A Comparative Study of a Potent CNS-Permeable RARβ-Modulator, Ellorarxine, in Neurons, Glia and Microglia Cells In Vitro

Zhang, Yunxi; Gailloud, Lilie; Shin, Alexander; Fewkes, Jessica; Pinckney, Rosella; Whiting, Andrew; Chazot, Paul

Abstract

Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis and various fundamental cellular processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), activating specific signalling pathways in the cells. The disruption of the retinoic acid signalling pathway can result in neuroinflammation, oxidative and ER stress and mitochondrial dysfunction and has been implicated in a wide range of neurodegenerative diseases. The present study explored the potential therapeutic application of our innovative CNS-permeable synthetic retinoid, Ellorarxine, for the treatment of neurodegenerative disorders in vitro. An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay, lactate dehydrogenase (LDH) assay, enzyme-linked immunosorbent assay (ELISA), immunocytochemistry and immunofluorescence staining were performed. Ellorarxine increased Cyp26 and, selectively, RARβ protein expression in neurons, glia and microglia. Ellorarxine significantly reduced cell death (neurons, glia), increased mitochondrial viability (neurons), modulated cytokine release (microglia), and positively regulated cellular autophagy (neurons, glia, microglia). These results suggest that Ellorarxine is a promising drug candidate that should be further investigated in the treatment of neurodegenerative diseases.

Citation

Zhang, Y., Gailloud, L., Shin, A., Fewkes, J., Pinckney, R., Whiting, A., & Chazot, P. (2025). A Comparative Study of a Potent CNS-Permeable RARβ-Modulator, Ellorarxine, in Neurons, Glia and Microglia Cells In Vitro. International Journal of Molecular Sciences, 26(8), 3551. https://doi.org/10.3390/ijms26083551

• Journal Article Type: Article
• Acceptance Date: Mar 20, 2025
• Online Publication Date: Apr 10, 2025
• Publication Date: Apr 10, 2025
• Deposit Date: Jun 4, 2025
• Publicly Available Date: Jun 4, 2025
• Journal: International Journal of Molecular Sciences
• Print ISSN: 1661-6596
• Electronic ISSN: 1422-0067
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 26
• Issue: 8
• Pages: 3551
• DOI: https://doi.org/10.3390/ijms26083551
• Keywords: neuroprotective effects, RARs, neuroinflammation, autophagy, retinoid, mitochondrial dysfunction, DC645, NVG0645, ellorarxine, neurodegeneration
• Public URL: https://durham-repository.worktribe.com/output/3944751