High-affinity sigma 1 protein agonist reduces clinical and pathological signs of experimental autoimmune encephalomyelitis

• Published in: British journal of pharmacology 2015-04, Vol.172 (7), p.1769-1782
• Main Authors: Oxombre, B, Lee-Chang, C, Duhamel, A, Toussaint, M, Giroux, M, Donnier-Marechal, M, Carato, P, Lefranc, D, Zephir, H, Prin, L, Melnyk, P, Vermersch, P
• Format: Article
• Language: English
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13037

Background and Purpose Selective 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 Approach EAE was induced in SJL/J female mice by active immunization with myelin proteolipid protein (PLP) sub(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 Results Prophylactic 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 Implications This 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.