Critical role of Cav3.2 T-type calcium channels in the peripheral neuropathy induced by bortezomib, a proteasome-inhibiting chemotherapeutic agent, in mice. (1st February 2019)

• Record Type: Journal Article
• Authors: Tomita, Shiori; Sekiguchi, Fumiko; Deguchi, Tomoyo; Miyazaki, Takaya; Ikeda, Yuya; Tsubota, Maho; Yoshida, Shigeru; Nguyen, Huy Du; Okada, Takuya; Toyooka, Naoki; Kawabata, Atsufumi
• Is Part Of: Toxicology. Volume 413(2019)
• Page Start: 33
• Page End: 39
• Publication Date: 2019-02-01
• Subjects: CIPN chemotherapy-induced peripheral neuropathy -- QoL quality of life -- BIPN bortezomib-induced peripheral neuropathy -- DRG dorsal root ganglion -- PNG prenylnaringenin -- AS antisense -- SC scrambled control -- ODN oligodeoxynucleotides -- T-currents T-channel dependent current; Cav3.2 T-type calcium channel -- Chemotherapy-induced peripheral neuropathy -- Proteasome -- Ubiquitin-specific protease 5 (USP5) -- Bortezomib; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2018.12.003
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: Bortezomib-induced neuropathy is reversed by Cav 3.2 blockers or knockdown in mice. Bortezomib increases Cav 3.2 proteins in mouse primary afferents and neuron-like cells. Bortezomib upregulates USP5 that inhibits proteasomal degradation of Cav 3.2 in mice. Cav 3.2 thus plays a critical role in bortezomib-induced peripheral neuropathy. Abstract: Bortezomib, a first-line agent for treatment of multiple myeloma, exhibits anticancer activity through proteasome inhibition. However, bortezomib-induced peripheral neuropathy (BIPN) is one of the most serious side effects. Since decreased proteasomal degradation of Cav 3.2 T-type calcium channels in the primary afferents is involved in persistent pain, we investigated whether BIPN involves increased protein levels of Cav 3.2 in mice. Six repeated i.p. administrations of bortezomib for 12 days developed persistent mechanical allodynia. Systemic administration of novel T-type calcium channel blockers, (2 R / S )-6-prenylnaringenin and KTt-45, and of TTA-A2, the well-known blocker, reversed the BIPN. Ascorbic acid, known to block Cav 3.2, but not Cav 3.1 or 3.3, and silencing of Cav 3.2 gene also suppressed BIPN. Protein levels of Cav 3.2 in the dorsal root ganglion (DRG) at L4-L6 levels increased throughout days 1–21 after the onset of bortezomib treatment. Protein levels of USP5, a deubiquitinating enzyme that specifically inhibits proteasomal degradation of Cav 3.2, increased in DRG on days 3–21, but not day 1, in bortezomib-treated mice. In DRG-derived ND7/23 cells, bortezomib increased protein levels of Cav 3.2 and T-channel-dependent currents, as assessed by a patch-clamp method, but did not upregulate expression of Cav 3.2 mRNA or USP5 protein. MG-132, another proteasome inhibitor, also increased Cav 3.2 protein levels in the cultured cells. Given the previous evidence for USP5 induction following nociceptor excitation, our data suggest that BIPN involves the increased protein levels of Cav 3.2 in nociceptors through inhibition of proteasomal degradation of Cav 3.2 by bortezomib itself and then by USP5 that is upregulated probably in an activity-dependent manner.