Bortezomib-induced neuropathy: axonal membrane depolarization precedes development of neuropathy
Bortezomib-induced neuropathy: axonal membrane depolarization precedes development of neuropathy
复制标题
硼替佐米诱导的神经病变：轴突膜去极化先于神经病变的发生
DOI：
10.1016/j.clinph.2013.07.014
复制
发表时间：
2014
影响因子：
4.7
通讯作者：
Kuwabara S S,
中科院分区：
文献类型：
--
作者：
Nasu S;Misawa S;Nakaseko C;Shibuya K;Isose S;Sekiguchi Y;Mitsuma;Ohmori S;Iwai Y;Beppu M;Shimizu N;Ohwada C;Takeda Y;Fujimaki Y;Kuwabara S S,
目的硼替佐米是一种治疗多发性骨髓瘤的高效蛋白酶体抑制剂，但具有严重的周围神经毒性，可导致剂量改变和严重的神经功能障碍。本研究旨在探讨硼替佐米引起的神经病变的病理生理学。方法采用阈值跟踪法评价感觉轴突和运动轴突的兴奋性。在9例新诊断的多发性骨髓瘤患者硼替佐米治疗前后依次进行测量。结果67%的患者最终出现症状性神经病变。感觉轴突兴奋性指数在给药后立即发生变化。兴奋性指数的变化模式提示膜去极化（超兴奋性降低，P< 0.001；去极化阈值电张力降低90-100 ms，P= 0.02）。第二疗程后出现提示轴突变性的神经传导参数异常。结论硼替佐米在神经病变发生前诱导静息膜电位的去极化转移。膜去极化可能与硼替佐米对线粒体的毒性作用引起的电致Na+ -K +- atp酶依赖性泵的损伤有关。轴突去极化和高兴奋性可能增强硼替佐米诱导的神经病变的神经退行性。
ObjectiveBortezomib is a proteasome inhibitor with high efficacy for multiple myeloma but with severe peripheral neurotoxicity, leading to dose modification and severe neurological disability. This study aimed to investigate the pathophysiology of bortezomib-induced neuropathy.MethodsThreshold tracking was used to assess the excitability of sensory and motor axons. Measurements were sequentially performed before and after bortezomib treatment in nine patients with newly diagnosed multiple myeloma.ResultsIn total, 67% of patients finally developed symptomatic neuropathy. Changes in sensory axonal excitability indices readily occurred after the first course of administration. Patterns of changes in excitability indices suggest membrane depolarization (decreased superexcitability,P< 0.001; decreased depolarizing threshold electrotonus 90–100 ms,P= 0.02). Abnormalities in nerve conduction parameters suggestive of axonal degeneration appeared after the second course of treatment.ConclusionsBortezomib induces a depolarizing shift in resting membrane potential prior to the development of neuropathy. Membrane depolarization could be associated with impairment of electrogenic Na+–K+-ATPase-dependent pump caused by toxic effects of bortezomib on mitochondria.SignificanceAxonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy.