Exploring a new disease-modifying approach for Neurodegenerative diseases based on retinoic acid receptor modulation

Neurodegenerative diseases (NDDs) have evolved into a global health crisis which shows no signs of slowing down. The retinoid signalling pathway through Retinoic Acid Receptors (RARs) functions is a vital mechanism for neuronal homeostasis and shows promise as a therapeutic target. The study investigates the pharmacological properties and therapeutic uses of two synthetic retinoids, Ellorarxine and MH21, which specifically target RAR−β receptors.
The researchers conducted a complete set of laboratory tests on neuronal and peripheral cell lines to evaluate both the neuroprotective effects of compounds and their biodistribution properties in the body. The research found that the two compounds Ellorarxine and MH21 showed strong neuroprotective effects on neuronal cells. Ellorarxine boosted mitochondrial viability in SH-SY5Y neuronal cells by 17% and enhanced cell viability by 19%, while MH21 also showed 20% alleviation in mitochondrial viability and 18% in cell viability. The research also found that both compounds enhance autophagy and have the capacity to stop Aβ aggregation, which together target major NDD disease mechanisms.
The compounds displayed differential bioavailability. Ellorarxine showed potential as a CNS-penetrant lead compound for direct brain action, but it demonstrated potential peripheral toxicity and pro-inflammatory responses in human skin models. MH21 showed CNS-sparing properties with better peripheral safety characteristics through its ability to reduce inflammation and show non-toxic effects in skin cells.
The research established two lead RAR−β selective agonists, which now enable scientists to develop them as distinct therapeutic agents. The CNS NDD treatment potential of Ellorarxine exists, while MH21 shows promise as a unique peripherally restricted neurotherapeutic drug.