H2O2- or l-DOPA-injured dopaminergic neurons trigger the release of soluble mediators that up-regulate striatal GDNF through different signalling pathways.
H2O2- or l-DOPA-injured dopaminergic neurons trigger the release of soluble mediators that up-regulate striatal GDNF through different signalling pathways.
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DOI：
10.1016/j.bbadis.2014.03.003
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发表时间：
2014-07
期刊：
影响因子：
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通讯作者：
C. P. Fonseca;Susana Gama;Ana Saavedra;G. Baltazar
中科院分区：
文献类型：
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作者：
C. P. Fonseca;Susana Gama;Ana Saavedra;G. Baltazar
胶质细胞源性神经营养因子(GDNF)是一种有效的神经保护分子，可保护帕金森病患者黑质纹状体通路的多巴胺能神经元。我们之前已经证明，过氧化氢或3，4-二羟基苯丙氨酸(L-多巴)刺激的多巴胺能神经元可以触发可溶性因子的释放，向腹侧中脑星形胶质细胞发出信号，促进胶质细胞源性神经营养因子的表达。在目前的工作中，我们评估了腹侧中脑挑战细胞释放的因子是否能够改变纹状体细胞中GDNF的表达，纹状体细胞是黑质投射的多巴胺能神经元的靶标，并研究了相关的信号通路。我们的数据显示，在H_2O_2-Orl-DOPA诱导的多巴胺能损伤中释放的可溶性介质上调了纹状体细胞中GDNF的表达，其时间模式取决于所使用的氧化剂。来自H_2O_2-O_1-DOPA挑战的中脑星形胶质细胞培养的条件培养液未能上调纹状体培养中的GDNF。同样，H_2O_2或l-DOPA对纹状体GDNF水平没有直接影响，提示GDNF的上调是由在多巴胺能神经元衰竭时释放的可溶性因子介导的。磷脂酰肌醇3-激酶(PI3K)和丝裂原活化蛋白激酶(MAPK)通路均参与了H_2O_2诱导的多巴胺能损伤引起的纹状体GDNF表达上调，而在1-DOPA刺激的多巴胺能神经元存在下释放的扩散因子通过激活MAPK通路诱导纹状体细胞GDNF表达。这些可溶介质在未来可能成为控制内源性GDNF表达的重要靶点，从而能够开发出新的、有望更有效的神经保护/神经恢复策略来治疗帕金森氏病。
Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective molecule for dopaminergic neurons of the nigrostriatal pathway that degenerate in Parkinson's disease. We have previously shown that H2O2- orl-3,4-dihydroxyphenylalanine (l-DOPA)-challenged dopaminergic neurons trigger the release of soluble factors that signal ventral midbrain astrocytes to increase GDNF expression. In the present work, we evaluated whether the factors released by ventral midbrain-challenged cells were able to alter GDNF expression in striatal cells, the targets of dopaminergic neurons projecting from thesubstantia nigra, and investigated the signalling pathways involved. Our data showed that soluble mediators released upon H2O2- orl-DOPA-induced dopaminergic injury up-regulated GDNF in striatal cells, with different temporal patterns depending on the oxidative agent used. Conditioned media from H2O2- orl-DOPA-challenged midbrain astrocyte cultures failed to up-regulate GDNF in striatal cultures. Likewise, there was no direct effect of H2O2orl-DOPA on striatal GDNF levels suggesting that GDNF up-regulation was mediated by soluble factors released in the presence of failing dopaminergic neurons. Both phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways were involved in striatal GDNF up-regulation triggered by H2O2-induced dopaminergic injury, while diffusible factors released in the presence ofl-DOPA-challenged dopaminergic neurons induced GDNF expression in striatal cells through the activation of the MAPK pathway. These soluble mediators may constitute, in the future, important targets for the control of endogenous GDNF expression enabling the development of new and, hopefully, more efficient neuroprotective/neurorestorative strategies for the treatment of Parkinson's disease.