Neurophysiological, histological and immunohistochemical characterization of bortezomib-induced neuropathy in mice

Bortezomib, a proteasome inhibitor, is an antineoplastic drug to treat multiple myeloma and mantle cell lymphoma. Its most clinically significant adverse event is peripheral sensory neuropathy. Our objective was to characterize the neuropathy induced by bortezomib in a mouse model. Two groups were used; one group received vehicle solution and another bortezomib (1 mg/kg/twice/week) for 6 weeks (total dose as human schedule). Tests were performed during treatment and for 4 weeks post dosing to evaluate electrophysiological, autonomic, pain sensibility and sensory-motor function changes. At the end of treatment and after washout, sciatic and tibial nerves, dorsal ganglia and intraepidermal innervation were analyzed. Bortezomib induced progressive significant decrease of sensory action potential amplitude, mild reduction of sensory velocities without effect in motor conductions. Moreover, it significantly increased pain threshold and sensory-motor impairment at 6 weeks. According to these data, histopathological findings shown a mild reduction of myelinated (−10%; p = 0.001) and unmyelinated fibers (−27%; p = 0.04), mostly involving large and C fibers, with abnormal vesicular inclusion body in unmyelinated axons. Neurons were also involved as shown by immunohistochemical phenotypic switch. After washout, partial recovery was observed in functional, electrophysiological and histological analyses. These results suggest that axon and myelin changes might be secondary to an initial dysfunctional neuronopathy.