RARb agonist drug (C286) demonstrates efficacy in a pre-clinical neuropathic pain model restoring multiple pathways via DNA repair mechanisms

Goncalves, Maria B, Moehlin, Julien, Clarke, Earl, Grist, John, Hobbs, Carl, Carr, Antony M, Jack, Julian, Mendoza-Parra, Marco Antonio and Corcoran, Jonathan P T (2019) RARb agonist drug (C286) demonstrates efficacy in a pre-clinical neuropathic pain model restoring multiple pathways via DNA repair mechanisms. iScience, 20. pp. 554-566. ISSN 2589-0042

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Abstract

Neuropathic pain (NP) is associated with profound gene expression alterations within the nociceptive system. DNA mechanisms, such as epigenetic remodelling and repair pathways have been implicated in NP. Here we have used a rat model of peripheral nerve injury to study the effect of a recently developed RARb agonist, C286, currently under clinical research, in NP. A four week treatment initiated two days after the injury normalised pain sensation. Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. Concomitant upregulation of DNA repair proteins, ATM and BRCA1, the latter being required for C286 mediated pain modulation, suggest that early DNA repair may be important to prevent phenotypic epigenetic imprints in NP. Thus, C286 is a promising drug candidate for neuropathic pain and DNA repair mechanisms may be useful therapeutic targets to explore.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Research Centres and Groups: Genome Damage and Stability Centre
Depositing User: Antony Carr
Date Deposited: 06 Nov 2019 08:20
Last Modified: 19 Nov 2019 10:15
URI: http://sro.sussex.ac.uk/id/eprint/87856

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Replication arrest, restart and genome instabilityG1829WELLCOME TRUST110047/Z/15/Z