Characterization of proteasome inhibition and tubulin stabilization in an in vivo rat model of bortezomib-induced peripheral neuropathy

Bortezomib-induced peripheral neuropathy (BIPN) is the major neurological side effect of bortezomib (BTZ). Mechanisms underlying BIPN are still poorly known; to improve our understanding of BIPN molecular pathways, we treated Wistar rats with bortezomib 0,20 mg/kg three times weekly for eight weeks followed by a four-week follow up period. We assessed nerve conduction velocity (NCV) and pathological changes in caudal nerve, dorsal root ganglia (DRGs), and sciatic nerve; afterwards, we verified tubulin stabilization and proteasome inhibition involvement in BTZ-treated animals. The neurophysiological examination demonstrated a reduction in NCV both at eight weeks and after the follow up period: at the pathologic analysis, caudal nerves were the most affected structures, whereas DRGs showed some vacuoles in satellite cell and sciatic nerves a mild axonopathy. Proteasome activity assay was performed on peripheral blood mononuclear cells (PBMCs), sciatic nerve and brain: PBMCs and sciatic nerve recovered quickly in the acute setting, while maintaining strong inhibition until 48 hours after last injection. Tubulin stabilization increase was observed at six and eight weeks, returning at baseline during follow up period. Our results demonstrated two possible neurotoxic mechanisms of BIPN induced by chronic BTZ treatment that are important for developing neuroprotective drugs. Supported in part by grants from the “Fondazione Banca del Monte di Lombardia”