Bortezomib-Induced Peripheral Neurotoxicity: a Preclinical Model to Study Neuropathic Pain in Rat

Bortezomib is a new proteasome inhibitor with a high antitumor activity, but also with a potentially severe peripheral neurotoxicity that induces neuropathic pain in the patients treated with this drug. To establish a preclinical model and to characterize the neuropathic pain, bortezomib was administered to Wistar rats (0.20mg/kg three times weekly [3q7d] for a total of 4 weeks). At the end of the treatment period sensory nerve conduction velocity (SNCV) was determined in the tail of each animal. Sciatic nerve, DRG and spinal cord specimens were processed for light and electron microscope observations and morphometry. Plantar test and Dynamic Aesthesiometer Test (Ugo Basile instruments) were used at the end of treatment to evaluate hyperalgesia and allodynia in treated animals. Bortezomib induced a significant reduction in SNCV. Sciatic nerve and DRG examination and morphometric determinations demonstrated mild to moderate pathological changes, while the spinal cord was morphologically normal. Bortezomib-induced changes were also observed in dynamic aesthesiometer test but not in plantar test, indicating the presence of allodynia in treated animals. This model is relevant to the neuropathy induced by bortezomib in the treatment of human malignancies and it could be useful in increasing our knowledge regarding the mechanisms underlying bortezomib neurotoxicity and neuropathic pain. Supported in part by a “Fondazione Banca del Monte” unrestricted research grant