The Ludwig Institute for Cancer Research, Stockholm Branch, Box 240, S-171 77 Stockholm.
BMC Neurosci. 2009 Dec 11;10:146. doi: 10.1186/1471-2202-10-146.
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.
帕金森病（PD）是由腹侧中脑（vMB）中的多巴胺（DA）神经元退化引起的，导致运动调节严重失调。这种疾病给患者及其家属带来了巨大的痛苦。目前，药物治疗的机会有限，需要新的技术。先前的研究表明，核受体视黄酸 X 受体（RXR）的激活为 DA 神经元提供了营养支持。由于体外缺乏易于获得的 DA 神经元，这些神经营养作用的详细研究受到了阻碍。本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，使用小鼠胚胎干细胞（mESCs）开发合适的体外平台。
我们研究了 RXR 配体 LG100268（LG268）和 RXR-Nurr1 配体 XCT0139508（XCT）在源自大鼠原代 vMB 和 mESCs 的神经元培养物中的潜在神经营养作用。RXR 配体可保护 DA 神经元免受应激，如 PD 模型毒素 6-羟多巴胺（6-OHDA）和缺氧引起的应激，但不能免受氧化氢过氧化物（H2O2）或兴奋性毒素海人酸（KA）引起的应激。神经营养作用对 DA 神经元具有选择性。大鼠原代 vMB 和 mESCs 来源的 DA 神经元表现相似，但 mESC 衍生的培养物含有更高比例的 DA 细胞，因此提供了更易于进行实验的条件。
RXR 配体可挽救由模拟 PD 的 6-OHDA 以及缺氧引起的 DA 神经元退化。因此，RXR 是 PD 研究的一个新的有前途的靶点。mESC 衍生的 DA 细胞为研究 PD 诱导毒素和潜在营养剂提供了有效的、易于获得的体外平台。
