id_854. SIGMA-1 RECEPTOR MODULATION AS A THERAPEUTIC STRATEGY FOR ENHANCING OLIGODENDROCYTE DIFFERENTIATION AND REMYELINATION
Kinga Tylek1, Tommaso Fabiano1, Giampiero Leanza2, Antonella Ragnini-Wilson1
1 Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
2 Department of Drug and Health Sciences, University of Catania, Catania, Italy
INTRODUCTION: Among the defining features of many central nervous system (CNS) diseases is demyelination, most prominently observed in Multiple sclerosis (MS), a chronic autoimmune and inflammatory disorder and the leading cause of disability in young adults. MS is characterized by focal demyelinating lesions in white matter of the brain and spinal cord, leading to progressive neurological impairment. Because endogenous remyelination is limited, the sigma-1 receptor (S1R) has gained attention as a therapeutic target. S1R acts as an intracellular chaperone regulating Ca²⁺ homeostasis and ER-mitochondria signaling, reducing oxidative stress and mitochondrial dysfunction. Thus, S1R activation represents a mechanistic strategy to enhance oligodendrocyte lineage progression, promote remyelination, and improve white matter integrity.
AIM(S): Given these discrepancies, we evaluated the promyelinating potential of S1R agonists in vitro using the oligodendroglial Oli-neuM model, which differentiates into a mature phenotype capable of remyelinating axons in vitro.
METHOD(S): Dose-dependent effects of two novel bifunctional S1R agonists (CVPO1 and GR01) on myelination were assessed by MBP immunofluorescence. Selected doses were then analyzed by qRT-PCR to evaluate effects on oligodendrocyte differentiation (Sox10, Gpr17), late myelin genes (Mog, Opalin), and ER stress markers (Atf4, Chop).
RESULTS: Our results showed increased Sox10 and myelination markers with reduced Gpr17 after CVPO1 and GR01 treatment, indicating enhanced oligodendrocyte differentiation. Importantly, both compounds reduce ER stress via different mechanisms: CVPO1 attenuates Chop levels, while GR01 decreases Atf4 gene expression.
CONCLUSIONS: Based on the presented results, it is possible to suggest that pharmacological targeting enhancement of the S1R activity may represent a promising therapeutic strategy for central nervous system demyelination disorders, including multiple sclerosis, by through the promotion of remyelination once lost as a result of pathology.
FINANCIAL SUPPORT: Supported by grant no. PRIN2022 - Prot. 2022ZSC4Z5