Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) has long represented one of the most relevant neurological side effects of oncological therapies. Nevertheless, despite the progress in drug regimens, the occurrence of troublesome adverse events still affects the efficacy of antineoplastic therapy, leading to the reduction or discontinuation of the treatment. Paclitaxel is an anti-tubulin drug which has emerged as an efficacious antitumor agent in the treatment of different cancers. However, its clinical use is often limited by the onset of paclitaxel-induced peripheral neuropathy (PIPN). Numerous alterations related to aging have been hypothesized to underlie age-related susceptibility to nerve damage. Nevertheless, the results of these studies are inconclusive and other targets, which might be used as potential biomarkers of nerve impairment, deserve to be considered. On these bases, the aim of our study was to investigate the age-related effects of paclitaxel treatment on the peripheral nervous system, and the metabolic changes that might be induced by paclitaxel administration at different ages. Our project included neurotoxicity experiments based on neurophysiological, behavioral and histopathological evaluations to assess age-related chemotherapy-induced phenotypic alterations in a neuropathic model of PIPN. We additionally investigated through a targeted Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS) based metabolomics approach differences in the plasma and liver metabolite profiles in order to identify potential biomarkers of PIPN development and progression, according to age. Our results suggest that age might be a potential risk factor for more severe CIPN, and should be considered in future studies in order to tailor the chemotherapy regimen and dosage on individual susceptibility of older cancer patients. Our study also identifies for the first time multiple related metabolic axes involved in paclitaxel-induced neurotoxicity, as promising molecular and therapeutic targets in PIPN.