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RARb agonist drug (C286) demonstrates efficacy in a pre-clinical neuropathic pain model restoring multiple pathways via DNA repair mechanisms
Version 2 2023-06-12, 09:13
Version 1 2023-06-09, 19:33
journal contribution
posted on 2023-06-12, 09:13 authored by Maria B Goncalves, Julien Moehlin, Earl Clarke, John Grist, Carl Hobbs, Antony CarrAntony Carr, Julian Jack, Marco Antonio Mendoza-Parra, Jonathan P T CorcoranNeuropathic 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.
Funding
Replication arrest, restart and genome instability; G1829; WELLCOME TRUST; 110047/Z/15/Z
History
Publication status
- Published
File Version
- Published version
Journal
iScienceISSN
2589-0042Publisher
ElsevierExternal DOI
Volume
20Page range
554-566Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2019-11-06First Open Access (FOA) Date
2019-11-06First Compliant Deposit (FCD) Date
2019-11-05Usage metrics
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