High-affinity σ1 protein agonist reduces clinical and pathological signs of experimental autoimmune encephalomyelitis

Background and PurposeSelective agonists of the sigma-1 receptor (sigma 1 protein) are generally reported to protect against neuronal damage and modulate oligodendrocyte differentiation. Human and rodent lymphocytes possess saturable, high-affinity binding sites for compounds binding to the sigma 1 protein and potential immunomodulatory properties have been described for sigma 1 protein ligands. Experimental autoimmune encephalomyelitis (EAE) is recognized as a valuable model of the inflammatory aspects of multiple sclerosis (MS). Here, we have assessed the role of a sigma 1 protein agonist, containing the tetrahydroisoquinoline-hydantoin structure, in EAE. Experimental ApproachEAE was induced in SJL/J female mice by active immunization with myelin proteolipid protein (PLP)(139-151) peptide. The sigma 1 protein agonist was injected i.p. at the time of immunization (day 0). Disease severity was assessed clinically and by histopathological evaluation of the CNS. Phenotyping of B-cell subsets and regulatory T-cells were performed by flow cytometry in spleen and cervical lymph nodes. Key ResultsProphylactic treatment of EAE mice with the sigma 1 protein agonist prevented mononuclear cell accumulation and demyelination in brain and spinal cord and increased T2 B-cells and regulatory T-cells, resulting in an overall reduction in the clinical progression of EAE. Conclusions and ImplicationsThis sigma 1 protein agonist, containing the tetrahydroisoquinoline-hydantoin structure, decreased the magnitude of inflammation in EAE. This effect was associated with increased proportions of B-cell subsets and regulatory T-cells with potential immunoregulatory functions. Targeting of the sigma 1 protein might thus provide new therapeutic opportunities in MS.