RARβ Agonist Drug (C286) Demonstrates Efficacy in a Pre-clinical Neuropathic Pain Model Restoring Multiple Pathways via DNA Repair Mechanisms

Abstract

SummaryNeuropathic 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.

Synthetic Retinoids Beyond Cancer Therapy

“…This functional recovery required NG2 + cells near the neuronal cells to produce RA by activating ALDH1a2 in response to the RARβ agonist (121). Synthetic RARβ agonists also showed efficacy in preclinical neuropathic pain models (27,122). From the publications summarized here, it is clear that synthetic RARβ agonists should continue to be tested for efficacy in models of various types of neuronal injuries and in models of neurodegenerative disorders (123).…”

Evaluation of the Mutagenic Potential in a Mouse Model of Peripheral Neuropathic Pain / Avaliação Do Potencial Mutagênico Em Um Modelo De Dor Neuropática Periférica Em Camundongos

“…Overall stress provoked by neuropathic pain and its concurrent inflammatory response has been linked to a large number of persisting adaptations at both cellular and molecular levels [27]. Among these, we highlight the occurrence of profound gene expression changes, though the underlying mechanisms by which these alterations are induced remain poorly understood [27,28]. Some studies, however, suggest that the inflammatory response is one of the main factors responsible for such DNA damage [21,29], while other authors have demonstrated that even neuronal activity can be enough to induce highly toxic DNA lesion, which may alter the expression of late response genes [30].…”

Recent advances in the design of RAR α and RAR β agonists as orally bioavailable drugs. A review

“…The RARβ agonist drug C286 24 also demonstrates efficacy in a pre-clinical neuropathic pain (NP) model restoring multiple pathways via DNA repair mechanisms. 47 …”

“…Using a rat model of peripheral nerve injury it has been found that a 4-week treatment with C286 24 initiated 2 days after the injury normalised pain sensation. 47 Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. 47 …”

“… 47 Genome-wide and pathway enrichment analysis showed that multiple mechanisms persistently altered in the spinal cord were restored to preinjury levels by the agonist. 47 …”