MORPHOLOGICAL AND METABOLOMIC CHANGES IN PIPN

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie nerve damage. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated. Twenty-four young (2-months) and 24 adult (9-months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Intraepidermal nerve fiber density and nerve morphology/morphometry were analysed. Blood and liver samples were collected for targeted metabolomics analysis. At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p<0.05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (p<0.05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (p<0.001), but not in adult PTX-ones. Nevertheless, both young and adult PTXrats had reduced IENF density (p<0.0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration. Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age-related differences in CIPN manifestations and in the metabolic profile.