Bortezomib-induced neuropathy: Axonal membrane depolarization precedes development of neuropathy

作者：Nasu Saiko; Misawa Sonoko^*; Nakaseko Chiaki; Shibuya Kazumoto; Isose Sagiri; Sekiguchi Yukari; Mitsuma Satsuki; Ohmori Shigeki; Iwai Yuta; Beppu Minako; Shimizu Naomi; Ohwada Chikako; Takeda Yusuke; Fujimaki Yumi; Kuwabara Satoshi

来源：Clinical Neurophysiology, 2014, 125(2): 381-387.

DOI：10.1016/j.clinph.2013.07.014

• Bortezomib
• Proteasome inhibitor
• Membrane depolarization
• Threshold tracking

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. %26lt;br%26gt;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. %26lt;br%26gt;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 %26lt; 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. %26lt;br%26gt;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. %26lt;br%26gt;Significance: Axonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy.

• 出版日期2014-2