Characterization of the painful peripheral neuropathy induced by bortezomib-based chemotherapy in mice

Bortezomib (BZ) is a potent and selective first-in-class proteasome inhibitor that is mainly used for the treatment of relapsed, refractory multiple myeloma. Peripheral neuropathy (PN) is a significant side effect of BZ-based chemotherapy and since it is one of the major reasons for a dose reduction and discontinuation of life-saving therapy, its mechanisms remain poorly understood. Metabolic changes resulting from BZ accumulation in the dorsal root ganglia (DRG) may contribute to the pathogenesis of the painful, distal sensory axonal neuropathy. Moreover BZ-induced pain is associated with deficits of all 3 major fibre types (Aβ, A , and C). Rat models of BZ-induced PN have been used to investigate pathophysiological features, but these models are not sufficient to examine drug neurotoxicity and the neuropathic pain with the effects of antineoplastic activity since most cancer models are developed in mice. We have characterized the effects produced by 4 weeks- period of intravenous administration of BZ in BALB/c mice. We examined caudal and digital nerve conduction velocities (NCV), the pathological alterations of DRG and sciatic nerve and we assessed changes in mechanical/thermal thresholds. Moreover, in order to investigate relevant spinal cord structures involved in neuropathic pain, we conducted electrophysiological recordings of neurons in the spinal dorsal horn to examine their electrical activity. BZ treatment induced a significant impairment of the caudal and the digital NCV and of nerve action potential amplitude. At the light and electron microscope analysis, the DRG of BZ-treated mice frequently presented degeneration of sensory neurons and satellite cells. Moreover BZ caused severe axonal degeneration of the myelinated fibres and some abnormalities of unmyelinated fibres in the sciatic nerve. In addition, BZ induced the development of significant mechanical allodynia starting from the first week of treatment. Finally, the electrophysiological assessments performed in the spinal dorsal horn revealed that, despite the incapacity of the drug to cross the blood-brain barrier, it resulted in an increase in the activity of the wide dynamic range neurons, particularly after light stimulations of the hind paw. Our results demonstrate that chronic treatment with BZ produces a painful neuropathy in a mouse model. Therefore, this model will enable us to conduct further mechanistic studies of BZ-related antineoplastic activity, peripheral neurotoxicity and pain and can be used as a reference in the preclinical discovery of new neuroprotective as well as of analgesic compounds. This work was partially funded by “AISAL, Associazione per le Scienze degli Animali da Laboratorio” and by P30 NR011396 to S.G.D.