Background: Vincristine is part of numerous chemotherapy regimen used for the treatment of several adult and pediatric tumors. However, the high toxicity of vincristine causes peripheral neuropathy in up to 90 % of treated patients and is characterized by e.g. numbness, tingling and neuropathic pain. Despite the wide range of treatments available, none successfully controls this side effect, leaving vincristine-treated patients with an additional burden often resulting in dose reduction or even cessation of the anticancer therapy. Therefore, the discovery of novel therapeutic targets for the treatment of vincristine induced peripheral neuropathy (VIPN) will enable us to develop new therapy strategies effectively improving quality of life and survival rates of patients.

Methods: We established an animal model of VIPN based on sequential local injections (intraplantar) of vincristine into one hind paw of C57BL/6 mice. Gait analysis (CatWalk XT), Von Frey mechanical and thermal threshold measurements (Topcat Metrology Ltd) as well as histological examination of injected hind paws were performed. The dorsal root ganglia (L3; L4 and L5) of vincristine treated and control animals were isolated to collect RNA for a full transcriptome.

Results: The intraplantar administration of vincristine caused dose- and time-dependent changes in the mechanical and thermal threshold as well as gait abnormalities. The transcriptomic analysis and the histological examination revealed a contribution of the innate immune system to the development of VIPN. In particular, the Toll-Like receptor (TLR) pathway seems to be involved as the inhibition of TLR4 with minocycline (25 mg/kg i.p.) partially prevented the development of vincristine induced mechanical allodynia.  

Conclusion: This study provides an improved mouse model of VIPN and a basis for the discovery and development of novel efficient therapeutic strategies based on inhibition of specific immune pathways.