Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity
© 2023 Peripheral Nerve Society..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Journal of the peripheral nervous system : JPNS - 29(2024), 1 vom: 01. März, Seite 58-71 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bonomo, Roberta [VerfasserIn] |
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| Links: |
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| Themen: |
Biochemical markers |
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| Anmerkungen: |
Date Completed 06.03.2024 Date Revised 14.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/jns.12609 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity |
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| 520 | |a © 2023 Peripheral Nerve Society. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a biochemical markers | |
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| 650 | 4 | |a neuropathy | |
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| 700 | 1 | |a Carozzi, Valentina Alda |e verfasserin |4 aut | |
| 700 | 1 | |a Meregalli, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Pozzi, Eleonora |e verfasserin |4 aut | |
| 700 | 1 | |a Alberti, Paola |e verfasserin |4 aut | |
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| 700 | 1 | |a Skene, Debra J |e verfasserin |4 aut | |
| 700 | 1 | |a Cavaletti, Guido |e verfasserin |4 aut | |
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