ACTIVATION OF σ1R AND 5-HT2A PATHWAYS MODULATES NEUROINFLAMMATION, GLIAL REPAIR PROGRAMS, AND BBB RESPONSES IN DEMYELINATING CNS MODELS

Chronic, compartmentalized neuroinflammation limits endogenous repair and contributes to progressive disability in demyelinating disorders such as multiple sclerosis (MS). While sigma-1 receptor (σ1R) and serotonin 5-HT2A receptor signalling are well characterized in neuropsychiatric pharmacology, their roles in regulating CNS-intrinsic inflammatory and repair mechanisms remain insufficiently defined. The purpose of this study was to determine whether activation of σ1R-and 5-HT2A–linked pathways modulates neuroinflammatory signalling and glial repair programs under demyelinating conditions. We employed organotypic cerebellar slice cultures subjected to lysophosphatidylcholine (LPC)–induced demyelination to assess inflammatory signalling, cytokine release, and glial responses. LPC exposure induced robust NF-κB–associated inflammatory activation accompanied by increased release of TNFα and IL-1β and loss of myelin-associated proteins. Treatment with N,N-dimethyltryptamine (DMT), a dual σ1R/5-HT2A agonist, significantly attenuated NF-κB signalling, reduced proinflammatory cytokine release, and preserved expression of the myelin marker CNPase. At the cellular level, DMT promoted oligodendrocyte progenitor cell (OPC) maturation, characterized by suppression of progenitor-associated transcriptional programs and increased expression of myelin-associated genes, including CNPase and MBP. In parallel, DMT enhanced microglial cholesterol phagocytosis, consistent with a shift toward a repair-permissive microglial state. These effects were ligand-specific and were not reproduced by other serotonergic or σ1R-active compounds, indicating engagement of a distinct receptor-linked signalling axis. Together, these findings establish σ1R-and 5-HT2A–linked signalling as a CNS-intrinsic regulatory axis that directly couples neuropsychiatric receptor pharmacology to modulation of neuroinflammation and glial plasticity. By demonstrating ligand-specific control of inflammatory and repair-relevant processes in CNS-resident cells, this work advances the field by providing mechanistic insight into how receptor targets traditionally studied in psychiatric contexts can be leveraged to develop CNS-directed, non-immunosuppressive therapeutic strategies for chronic neuroinflammatory and demyelinating disorders.