INTRODUCTION: Persistent neuroinflammation is a major barrier to myelin repair in disorders such as multiple sclerosis (MS). We have investigated two distinct strategies—psychedelics and oxysterol-driven EBI2 activation—that modulate inflammatory signaling in the CNS and may independently support remyelination.

AIM(S): To evaluate (1) whether classical psychedelics can dampen inflammation-induced damage to oligodendrocytes and the blood–brain barrier (BBB), and (2) whether a synthetic EBI2 agonist promotes remyelination in a toxin model by altering glial inflammation and lipid profiles.

METHOD(S): Psychedelics: Organotypic mouse cerebellar slices were chemically demyelinated and treated with various psychodelics, alone or combined with ketanserin (5-HT₂A antagonist) or BD-1063 (Sigma-1 antagonist). In parallel, a human tri-cellular BBB model was exposed to pro-inflammatory stimuli with or without psychodelics and antagonists to assess the effects on barrier function. EBI2 agonist (CF₃-7α,25-OHC): Adult mice received cuprizone (CPZ) diet and then underwent two weeks of daily CF₃-7α,25-OHC injections.

RESULTS: Psychedelics: DMT reduced LPC-induced cytokine release and downregulated inflammatory transcription factors in both slice and BBB models. These effects were reversed by ketanserin or BD-1063, confirming 5-HT₂A and Sigma-1 receptor involvement in anti-inflammatory signaling. EBI2 agonist: CF₃-7α,25-OHC treatment accelerated MBP recovery in the corpus callosum. Treated mice exhibited increased levels of 15 lipid classes. Peripheral lymphocyte and monocyte counts decreased by ~50–60%, and brain Ebi2 transcripts rose significantly during remyelination.

CONCLUSIONS: Both approaches act on neuroinflammatory pathways—one via modulation of serotonin/Sigma-1 signaling, the other through oxysterol-EBI2–mediated effects on glial cells and lipids—to create a more favorable environment for myelin repair. These findings suggest that targeting neuroinflammatory signaling represents a promising therapeutic strategy for MS.

FINANCIAL SUPPORT: This project received funding from the National Science Centre, Poland, grant registration number: 2022/47/D/NZ3/02613