Saavedra Ana, Baltazar Graça, Santos Paulo, Carvalho Caetana M, Duarte Emília P
Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
Neurobiol Dis. 2006 Sep;23(3):533-42. doi: 10.1016/j.nbd.2006.04.008.
The effect of selective injury to dopaminergic neurons on the expression of glial cell line-derived neurotrophic factor (GDNF) was examined in substantia nigra cell cultures. H(2)O(2), mimicking increased oxidative stress, or l-DOPA, the main symptomatic treatment for Parkinson's disease, increased GDNF mRNA and protein levels in a time-dependent mode in neuron-glia mixed cultures. The concentration dependence indicated that mild, but not extensive, injury induced GDNF up-regulation. GDNF neutralization with an antibody decreased dopaminergic cell viability in H(2)O(2)-treated cultures, showing that up-regulation of GDNF was protecting dopaminergic neurons. Neither H(2)O(2) nor l-DOPA directly affected GDNF expression in astrocyte cultures, but conditioned media from challenged mixed cultures increased GDNF mRNA and protein levels in astrocyte cultures, indicating that GDNF up-regulation was mediated by neuronal factors. Since pretreatment with 6-OHDA completely abolished H(2)O(2)-induced GDNF up-regulation, we propose that GDNF up-regulation is triggered by failing dopaminergic neurons that signal astrocytes to increase GDNF expression.
在黑质细胞培养物中研究了对多巴胺能神经元的选择性损伤对胶质细胞源性神经营养因子（GDNF）表达的影响。模拟氧化应激增加的H₂O₂或帕金森病的主要对症治疗药物左旋多巴（l-DOPA），在神经元-胶质细胞混合培养物中以时间依赖性方式增加GDNF mRNA和蛋白水平。浓度依赖性表明，轻度而非广泛的损伤诱导GDNF上调。用抗体中和GDNF会降低H₂O₂处理的培养物中多巴胺能细胞的活力，表明GDNF的上调对多巴胺能神经元具有保护作用。H₂O₂和l-DOPA均未直接影响星形胶质细胞培养物中GDNF的表达，但来自受挑战的混合培养物的条件培养基会增加星形胶质细胞培养物中GDNF mRNA和蛋白水平，表明GDNF的上调是由神经元因子介导的。由于用6-羟基多巴胺（6-OHDA）预处理完全消除了H₂O₂诱导的GDNF上调，我们提出GDNF上调是由功能失调的多巴胺能神经元触发的，这些神经元向星形胶质细胞发出信号以增加GDNF的表达。
