Activation of Retinoid X Receptor increases dopamine cell survival in models for Parkinson's disease.
Activation of Retinoid X Receptor increases dopamine cell survival in models for Parkinson's disease.
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DOI：
10.1186/1471-2202-10-146
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发表时间：
2009-12-11
期刊：
影响因子：
2.4
通讯作者：
Kjellander S
中科院分区：
文献类型：
--
作者：
Friling S;Bergsland M;Kjellander S
帕金森病(PD)是由腹侧中脑(VMB)中的多巴胺(DA)神经元变性引起的，导致严重的运动调节障碍。这种疾病给受影响的人及其家人造成了相当大的痛苦。今天，药物治疗的机会微乎其微，需要新的技术。以往的研究表明，核受体维甲酸X受体(RXR)的激活为DA神经元提供营养支持。这些神经营养作用的详细研究因缺乏容易获得的体外DA神经元而受到阻碍。这项研究的目的是进一步描述RXR配体的潜在神经营养作用，并为此和未来的目的，开发一个合适的体外平台使用小鼠胚胎干细胞(MESCs)。我们研究了RXR配体LG100268(LG268)和RXR-Nurr1配体XCT0139508(XCT)在原代培养的大鼠VMB和MESCs中的潜在神经营养作用。RXR配体保护DA神经元免受应激，如PD模型毒素6-羟基多巴胺(6-OHDA)诱导的应激和缺氧，但不能保护DA神经元免受氧化过氧化氢(H_2O_2)或兴奋性毒性物质红藻氨酸(KA)诱导的应激。神经营养作用对多巴胺能神经元具有选择性。来自大鼠原代VMB和mESCs的DA神经元的行为相似，但mESC来源的培养含有更多的DA细胞，因此提供了更容易获得的实验条件。RXR配体可使DA神经元免于PD模拟6-OHDA和低氧所致的变性。因此，RXR是局部放电研究的一个新的有前途的靶点。MESC来源的DA细胞为研究PD诱导的毒素和潜在的营养因子提供了一个有效的、可获得的体外平台。
Parkinson's disease (PD) is caused by degeneration of dopamine (DA) neurons in the ventral midbrain (vMB) and results in severely disturbed regulation of movement. The disease inflicts considerable suffering for the affected and their families. Today, the opportunities for pharmacological treatment are meager and new technologies are needed. Previous studies have indicated that activation of the nuclear receptor Retinoid X Receptor (RXR) provides trophic support for DA neurons. Detailed investigations of these neurotrophic effects have been hampered by the lack of readily available DA neurons in vitro. The aim of this study was to further describe the potential neurotrophic actions of RXR ligands and, for this and future purposes, develop a suitable in vitro-platform using mouse embryonic stem cells (mESCs). We studied the potential neurotrophic effects of the RXR ligand LG100268 (LG268) and the RXR-Nurr1 ligand XCT0139508 (XCT) in neuronal cultures derived from rat primary vMB and mESCs. RXR ligands protect DA neurons from stress, such as that induced by the PD-modeling toxin 6-hydroxy dopamine (6-OHDA) and hypoxia, but not from stress induced by oxidative hydrogen peroxide (H2O2) or the excitotoxic agent kainic acid (KA). The neurotrophic effect is selective for DA neurons. DA neurons from rat primary vMB and mESCs behaved similarly, but the mESC-derived cultures contained a much higher fraction of DA cells and thus provided more accessible experimental conditions. RXR ligands rescue DA neurons from degeneration caused by the PD simulating 6-OHDA as well as hypoxia. Thus, RXR is a novel promising target for PD research. mESC-derived DA cells provide a valid and accessible in vitro-platform for studying PD inducing toxins and potential trophic agents.