RARß Agonist Drug (C286) Demonstrates Efficacy in a Pre-clinical Neuropathic Pain Model Restoring Multiple Pathways via DNA Repair Mechanisms
RARß Agonist Drug (C286) Demonstrates Efficacy in a Pre-clinical Neuropathic Pain Model Restoring Multiple Pathways via DNA Repair Mechanisms
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RAR™ 激动剂药物 (C286) 在临床前神经病理性疼痛模型中显示出功效，可通过 DNA 修复机制恢复多条通路
DOI：
10.1016/j.isci.2019.10.068
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发表时间：
2019
期刊：
影响因子：
5.8
通讯作者：
Goncalves M
中科院分区：
文献类型：
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作者：
Goncalves M
神经病理性疼痛（NP）与伤害性系统内深刻的基因表达改变有关。DNA机制，如表观遗传重塑和修复途径已被牵连在NP。在这里，我们使用大鼠周围神经损伤模型来研究最近开发的RARβ激动剂C286，目前正在临床研究中，在NP中的作用。在损伤后2天开始的4周治疗使疼痛感觉正常化。全基因组和途径富集分析表明，在脊髓中持续改变的多种机制被激动剂恢复到损伤前水平。同时上调的DNA修复蛋白，ATM和BRCA1，后者是C286介导的疼痛调制所需的，表明早期DNA修复可能是重要的，以防止表型表观遗传印记在NP。因此，C286是一个有前途的候选药物神经病理性疼痛和DNA修复机制可能是有用的治疗靶点探索。
Neuropathic pain (NP) is associated with profound gene expression alterations within the nociceptive system. DNA mechanisms, such as epigenetic remodeling 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 RARβ agonist, C286, currently under clinical research, in NP. A 4-week treatment initiated 2 days after the injury normalized 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, suggests 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.