Peripheral neuropathy induced by microtubule-targeted chemotherapies: insights into acute injury and long-term recovery

Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the anti-tubulin cancer drugs eribulin (ERIB), ixabepilone (IXA), paclitaxel (PACLI) or vinorelbine (VINO) at maximal tolerated doses. All of the drugs ablated intra-epidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within two weeks of drug administration. Additionally, all of the drugs reduced sensory NCV and amplitude, with greater deficits after PACLI and lesser deficits after IXA. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. While most injuries were fully reversible after 3-6 months after administration of ERIB, VINO, and IXA, we observed delayed recovery after PACLI that produced a more severe, pervasive and prolonged neurotoxicity. Compared to other agents, PACLI also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intra-epidermal nerve fiber density. Taken together, our findings suggest that intra-epidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.

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