Combinatorial influences of paclitaxel and strain on axonal transport
Combinatorial influences of paclitaxel and strain on axonal transport
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DOI：
10.1016/j.expneurol.2015.06.023
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发表时间：
2015-09-01
影响因子：
5.3
通讯作者：
Shah, Sameer B.
中科院分区：
文献类型：
--
作者：
Bober, Brian G.;Gutierrez, Edgar;Shah, Sameer B.
紫杉醇是一种有效的化疗药物，尽管常用，但经常引起周围感觉神经病变。在神经元中，紫杉醇结合并稳定微管，并通过未知的机制使微管成束并破坏其组织。由于微管充当各种轴突货物运输的轨道，因此紫杉醇诱导的神经病病因学的主要假设是微管组织的这些变化损害了轴突运输。除了支持运输之外，微管还发挥结构作用，适应轴突生长或关节运动期间发生的轴突延伸。鉴于微管的这种双重作用，我们测试了轴突拉伸放大紫杉醇对轴突运输的影响的假设。在可拉伸的硅胶基质上培养胚胎大鼠背根神经节，并在有或没有紫杉醇处理和轴突应变的情况下测量描述三种不同货物（线粒体、突触素和肌动蛋白）轴突运输的参数。紫杉醇治疗，特别是与拉伸相结合，会导致几个运输参数的严重扰动，包括轴突中货物的数量、速度和行进距离。我们的结果表明，神经元的机械负荷会加剧与紫杉醇治疗相关的运输缺陷，这提出了紫杉醇以多因素方式影响神经元功能的有趣可能性。 (C) 2015 Elsevier Inc. 保留所有权利。
Paclitaxel is an effective chemotherapeutic agent that, despite its common use, often causes peripheral sensory neuropathy. In neurons, paclitaxel binds to and stabilizes microtubules, and through unknown mechanisms, bundles microtubules and disrupts their organization. Because microtubules serve as tracks on which a variety of axonal cargoes are transported, a leading hypothesis for the etiology of paclitaxel-induced neuropathy is that these changes to microtubule organization impair axonal transport. In addition to supporting transport, microtubules also serve a structural role, accommodating axonal extension occurring during axonal growth or joint movement. In light of this dual role for microtubules, we tested the hypothesis that axonal stretch amplified the effects of paclitaxel on axonal transport. Embryonic rat dorsal root ganglia were cultured on stretchable silicone substrates, and parameters describing the axonal transport of three distinct cargoes - mitochondria, synaptophysin, and actin - were measured with and without paclitaxel treatment and axonal strain. Paclitaxel treatment, particularly in combination with stretch, led to severe perturbations in several transport parameters, including the number, velocity, and travel distance of cargoes in the axon. Our results suggest that mechanical loading of neurons can exacerbate transport deficits associated with paclitaxel treatment, raising the interesting possibility that paclitaxel influences neuronal function in a multi-factorial manner. (C) 2015 Elsevier Inc. All rights reserved.