title: Bortezomib-induced neuropathy: axonal membrane depolarization precedes development of neuropathy.
abstract: 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 90-100ms, 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.
  
  
  CONCLUSIONS
  Axonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy.
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Saiko
authors: S
authors: Nasu
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan. Electronic address: sonoko.m@mb.infoweb.ne.jp.
authors: Sonoko
authors: S
authors: Misawa
authors: Department of Hematology, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Chiaki
authors: C
authors: Nakaseko
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Kazumoto
authors: K
authors: Shibuya
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Sagiri
authors: S
authors: Isose
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Yukari
authors: Y
authors: Sekiguchi
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Satsuki
authors: S
authors: Mitsuma
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Shigeki
authors: S
authors: Ohmori
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Yuta
authors: Y
authors: Iwai
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Minako
authors: M
authors: Beppu
authors: Department of Hematology, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Naomi
authors: N
authors: Shimizu
authors: Department of Hematology, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Chikako
authors: C
authors: Ohwada
authors: Department of Hematology, Chiba University Hospital, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Yusuke
authors: Y
authors: Takeda
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Yumi
authors: Y
authors: Fujimaki
authors: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors: Satoshi
authors: S
authors: Kuwabara
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D001897:Boronic Acids / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D005260:Female; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D011446:Prospective Studies; D011719:Pyrazines / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Bortezomib; Membrane depolarization; Proteasome inhibitor; Threshold tracking