Paclitaxel-induced neuroinflammation after systemic administration in male and female mice

Peripheral neuropathy is one of the most prevalent neurotoxic, dose-limiting side effects of paclitaxel, a chemotherapy agent used widely in solid cancers. The mechanism of paclitaxel-induced peripheral neuropathy (PIPN) is poorly understood, and thus there are no approved treatments currently. Notably, neuroinflammation has been described as a cardinal component in the pathogenesis of PIPN. However, animal studies of PIPN assessing neuroinflammation mediators have mostly focused on gene expression, not protein, and usually in one neuronal tissue and/or at one time point in male mice. Thus, characterization of inflammation mediators at different timepoints, in both sexes, and in different neuronal tissues is critical to understanding PIPN. Paclitaxel (8 mg/kg, i.p.) or vehicle was administered every other day for a total of four injections in male and female C57BL/6J mice. Mechanical and cold sensitivity, nerve conductance, and 22 cytokines and chemokines levels in the dorsal root ganglia (DRG) and spinal cord (SC) were measured at different time points (7, 14, and 21 days) post injections in both sexes. Paclitaxel induced mechanical and cold hypersensitivity and decreased nerve conduction amplitude similarly in both male and female mice. Multiplex cytokine analysis revealed that paclitaxel-induced increase in neuroinflammation is time-, sex-, and tissue- dependent. Our findings provide novel contribution to current knowledge about neuroinflammation as an important mechanism in PIPN. In addition, the results could explain potential mechanistic sex differences in immune pain signaling that can guide precision medicine in the future.

Perspective

Our study demonstrated that the chemodrug paclitaxel induces nociceptive and physiological changes similarly in male and female mice. However, paclitaxel-induced increase in neuroinflammation is time-, sex-, and tissue- dependent. These findings could pave the way for more effective and personalized management of CIPN.