ohmachi, S;Mikami, T;Itoh, N
通讯作者：
Itoh, N
影响因子：
6.1
作者：
Tong J;Ang LC;Williams B;Furukawa Y;Fitzmaurice P;Guttman M;Boileau I;Hornykiewicz O;Kish SJ
通讯作者：
Kish SJ
影响因子：
7.3
作者：
Betts, Matthew J.;O'Neill, Michael J.;Duty, Susan
通讯作者：
Duty, Susan