RXR agonist, 9-cis-13,14-dihydroretinoic acid (9CDHRA), reduces damage and protects from demyelination in transsynaptic degeneration model

• Published in: Neuroscience 2024-11, Vol.559, p.91-104
• Main Authors: Parrilla, Gabriella E., Vander Wall, Roshana, Chitranshi, Nitin, Basavarajappa, Devaraj, Gupta, Vivek, Graham, Stuart L., You, Yuyi
• Format: Article
• Language: English
• Subjects: Demyelination; Optic nerve crush; Retinoid-X receptor agonist; Transsynaptic degeneration
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2024.08.030

[Display omitted] •The RXR agonist 9CDHRA was utilised to determine its neuroprotective abilities.•Signs of transsynaptic degeneration were reduced in mice administered 9CDHRA.•Injured mice had restored VEP visual assessments with 9CDHRA treatment.•This supports previous research defining RXR agonist’s remyelinating properties. Neurodegenerative and demyelinating disease, such as multiple sclerosis (MS) are at the forefront of medical research and the discovery of new drugs and therapeutics. One phenomenon of degeneration seen in these diseases is transsynaptic degeneration (TSD), where damage from one axon spreads to the other axons that are connected to it synaptically. It has previously been found that demyelination occurs prior to neuronal loss in an experimental form of induced TSD. Retinoid-x receptor (RXR) agonists have been shown to promote remyelination. Therefore, this study aimed to reveal the effects of a novel endogenous RXR-γ agonist, 9-cis-13,14-dihydroretinoic acid (9CDHRA), on preventing or restoring the effects of TSD. 9CDHRA was administered to mice following optic nerve crush (ONC) procedures, and electrophysiology (visual evoked potential, VEP) and histological (immunofluorescent) assessments were performed. It was found that 9CDHRA treatment effectively delayed glial activation and reduced the presence of apoptosis at the site of injury and further anterogradely in the visual system, including the lateral geniculate nucleus (LGN) and primary visual cortex (V1). Most notably, 9CDHRA was able to maintain myelin levels following ONC, and effectively protected from demyelination. This was corroborated by VEP recordings with improved P1 latency. The promising findings regarding the injury attenuating and myelin protecting properties of 9CDHRA necessitates further investigations into the potential therapeutic uses of this compound.