ENDOCANNABINOID SYSTEM IN BORTEZOMIB NEUROTOXICITY

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common complication in the successful treatment of cancer. This side effect is dose-limiting and clinically reflects in an axonal peripheral neuropathy with sensory loss, combined often with neuropathic pain. These symptoms may be disabling, dversely affecting the quality of life of patients. Here we focussed on bortezomib (BTZ), a first-in-class proteasome inhibitor used for the treatment of ultiple myeloma, which is associated with a relatively high incidence of CIPN. The pathogenesis of CIPN has not been completely understood, and there are no effective strategies or drugs to prevent or treat this side effect. Among possible pharmacological treatments of CIPN, modulation of the endocannabinoid system might be particularly promising. To investigate this hypothesis, we performed electrophysiological, behavioral and pathological analyses in a rat model of painful CIPN induced by BTZ-treatment. Animals were intravenously injected with BTZ 0.20 mg/kg, 3 times a week for 8 weeks. Moreover, localization of CB1R/CB2R-like immunoreactivity (LI) and protein quantification for CB1R/CB2R were performed in dorsal root ganglia (DRG) nd in the spinal cord. In addition, cd68-LI macrophages in the peripheral nerve as well as resident Iba-1 positive cells, macrophages or microglia, were lso evaluated in the DRG and spinal cord dorsal horn (DH), respectively. BTZ induced alterations in rat electrophysiological endpoints and behavioral tudies of pain associated with a reduction in intraepidermal nerve fiber density if compared to control rats. Moreover, huge M1 proinflammatory nfiltrating cells in caudal nerves and increased Iba-1 positive cells in DRG and microglia in the DH of rats after 8 weeks of treatment were also observed. In addition, BTZ induced an increase in the number of CB1Rand CB2R-LI DRG neurons, as well as an increase in CB1R and CB2R protein expression in dRG. The densitometric analysis on BTZ-treated DH showed an increase in CB1R-LI. In conclusion, the results suggest that the alteration of the endocannabinoid levels in peripheral and central nervous tissues appears involved in the development and progression of CIPN. Therefore, improved understanding of the pathophysiology of BTZ-induced neurotoxicity will inevitably assist in the development of effective pharmacological intervention n the cannabinoid system as potential therapy for CIPN.