Interferon-γ Mitigates Oxaliplatin-Induced Neurotoxicity: Analogies With Connexin 43.
4 affiliations
- 1Department of Neuroscience, Psychology, Drug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology Section, University of Florence, Florence, Italy.
- 2European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy.
- 3Department of Health Science, University of Florence, Florence, Italy.
- 4Clinical Gastroenterology Unit, Department of Biomedical Clinical and Experimental Sciences "Mario Serio", University of Florence, Florence, Italy.
Abstract
Aims
Chemotherapy-induced neuropathy is a major side effect of platinum-based drugs such as oxaliplatin. Given the context-dependent pro-inflammatory or neuroprotective actions of interferon-γ (IFN-γ), this study investigated its role in an in vitro model of oxaliplatin-induced neurotoxicity (OIPN).Methods
Rat organotypic spinal cord slices were exposed to oxaliplatin to model chemotherapy-induced neurotoxicity responses in vitro. IFN-γ cytotoxicity was assessed at 6 and 24 h. Neurotoxicity, inflammatory mediators, neurotrophic factors, and markers of glial and neuronal activation were analyzed by biochemical and immunohistochemical assays. Connexin 43 (Cx43) was assessed using Gap19 and Gap27 to probe hemichannel and gap-junction contributions. Electrophysiological recordings characterized neuronal excitability.Results
IFN-γ (6.5-200 ng/mL) was non-toxic and, at 65 ng/mL, significantly reduced oxaliplatin-induced neurotoxicity, decreasing LDH release and suppressing pro-inflammatory mediators (CCL2, SerpinA3N, CGRP, substance P, c-Fos). IFN-γ modulated its signaling by reducing IFNγR and increasing IRF1 expression. It prevented oxaliplatin-induced overexpression of neurotrophic factors and reduced glial and neuronal hyperactivation markers, preserving neuronal integrity. IFN-γ reduced Cx43 expression and hemichannel activity, and Gap19 reproduced selected protective effects. Electrophysiology showed attenuation of oxaliplatin-induced neuronal hyperexcitability.Conclusion
IFN-γ attenuates oxaliplatin-induced neurotoxic responses in an in vitro spinal cord model. The parallel reduction in Cx43 expression and hemichannel activity supports further investigation of Cx43 signaling as a candidate pharmacological target in OIPN.
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BibTeX
@article{toti2026interferonγ,
title = {{Interferon-γ Mitigates Oxaliplatin-Induced Neurotoxicity: Analogies With Connexin 43.}},
author = {Alessandra Toti and Valentina Ferrara and Elena Lucarini and Laura Micheli and Clara Ciampi and Francesco Margiotta and Daniel Venturi and Carmen Parisio and Elisabetta Gerace and Lorenzo Curti and Alessio Masi and Tommaso Mello and Guido Mannaioni and Carla Ghelardini and Lorenzo Di Cesare Mannelli},
journal = {CNS neuroscience \& therapeutics},
year = {2026},
month = oct,
doi = {10.1002/cns.71197},
url = {https://europepmc.org/article/MED/42908325},
note = {CC BY},
}
RIS
TY - JOUR
TI - Interferon-γ Mitigates Oxaliplatin-Induced Neurotoxicity: Analogies With Connexin 43.
AU - Alessandra Toti
AU - Valentina Ferrara
AU - Elena Lucarini
AU - Laura Micheli
AU - Clara Ciampi
AU - Francesco Margiotta
AU - Daniel Venturi
AU - Carmen Parisio
AU - Elisabetta Gerace
AU - Lorenzo Curti
AU - Alessio Masi
AU - Tommaso Mello
AU - Guido Mannaioni
AU - Carla Ghelardini
AU - Lorenzo Di Cesare Mannelli
PY - 2026
DA - 2026/10/01
JO - CNS neuroscience & therapeutics
DO - 10.1002/cns.71197
UR - https://europepmc.org/article/MED/42908325
AB - Aims Chemotherapy-induced neuropathy is a major side effect of platinum-based drugs such as oxaliplatin. Given the context-dependent pro-inflammatory or neuroprotective actions of interferon-γ (IFN-γ), this study investigated its role in an in vitro model of oxaliplatin-induced neurotoxicity (OIPN).Methods Rat organotypic spinal cord slices were exposed to oxaliplatin to model chemotherapy-induced neurotoxicity responses in vitro. IFN-γ cytotoxicity was assessed at 6 and 24 h. Neurotoxicity, inflammatory mediators, neurotrophic factors, and markers of glial and neuronal activation were analyzed by biochemical and immunohistochemical assays. Connexin 43 (Cx43) was assessed using Gap19 and Gap27 to probe hemichannel and gap-junction contributions. Electrophysiological recordings characterized neuronal excitability.Results IFN-γ (6.5-200 ng/mL) was non-toxic and, at 65 ng/mL, significantly reduced oxaliplatin-induced neurotoxicity, decreasing LDH release and suppressing pro-inflammatory mediators (CCL2, SerpinA3N, CGRP, substance P, c-Fos). IFN-γ modulated its signaling by reducing IFNγR and increasing IRF1 expression. It prevented oxaliplatin-induced overexpression of neurotrophic factors and reduced glial and neuronal hyperactivation markers, preserving neuronal integrity. IFN-γ reduced Cx43 expression and hemichannel activity, and Gap19 reproduced selected protective effects. Electrophysiology showed attenuation of oxaliplatin-induced neuronal hyperexcitability.Conclusion IFN-γ attenuates oxaliplatin-induced neurotoxic responses in an in vitro spinal cord model. The parallel reduction in Cx43 expression and hemichannel activity supports further investigation of Cx43 signaling as a candidate pharmacological target in OIPN.
SN - 1755-5930
SN - 1755-5949
ER -