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Epigenetics Involvement in Oxaliplatin-Induced Potassium Channel Transcriptional Downregulation and Hypersensitivity

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Abstract

Peripheral neuropathy is the most frequent dose-limiting adverse effect of oxaliplatin. Acute pain symptoms that are induced or exacerbated by cold occur in almost all patients immediately following the first infusions. Evidence has shown that oxaliplatin causes ion channel expression modulations in dorsal root ganglia neurons, which are thought to contribute to peripheral hypersensitivity. Most dysregulated genes encode ion channels involved in cold and mechanical perception, noteworthy members of a sub-group of potassium channels of the K2P family, TREK and TRAAK. Downregulation of these K2P channels has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. We investigated the molecular mechanisms underlying this peripheral dysregulation in a murine model of neuropathic pain triggered by a single oxaliplatin administration. We found that oxaliplatin-mediated TREK-TRAAK downregulation, as well as downregulation of other K+ channels of the K2P and Kv families, involves a transcription factor known as the neuron-restrictive silencer factor (NRSF) and its epigenetic co-repressors histone deacetylases (HDACs). NRSF knockdown was able to prevent most of these K+ channel mRNA downregulation in mice dorsal root ganglion neurons as well as oxaliplatin-induced acute cold and mechanical hypersensitivity. Interestingly, pharmacological inhibition of class I HDAC reproduces the antinociceptive effects of NRSF knockdown and leads to an increased K+ channel expression in oxaliplatin-treated mice.

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Acknowledgements

We would like to thank Florian Lesage (IPMC, Nice, France) who provided us with the triple TREK-TRAAK knockout mice, and Yoan Renaud who performed the in silico data analysis using the TRANSFAC and FIMO programs.

Data Availability Statement

Data will be made available on a reasonable request.

Funding

This project was funded by the Regional Council of Auvergne (Conseil Régional d’Auvergne) together with the European Fund for Regional Economic Development (FEDER), Clermont Auvergne University, and the French government through the programme “Investissements d’Avenir” (I-Site CAP 20-25).

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  1. Université Clermont Auvergne, Inserm UMR-U1107, Neuro-Dol, 28, pl. H.Dunant, F-63000, Clermont-Ferrand, France

    Vanessa Pereira, Sylvain Lamoine, Mélissa Cuménal, Stéphane Lolignier, Youssef Aissouni, Laetitia Prival, David Balayssac, Alain Eschalier & Jérôme Busserolles

  2. Institut Analgesia, Faculté de Médecine, BP38, F-63001, Clermont-Ferrand, France

    Vanessa Pereira, Sylvain Lamoine, Mélissa Cuménal, Stéphane Lolignier, Youssef Aissouni, Laetitia Prival, David Balayssac, Alain Eschalier & Jérôme Busserolles

  3. Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS UMR-5203, INSERM U1091, F-34094, Montpellier, France

    Anne Pizzoccaro & Emmanuel Bourinet

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Contributions

V.P. and S. Lamoine conducted the experiments, analyzed the data, and participated in the preparation of the manuscript. M.C., Y.A., and L.P. participated in experiments. S. Lolignier, D.B., and A.P. were associated with the design and analysis of the research. J.B., A.E., and E.B. designed the research, supervised the project, participated in data analysis, and wrote the paper.

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Correspondence to Jérôme Busserolles.

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All the animal procedures were approved by the local Animal Ethics Committee and the experiments were performed according to the guidelines provided by the European Community on the care and use of animals (Directive 2010/63/EU).

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Vanessa Pereira and Sylvain Lamoine are co-first author.

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Pereira, V., Lamoine, S., Cuménal, M. et al. Epigenetics Involvement in Oxaliplatin-Induced Potassium Channel Transcriptional Downregulation and Hypersensitivity. Mol Neurobiol 58, 3575–3587 (2021). https://doi.org/10.1007/s12035-021-02361-6

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