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

Abstract Background and Aims 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 susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated. Methods 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. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis. Results At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude ( p < .05) in the caudal nerve of young PTX‐animals, and in both the digital and caudal nerve of adult PTX‐animals ( p < .05). A significant decrease in the mechanical threshold was observed only in young PTX‐animals ( p < .001), but not in adult PTX‐ones. Nevertheless, both young and adult PTX‐rats had reduced IENF density ( p < .0001), which persisted at the end of follow‐up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX‐animals developing peripheral neuropathy 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. Interpretation 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.