Barroso-Chinea Pedro, Cruz-Muros Ignacio, Aymerich María S, Rodríguez-Díaz Manuel, Afonso-Oramas Domingo, Lanciego José L, González-Hernández Tomás
Departamento de Anatomía, Facultad de Medicina, Universidad de La Laguna, 38207 La Laguna,Tenerife, Spain.
Eur J Neurosci. 2005 Apr;21(7):1815-27. doi: 10.1111/j.1460-9568.2005.04024.x.
Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily that when exogenously administrated exerts a potent trophic action on dopaminergic (DA) cells. Although we know a lot about its signalling mechanisms and pharmacological effects, physiological actions of GDNF on the adult brain remain unclear. Here, we have used morphological and molecular techniques, and an experimental model of Parkinson's disease in rats, to investigate whether GDNF constitutively expressed in the adult mesostriatal system plays a neuroprotective role on midbrain DA cells. We found that although all midbrain DA cells express both receptor components of GDNF (GFRalpha1 and Ret), those in the ventral tegmental area (VTA) and rostromedial substantia nigra (SNrm) also contain GDNF but not GDNFmRNA. The levels of GDNFmRNA are significantly higher in the ventral striatum (vSt), the target region of VTA and SNrm cells, than in the dorsal striatum (dSt), the target region of DA cells in the caudoventral substantia nigra (SNcv). After fluoro-gold injection in striatum, VTA and SNrm DA cells show triple labelling for tyrosine hydroxylase, GDNF and fluoro-gold, and after colchicine injection in the lateral ventricle, they become GDNF-immunonegative, suggesting that GDNF in DA somata comes from their striatal target. As DA cells in VTA and SNrm are more resistant than those in SNcv to intracerebroventricular injection of 6-OHDA, as occurs in Parkinson's disease, we can suggest that the fact that they project to vSt, where GDNF expression is significantly higher than in the dSt, is a neuroprotective factor involved in the differential vulnerability of midbrain DA neurons.
胶质细胞系源性神经营养因子（GDNF）是转化生长因子-β超家族的成员，外源性给予时对多巴胺能（DA）细胞具有强大的营养作用。尽管我们对其信号传导机制和药理作用了解很多，但GDNF在成人大脑中的生理作用仍不清楚。在这里，我们使用形态学和分子技术以及大鼠帕金森病实验模型，来研究在成年中脑纹状体系统中组成性表达的GDNF是否对中脑DA细胞发挥神经保护作用。我们发现，尽管所有中脑DA细胞都表达GDNF的两种受体成分（GFRα1和Ret），但腹侧被盖区（VTA）和嘴内侧黑质（SNrm）中的细胞也含有GDNF，但不含GDNFmRNA。GDNFmRNA在VTA和SNrm细胞的靶区腹侧纹状体（vSt）中的水平明显高于尾腹侧黑质（SNcv）中DA细胞的靶区背侧纹状体（dSt）。在纹状体注射氟金后，VTA和SNrm的DA细胞对酪氨酸羟化酶、GDNF和氟金呈三重标记，在侧脑室注射秋水仙碱后，它们变为GDNF免疫阴性，这表明DA细胞体中的GDNF来自其纹状体靶区。由于帕金森病中出现的脑室内注射6-羟基多巴胺（6-OHDA）时，VTA和SNrm中的DA细胞比SNcv中的DA细胞更具抗性，我们可以认为它们投射到GDNF表达明显高于dSt的vSt这一事实，是参与中脑DA神经元不同易损性的神经保护因素。
