Effect of age on metabolomic changes in a model of paclitaxel-induced neurotoxicity

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other targets, which might be used as potential biomarkers of nerve impairment, need to be investigated.Twenty-four young (2 months of age) and 24 adult (9 months of age) Wistar male rats were randomized to either paclitaxel (PTX) treatment (10 mg/kg i.v. once/ week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed to investigate nerve damage at baseline, af er 4 eeks and the 2-week follow-up period. Skin biopsies from sacrifced animals were examined for intraepidermal nerve fiber (IENF) density assessment. Blood and liver samples were collected for targeted metabolomics analysis using UltraPerformance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS). 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-treated animals, and in both the digital and caudal nerve of adult treated animals (p < 0.05). Behavioral tests revealed a significant decrease in the mechanical threshold in young PTX-treated animals (p < 0.001),while adult treated rats showed no signif cant dif erence in mechanical threshold compared to controls. Concerning IENF assessment, both young and adult PTX-rats had reduced IENF density (p < 0.0001), which persisted at the end of follow-up.T argeted metabolomics analysis showed signif cant dif erences in the plasma metabolite prof les between PTX-treated animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, phingolipids, and bile acids playing a major role in the response to PTX administration. Our study identif es for the f rst time multiple related metabolic axes involved in paclitaxel-induced peripheral neuropathy, and suggests age-related dif erences in CIPN manifestations and in the metabolic profile