Serum neurofilament light chain levels suggest neuroprotection following bexarotene-induced remyelination in people with relapsing remitting multiple sclerosis

Article

作者: Brown, William ; Coles, Alasdair ; Kuhle, Jens ; McMurran, Chris ; Needham, Edward ; Riboni-Verri, Gioia ; Cunniffe, Nick G ; Hofer, Lisa

BACKGROUND:

Remyelination offers a potential neuroprotective strategy in multiple sclerosis (MS). In the Cambridge Centre of Myelin Repair One (CCMR-One) trial, bexarotene, an RXR agonist, promoted remyelination in people with MS, evidenced through a reduction in the latency of the full-field visual evoked potential (VEP). However, it remained uncertain whether bexarotene additionally promoted neuroprotection.

METHODS:

We conducted a sub-study of the Cambridge-based (n = 31) participants of the CCMR-One trial. Participants were aged 18-50 years, had baseline EDSS 0-6.0 and had been stable on dimethyl fumarate for at least 6 months. Consenting participants contributed serum samples at baseline and month 6, which were analysed for neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total Tau protein (Tau), and C-terminal hydrolase L1 (UCHL1). The change in serum biomarker values and their associations with changes in VEP latency were assessed using linear models adjusted for age, sex, EDSS, disease duration and baseline biomarker levels.

RESULTS:

27 participants consented to provide blood samples (15 bexarotene, 12 placebo). There were no significant differences in biomarker change between these groups. However, a significant interaction was observed between treatment group and sNfL change (p = 0.001) among those with prolonged baseline VEP latency (≥118 ms). In the bexarotene group, latency improvement was associated with a reduction in sNfL (β = 23.4 ms per log[pg/mL] decrease; 95 % CI 11.1 to 36.2); this relationship was not seen in the placebo group.

CONCLUSIONS:

Bexarotene-induced remyelination was associated with reduced sNfL in individuals with prior demyelination, suggesting a potential neuroprotective effect.

2025-10-13·Journal of biomolecular structure & dynamics

Discovery of small molecules from natural compound databases as potent retinoid X alpha receptor agonists to treat Alzheimer’s disease

Article

作者: Mafakher, Ladan ; Shahbazi, Behzad ; Rahimpour, Alireza

Alzheimer's is characterized as a progressive neurodegenerative disease due to beta-amyloid accumulation in the brain. Some previous studies reported that RXR agonists could be effective in the treatment of Alzheimer's disease. There are currently numerous attempts being made to discover a natural RXR agonist that is more potent than 9-cis-retinoic acid (9CR). One of the most efficient resources for finding high-potential compounds is natural databases. In this study, 81215 compounds from the IB screen library as natural databases were docked against the RXR-alpha binding site. The best compounds discovered interact with the RXR-alpha binding site with a lower binding energy (-11 to -13 kcal/mol) than the binding energy of -10.94 kcal/mol for 9-cis, which means that these compounds could interact stronger with RXR-alpha than 9CR. All selected compounds could pass the blood-brain barrier. Physiochemical properties assessment indicated that all compounds passed Lipinski's rule and had the potential to be oral drug candidates. The stability of protein-ligand complexes during a timescale of 100 ns by Molecular Dynamics simulation demonstrated that all compounds could effectively interact with the RXR binding site. The molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) represented that all selected hit compounds had a better binding affinity to the alpha RXR binding site compared to 9CR, which means these hit compounds had potential drug candidates for the treatment of Alzheimer's disease. However, experimental assessment is needed to validate this result.

2025-09-10·JOURNAL OF NEUROSCIENCE

Retinoid-X-Receptor as a Mediator of Poststroke Recovery by Reversing Age-Associated Phenotypes of Microglia/Hematogenous Macrophages

Article

作者: Ricote, Mercedes ; Ting, Shun-Ming ; Sun, Guanghua ; Aronowski, Jaroslaw ; Zhao, Xiurong

After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore, aged MΦ become overactivated in response to stroke, enhancing secondary brain injury. In this study, we demonstrated that by reversing the age-related dysfunctions in MΦ through activating the retinoid X receptor (RXR), the recovery after stroke in the aged brain could be improved. Using RNA-sequencing, we compared the transcriptomes between MΦ isolated from the brains of young and aged male mice. We observed higher levels of proinflammatory genes and lower levels of phagocytosis-facilitating genes (Cd206 and Cd36) expressed by aged MΦ. Meanwhile, the treatment with RXR agonist bexarotene (BEX) reversed the signature genes of microglia aging in the aged MΦ. With the in vivo phagocytosis model, we showed that BEX enhanced the phagocytic ability of aged MΦ. Using the MCAo stroke model and male and female mice, we established that BEX improved sensorimotor and cognitive recovery after MCAo in a myeloid-RXRα–specific and myeloid-RXRα–dependent manner. In conclusion, we showed that activating RXRα partially restores age-related MΦ dysfunctions and that RXRα deficiency in MΦ limits the therapeutic effect of RXR in improving poststroke recovery in the aged brain.

100 项与 RXR agonist 相关的药物交易

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