- 作者：Saiko Nasu ; Sonoko Misawa ; Chiaki Nakaseko ; Kazumoto Shibuya ; Sagiri Isose ; Yukari Sekiguchi ; Satsuki Mitsuma ; Shigeki Ohmori ; Yuta Iwai ; Minako Beppu ; Naomi Shimizu ; Chikako Ohwada ; Yusuke Takeda ; Yumi Fujimaki ; Satoshi Kuwabara
- 关键词：Bortezomib ; Proteasome inhibitor ; Membrane depolarization ; Threshold tracking
- 刊名：Clinical Neurophysiology
- 出版年：February, 2014
- 年：2014
- 卷：125
- 期：2
- 页码：381-387
- 全文大小：897 K
Objective
Bortezomib 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.Methods
Threshold 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.
Results
In 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.
Conclusions
Bortezomib 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.
Significance
Axonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy.