Behavioral and pharmacological characteristics of bortezomib-induced peripheral neuropathy in rats

Abstract

Bortezomib, an effective anticancer drug for multiple myeloma, often causes peripheral neuropathy which is mainly characterized by numbness and painful paresthesia. Nevertheless, there is no effective strategy to escape or treat bortezomib-induced peripheral neuropathy (BIPN), because we have understood few mechanism of this side effect. In this study, we evaluated behavioral and pathological characteristics of BIPN, and investigated pharmacological efficacy of various analgesic drugs and adjuvants on mechanical allodynia induced by bortezomib treatment in rats. The repeated administration of bortezomib induced mechanical and cold allodynia. There was axonal degeneration of sciatic nerve behind these neuropathic symptoms. Furthermore, the exposure to bortezomib shortened neurite length in PC12 cells. Finally, the result of evaluation of anti-allodynic potency, oral administration of tramadol (10 mg/kg), pregabalin (3 mg/kg), duloxetine (30 mg/kg) or mexiletine (100 mg/kg), but not amitriptyline or diclofenac, transiently relieved the mechanical allodynia induced by bortezomib. These results suggest that axonal degeneration of the sciatic nerve is involved in BIPN and that some analgesic drugs and adjuvants are effective in the relief of painful neuropathy.

Characterization of a rat model of bortezomib‐induced painful neuropathy

“…Existing models of BIPN have also reported mechanical hypersensitivity due to bortezomib dosing, but in a shorter-lasting manner, 29 days (0.2 mg·kg À1 bortezomib; Yamamoto et al, 2015) and 54 days (0.2 mg·kg À1 Velcade; Robinson et al, 2014), compared to~80 days in our investigation. Dosing with bortezomib has also previously been shown to induce cold allodynia at days 11 and 15 (Zheng et al, 2012;Yamamoto et al, 2015), whereas Velcade® administration was not associated with development of cold allodynia following four doses at 0.15 mg·kg À1 (Robinson et al, 2014). In conjunction with long-lasting mechanical hypersensitivity, we found evidence of a short-lasting cold allodynia resulting from four doses of 0.2 mg·kg À1 Velcade®, evident at day 14 only.…”

“…The model characterized in this study did not find loss of motor function or reduced axon myelination and IENF crossings in bortezomib‐treated animals compared to vehicle‐treated controls. Previous studies have identified degeneration of myelinated sciatic nerve fibres following the same dosing regimen (albeit using non‐Velcade® bortezomib) used in this study, but an absence of ATF3‐positive staining (Yamamoto et al, ). Another investigation has reported, but did not quantify, ATF3‐positive staining in the DRG following bortezomib administration following a significantly higher cumulative dose of 6.4 mg·kg −1 (Carozzi et al, ).…”

“…The model described by Yamamoto et al . () showed that administration of tramadol, pregabalin, duloxetine and mexiletine could ameliorate bortezomib‐induced mechanical hypersensitivity, but only the effects of pregabalin exceeded 1 h (up to 3 h; Yamamoto et al, ). In our investigation, administration of another calcium channel blocker, ethosuximide, was shown to robustly inhibit bortezomib‐induced mechanical hypersensitivity at 1 and 3 h after a single administration.…”

New pharmacological effect of fulvestrant to prevent oxaliplatin‐induced neurodegeneration and mechanical allodynia in rats

“…The preventive effect of fulvestrant against mechanical allodynia appears to be associated with its protective effect against neuronal damage. Indeed, we observed a significant alteration in the circularity of the sciatic nerve (a parameter of axonal degeneration 17,18 ) in oxaliplatin-treated rats, and nerve damage and mechanical allodynia have been reported to concurrently occur in oxaliplatin-treated rats. 5 However, it has also been reported that axonal degeneration (e.g., axonal diameter and fibre area) of the sciatic nerve is not observed in oxaliplatin-treated rats.…”

“…a ). Quantitative analysis revealed that an oxaliplatin‐induced decrease in the circularity of fibres, an index of axonal degeneration, was not observed in the sciatic nerve of oxaliplatin‐treated rats that were also treated with fulvestrant (Fig. b ).…”