Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice.
Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice.
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DOI：
10.1038/srep06370
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发表时间：
2014-09-18
影响因子：
4.6
通讯作者：
Endres M
中科院分区：
文献类型：
--
作者：
Boehmerle W;Huehnchen P;Peruzzaro S;Balkaya M;Endres M
多发性神经病是临床肿瘤化疗常见的潜在严重副作用。本研究的目的是采用比较方法表征C57 BL/6小鼠中紫杉醇、顺铂、长春新碱和硼替佐米诱导的神经病变。在四个时间点用行为和电生理学试验评价动物的表型，然后进行组织学检查。本研究中使用的治疗方案耐受性良好，并诱导感觉和主要轴突多发性神经病。行为测试显示正常的运动协调，而所有接受verum治疗的小鼠均出现机械性异常性疼痛和明显的步态改变。电生理学评价显示，所有细胞生长抑制剂的尾侧感觉神经动作电位振幅显著降低，顺铂和紫杉醇的神经传导速度中度降低。坐骨神经的组织学分析证实了这一发现，坐骨神经主要显示轴突损伤：紫杉醇和长春新碱主要影响大的有髓纤维，硼替佐米影响小的有髓纤维，顺铂以相似的程度损伤所有类型的有髓纤维。与顺铂和硼替佐米治疗相比，紫杉醇和长春新碱治疗动物的神经病症状发展更快。本研究中的动物模型可用于阐明化疗诱导的多发性神经病的病理机制，并用于开发新的治疗和预防策略。
Polyneuropathy is a frequent and potentially severe side effect of clinical tumor chemotherapy. The goal of this study was to characterize paclitaxel-, cisplatin-, vincristine- and bortezomib-induced neuropathy in C57BL/6 mice with a comparative approach. The phenotype of the animals was evaluated at four time points with behavioral and electrophysiological tests, followed by histology. Treatment protocols used in this study were well tolerated and induced a sensory and predominantly axonal polyneuropathy. Behavioral testing revealed normal motor coordination, whereas all mice receiving verum treatment developed mechanical allodynia and distinct gait alterations. Electrophysiological evaluation showed a significant decrease of the caudal sensory nerve action potential amplitude for all cytostatic agents and a moderate reduction of nerve conduction velocity for cisplatin and paclitaxel. This finding was confirmed by histological analysis of the sciatic nerve which showed predominantly axonal damage: Paclitaxel and vincristine affected mostly large myelinated fibers, bortezomib small myelinated fibers and cisplatin damaged all types of myelinated fibers to a similar degree. Neuropathic symptoms developed faster in paclitaxel and vincristine treated animals compared to cisplatin and bortezomib treatment. The animal models in this study can be used to elucidate pathomechanisms underlying chemotherapy-induced polyneuropathy and for the development of novel therapeutic and preventative strategies.