Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity.
J Peripher Nerv Syst
; 29(1): 58-71, 2024 Mar.
Article
en En
| MEDLINE
| ID: mdl-38126610
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades del Sistema Nervioso Periférico
/
Síndromes de Neurotoxicidad
Límite:
Animals
Idioma:
En
Revista:
J Peripher Nerv Syst
Asunto de la revista:
NEUROLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Italia
Pais de publicación:
Estados Unidos