Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture.
Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture.
复制标题
紫杉醇改变培养物中大鼠感觉神经元的降钙素基因相关肽的诱发释放。
DOI：
10.1016/j.expneurol.2013.12.011
复制
发表时间：
2014
影响因子：
5.3
通讯作者：
Fehrenbacher,JillC
中科院分区：
文献类型：
--
作者：
Pittman,SherryK;Gracias,NeiliaG;Vasko,MichaelR;Fehrenbacher,JillC
周围神经病变（PN）是化疗药物紫杉醇治疗的一种衰弱和剂量限制的副作用。了解紫杉醇对感觉神经元功能的影响以及介导这些紫杉醇诱导的功能变化的信号通路对于开发预防或减轻PN的治疗方法至关重要。以降钙素基因相关肽（CGRP）的释放作为感觉神经元功能的终点，研究了紫杉醇长期给药对培养感觉神经元功能的影响。背根神经节培养物分别用低浓度（10 nM）和高浓度（300 nM）紫杉醇处理1、3或5天。紫杉醇治疗后，用辣椒素（一种TRPV1激动剂）测定CGRP的释放；异硫氰酸烯丙酯（AITC）， TRPA1激动剂；或者细胞外钾含量高。紫杉醇对CGRP释放的影响是兴奋剂、浓度和时间依赖性的。当辣椒素或AITC刺激神经元时，低浓度的紫杉醇（10 nM）增加了递质释放，而高浓度（300 nM）以时间依赖性的方式减少了递质释放；然而，当使用高细胞外钾作为唤醒刺激时，所有浓度的紫杉醇都增加了感觉神经元的CGRP释放。这些结果表明紫杉醇改变了体外感觉神经元的功能，并提示紫杉醇改变神经元功能的机制可能包括TRP通道活性的功能改变。所描述的体外模型将有助于未来的研究，以确定紫杉醇改变神经元敏感性的信号通路。
Peripheral neuropathy (PN) is a debilitating and dose-limiting side effect of treatment with the chemotherapeutic agent, paclitaxel. Understanding the effects of paclitaxel on sensory neuronal function and the signaling pathways which mediate these paclitaxel-induced changes in function are critical for the development of therapies to prevent or alleviate the PN. The effects of long-term administration of paclitaxel on the function of sensory neurons grown in culture, using the release of the neuropeptide calcitonin gene-related peptide (CGRP) as an endpoint of sensory neuronal function, were examined. Dorsal root ganglion cultures were treated with low (10 nM) and high (300 nM) concentrations of paclitaxel for 1, 3, or 5 days. Following paclitaxel treatment, the release of CGRP was determined using capsaicin, a TRPV1 agonist; allyl isothiocyanate (AITC), a TRPA1 agonist; or high extracellular potassium. The effects of paclitaxel on the release of CGRP were stimulant-, concentration-, and time-dependent. When neurons were stimulated with capsaicin or AITC, a low concentration of paclitaxel (10 nM) augmented transmitter release, whereas a high concentration (300 nM) reduced transmitter release in a time-dependent manner; however, when high extracellular potassium was used as the evoking stimulus, all concentrations of paclitaxel augmented CGRP release from sensory neurons. These results suggest that paclitaxel alters the function of sensory neurons in vitro, and suggest that the mechanisms by which paclitaxel alters neuronal function may include functional changes in TRP channel activity. The described in vitro model will facilitate future studies to identify the signaling pathways by which paclitaxel alters neuronal sensitivity.