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

• Published in: Molecular neurobiology 2021-07, Vol.58 (7), p.3575-3587
• Main Authors: Pereira, Vanessa, Lamoine, Sylvain, Cuménal, Mélissa, Lolignier, Stéphane, Aissouni, Youssef, Pizzoccaro, Anne, Prival, Laetitia, Balayssac, David, Eschalier, Alain, Bourinet, Emmanuel, Busserolles, Jérôme
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antineoplastic Agents - toxicity; Biomedical and Life Sciences; Biomedicine; Cell Biology; Dorsal root ganglia; Down-Regulation - drug effects; Down-Regulation - physiology; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - physiology; Epigenetics; Histone deacetylase; Histones; Hyperalgesia - chemically induced; Hyperalgesia - genetics; Hyperalgesia - metabolism; Hypersensitivity; Ion channels; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular modelling; Neurobiology; Neurology; Neurons and Cognition; Neurosciences; Oxaliplatin; Oxaliplatin - toxicity; Pain perception; Peripheral neuropathy; Pharmaceutical sciences; Pharmacology; Potassium; Potassium channels; Potassium Channels - biosynthesis; Potassium Channels - genetics; Potassium Channels, Tandem Pore Domain - biosynthesis; Potassium Channels, Tandem Pore Domain - genetics; Regulatory sequences; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - biosynthesis; Repressor Proteins - genetics; Repressors; Temperature perception; Transcription, Genetic - drug effects; Transcription, Genetic - physiology
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-021-02361-6

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.