Bortezomib‐induced painful neuropathy in rats: A behavioral, neurophysiological and pathological study in rats

Abstract

Bortezomib is a proteasome inhibitor showing strong antitumor activity against many tumors, primarily multiple myeloma. Bortezomib-induced neuropathic pain is the main side effect and the dose-limiting factor of the drug in clinical practice. In order to obtain a pre-clinical model to reproduce the characteristic pain symptoms in bortezomib-treated patients, we developed an animal model of bortezomib-induced nociceptive sensory neuropathy. In this study, bortezomib (0.15 or 0.20mg/kg) was administered to Wistar rats three times/week for 8 weeks, followed by a 4 week follow-up period. At the end of the treatment period a significant decrease in weight gain was observed in the treated groups vs. controls, and hematological and histopathological parameters were evaluated. After the treatment period, both doses of bortezomib induced a severe reduction in nerve conduction velocity and demonstrated a dose-cumulative effect of the drug. The sensory behavioral assessment showed the onset of mechanical allodynia, while no effect on thermal perception was observed. Sciatic nerves and dorsal root ganglia (DRG) were collected at the end of the 8-week treatment and at the end of the follow-up period. The pathological examination revealed a dose-dependent axonopathy of the unmyelinated fibers in nerves of treated animals. No pathological alteration in most of DRG satellite cells and neurons was observed. Therefore, this animal model may be useful for studying the neurotoxicity and pain onset mechanisms related to bortezomib treatment.

Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy

“…17, 25 The rat model used in this study has already been thoroughly assessed, and it reproduces the hallmarks of BiPN in humans, i.e., painful sensory neuropathy with nerve axonopathy, a distal-to-proximal severity gradient, and tendency to recovery in the follow-up period after BTZ withdrawal. 18,26 Most of these results, included the involvement of DRG, were independently confirmed in similar studies in mice. 19,20 In this model we assessed for the first time the temporal profile of proteasome inhibition within PBMC and nervous tissue following BTZ administration.…”

“…1) and recovered soon after, as already observed in previous experiments. 18 Overall, no statistically significant difference in body weight between treated and untreated animals was observed at any time of observation.…”

“…1,13 Several preclinical models reproducing the features of BiPN have been reported, and they can be reliably used to investigate the molecular mechanisms underlying BiPN. 18,20,23 In this study we explored the effects of acute and protracted proteasome inhibition on the modulation of tubulin dynamics. Altered dynamics of α-tubulin polymerization has an important effect on microtubule function and may be an important pathogenic mechanism underlying peripheral neurotoxicity in addition to the proposed effects of proteasome inhibition on apoptosis.…”

“…4A and B). DRG As previously reported, 18 the observations at the light microscope of DRG collected from treated rats at Measures of somatic, nuclear and nucleolar areas in control (CtRL), bortezomib (BtZ), and bortezomib follow up (BtZ-FU) treated animals. Data are expressed as mean ± standard deviation; °P < 0.001 vs. CtRL, § P < 0.01 vs. CtRL, *P < 0.01 vs. BtZ-FU, # P < 0.001 vs. BtZ-FU the end of BTZ-treatment showed a cytoplasmic vacuolization in satellite cells, while only occasional alterations were observed in neurons (data not shown).…”

“…16,17 Pathogenic hypotheses can be reliably investigated in vivo using well-characterized animal models reproducing chronic BiPN as well as neuronal systems in vitro. [18][19][20][21] In this context, we have studied for the first time, using parallel in vivo and in vitro experiments, the possible correlation existing between proteasome inhibition and α-tubulin polymerization in order to understand the pathogenic basis of BiPN onset.…”