Compartmentalized microfluidic culture platform to study mechanism of paclitaxel-induced axonal degeneration.
Compartmentalized microfluidic culture platform to study mechanism of paclitaxel-induced axonal degeneration.
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DOI：
10.1016/j.expneurol.2009.04.017
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发表时间：
2009-07
影响因子：
5.3
通讯作者：
Hoeke, Ahmet
中科院分区：
文献类型：
--
作者：
Yang, In Hong;Siddique, Rezina;Hosmane, Suneil;Thakor, Nitish;Hoeke, Ahmet
关键词：
化疗所致的周围神经病变是抗癌药物常见且剂量受限的副作用。旨在了解化疗药物神经毒性的潜在机制的研究因缺乏合适的培养体系而受到阻碍，这些培养体系可以分化为神经元胞体、轴突或相关的胶质细胞。在这里，我们开发了一种体外分室微流控培养系统，用于检测化疗药物的毒性部位。为了测试培养平台，我们使用了广泛使用的乳腺癌抗癌药物紫杉醇，因为它在很大一部分患者中会导致感觉性多发性神经病，而且没有有效的治疗方法。在先前的体外研究中，紫杉醇诱导远端轴突变性，但尚不清楚这是由于对轴突的直接毒性还是对神经元胞体的毒性的结果。使用微流控通道，允许对神经元和轴突进行分区培养，我们证明轴突更容易受到紫杉醇的毒性影响。当紫杉醇应用于轴突一侧时，轴突有明显的变性；而当紫杉醇应用于胞体一侧时，轴突长度没有变化。此外，我们还证明了重组人促红细胞生成素对紫杉醇神经毒性具有神经保护作用，无论它是直接应用于细胞体还是轴突，都提供了神经保护。这一观察结果对开发治疗化疗所致周围神经病的神经保护药物具有重要意义，因为背根神经节不具有血-神经屏障，从而消除了药物开发对神经系统的基本要求之一。这种分区化的微流控培养系统可用于研究轴突变性、神经保护和神经系统的发育。
Chemotherapy induced peripheral neuropathy is a common and dose-limiting side effect of anticancer drugs. Studies aimed at understanding the underlying mechanism of neurotoxicity of chemotherapeutic drugs have been hampered by lack of suitable culture systems that can differentiate between neuronal cell body, axon or associated glial cells. Here, we have developed an in vitro compartmentalized microfluidic culture system to examine the site of toxicity of chemotherapeutic drugs. To test the culture platform, we used paclitaxel, a widely used anticancer drug for breast cancer, because it causes sensory polyneuropathy in a large proportion of patients and there is no effective treatment. In previous in vitro studies, paclitaxel induced distal axonal degeneration but it was unclear if this was due to direct toxicity on the axon or a consequence of toxicity on the neuronal cell body. Using microfluidic channels that allow compartmentalized culturing of neurons and axons, we demonstrate that the axons are much more susceptible to toxic effects of paclitaxel. When paclitaxel was applied to the axonal side, there was clear degeneration of axons; but when paclitaxel was applied to the soma side, there was no change in axon length. Furthermore, we show that recombinant human erythropoietin, which had been shown to be neuroprotective against paclitaxel neurotoxicity, provides neuroprotection whether it is applied to the cell body or the axons directly. This observation has implications for development of neuroprotective drugs for chemotherapy induced peripheral neuropathies as dorsal root ganglia do not possess blood–nerve-barrier, eliminating one of the cardinal requirements of drug development for the nervous system. This compartmentalized microfluidic culture system can be used for studies aimed at understanding axon degeneration, neuroprotection and development of the nervous system.
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影响因子：
3.8
作者：
Silva, Angelica;Wang, Qingbo;Glass, Jonathan D.
通讯作者：
Glass, Jonathan D.
DOI：
10.1073/pnas.0401103101
发表时间：
2004-05-04
影响因子：
11.1
作者：
Harper, JM;Krishnan, C;Kerr, DA
通讯作者：
Kerr, DA
影响因子：
7.4
作者：
Chen, XX;Wu, HK;Whitesides, GM
通讯作者：
Whitesides, GM
影响因子：
9.9
作者：
Periquet, MI;Novak, V;Mendell, JR
通讯作者：
Mendell, JR
影响因子：
8.8
作者：
Johnson, ME;Uhl, CB;Gores, GJ
通讯作者：
Gores, GJ