S100B inhibition protects from chronic experimental autoimmune encephalomyelitis

• Published in: Brain communications Vol. 4; no. 3; p. fcac076
• Main Authors: Barros, Catarina, Barateiro, Andreia, Neto, Alexandre, Soromenho, Beatriz, Basto, Afonso P., Mateus, Joana M., Xapelli, Sara, Sebastião, Ana M., Brites, Dora, Graça, Luís, Fernandes, Adelaide
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 2022
• Subjects: Experimental autoimmune encephalomyelitis; Immunity; Multiple sclerosis; Neuroinflammation; Original; S100B; experimental autoimmune encephalomyelitis; immunity; S100B; neuroinflammation; multiple sclerosis
• ISSN: 2632-1297; 2632-1297
• DOI: 10.1093/braincomms/fcac076

Abstract Studies have correlated excessive S100B, a small inflammatory molecule, with demyelination and associated inflammatory processes occurring in multiple sclerosis. The relevance of S100B in multiple sclerosis pathology brought an emerging curiosity highlighting its use as a potential therapeutic target to reduce damage during the multiple sclerosis course, namely during inflammatory relapses. We examined the relevance of S100B and further investigated the potential of S100B-neutralizing small-molecule pentamidine in chronic experimental autoimmune encephalomyelitis. S100B depletion had beneficial pathological outcomes and based on promising results of a variety of S100B blockade strategies in an ex vivo demyelinating model, we choose pentamidine to assay its role in the in vivo experimental autoimmune encephalomyelitis. We report that pentamidine prevents more aggressive clinical symptoms and improves recovery of chronic experimental autoimmune encephalomyelitis. Blockade of S100B by pentamidine protects against oligodendrogenesis impairment and neuroinflammation by reducing astrocyte reactivity and microglia pro-inflammatory phenotype. Pentamidine also increased regulatory T cell density in the spinal cord suggesting an additional immunomodulatory action. These results showed the relevance of S100B as a main driver of neuroinflammation in experimental autoimmune encephalomyelitis and identified an uncharacterized mode of action of pentamidine, strengthening the possibility to use this drug as an anti-inflammatory and remyelinating therapy for progressive multiple sclerosis. Barros et al. report that S100B deletion is beneficial in an animal model of chronic multiple sclerosis, setting the rationale for S100B modulation by pentamidine, an S100B-binding drug, to ameliorate disease development and reduce inflammatory/immune response. These data strengthened the use of S100B inhibition for effective multiple sclerosis treatment. Graphical Abstract Graphical Abstract Video Abstract 10.1093/brain/fcac076_video1 Video Abstract fcac076media1 6305837788112