Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease
Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease
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DOI：
10.1016/j.brainres.2010.12.090
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发表时间：
2011-03-10
期刊：
影响因子：
2.9
通讯作者：
Torp, R.
中科院分区：
文献类型：
--
作者：
Stahl, K.;Mylonakou, M. N.;Torp, R.
帕金森病（Parkinson's disease，PD）是一种以黑质多巴胺能神经元（DA能神经元）优先丢失为特征的神经退行性疾病。胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）在维持DA能表型中起关键作用，并在体内和体外对这些神经元发挥细胞保护作用。然而，关于这两个因素的相对效力以及它们协同作用的程度仍然存在争议。在这项研究中，我们使用了一个完善的版本的器官型文化作为PD的模型。将神经毒素6-羟基多巴胺（6-OHDA）单侧应用于大鼠中脑切片中，允许内部对照，并能够精确比较中脑两侧。我们评估了BDNF，GDNF和这些的组合在存活的酪氨酸羟化酶阳性（TH+）细胞和TH mRNA表达方面的细胞保护和再生作用。用神经营养因子预处理、共处理或后处理明显保护DA能神经元免于细胞死亡。在用BDNF预处理的培养物中，细胞存活特别明显，并且当BDNF与GDNF以等摩尔剂量组合应用时，细胞存活没有进一步增加。在病变侧，存活的TH+细胞暴露于神经营养因子表现出广泛的发芽，和BDNF治疗导致TH mRNA的两倍增加。在没有毒素暴露的情况下没有观察到这种影响。因此，我们观察到BDNF诱导DA能表型的上调，这表明了细胞保护和再生作用。(C)2011 Elsevier B. V.保留所有权利。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a preferential loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc). Both glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) play key roles in maintaining the DAergic phenotype and exert a cytoprotective effect on these neurons in vivo and in vitro. However, controversy still exists regarding the relative potency of the two factors and the extent to which they act synergistically. In this study, we used a refined version of organotypic cultures as a model for PD. The neurotoxin 6-hydroxydopamine (6-OHDA) was applied unilaterally in slices of rat mesencephalon, allowing for internal controls and enabling a precise comparison between the two sides of the midbrain. We evaluated the cytoprotective and regenerative effects of BDNF, GDNF and the combination of these in terms of surviving tyrosine hydroxylase positive (TH+) cells and TH mRNA expression. Pre-, co-, or post-treatment with neurotrophic factors clearly protects DAergic neurons from cell death. Cell survival is particularly pronounced in cultures pre-treated with BDNF and is not further increased when BDNF is applied in combination with GDNF in equimolar dose. On the lesion side, surviving TH+ cells exposed to neurotrophic factors showed extensive sprouting, and BDNF treatment resulted in a two-fold increase in TH mRNA. Such effects were not seen in the absence of toxin exposure. Thus, we observed that BDNF induced an upregulation of the DAergic phenotype, which suggest a cytoprotective and regenerative effect. (C) 2011 Elsevier B.V. All rights reserved.