Human Remyelination Promoting Antibody Stimulates Astrocytes Proliferation Through Modulation of the Sphingolipid Rheostat in Primary Rat Mixed Glial Cultures

Abstract

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Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases

“…Among them, S1P mediates crucial signaling pathways relevant to neurodegeneration (Hagen et al, 2011; Assi et al, 2013; Blaho and Hla, 2014; Proia and Hla, 2015; Pyne et al, 2018; Wang and Bieberich, 2018). In the brain, S1P regulates several fundamental processes, such as proliferation, survival, differentiation, and migration of all the different cell populations, including neurons, astrocytes, microglia, and oligodendrocytes, as well as infiltration of peripheral immune cells in the CNS during neuroinflammation (Kleger et al, 2007; Riccitelli et al, 2013; Smith et al, 2013; Marfia et al, 2014; Chiricozzi et al, 2018; Grassi et al, 2019). S1P can act both as an extracellular and as an intracellular mediator (Hait et al, 2009; Alvarez et al, 2010; Blaho and Hla, 2014; Proia and Hla, 2015; Park et al, 2016).…”

“…Although some studies suggest that the rHIgM22 remyelination-promoting effect is exerted directly on myelin-producing cells (Watzlawik et al, 2010; Watzlawik et al, 2013), others suggest that it acts on other cell types present in the lesion niche, including astrocytes (Paz Soldan et al, 2003) and microglia (Zorina et al, 2018). We recently showed that rHIgM22 stimulated the proliferation of astrocytes in mixed glial cells because of the increased production and release of S1P, suggesting that S1P signaling might be significant in the interplay of different cell types involved in the complex series of events eventually leading to myelin repair (Grassi et al, 2019).…”

A double-blind, placebo-controlled, single-ascending-dose intravenous infusion study of rHIgM22 in subjects with multiple sclerosis immediately following a relapse

“…5 rHIgM22 has been shown to promote remyelination in chronic virus-induced demyelinated 3,6 and cuprizonetreated mice, and was well tolerated and showed beneficial effects on myelination. [7][8][9][10] It also showed a significant acceleration in remyelination in animal experiments using lysolecithin injections in the spinal cord. 11 In murine and rat cell line studies, rHIgM22 has been shown to promote the differentiation of oligodendrocyte precursor cells to mature oligodendrocytes consistent with their role in remyelination, where their failure to differentiate and remyelinate axons is thought to be an important cause of the demyelination seen in MS. 6,7,9,10 In a phase 1, double-blind, placebo-controlled, singleascending-dose study of rHIgM22 in people with clinically stable MS, doses of 0.025 to 2.0 mg/kg were well tolerated and demonstrated dose proportionality in pharmacokinetics.…”

“…[7][8][9][10] It also showed a significant acceleration in remyelination in animal experiments using lysolecithin injections in the spinal cord. 11 In murine and rat cell line studies, rHIgM22 has been shown to promote the differentiation of oligodendrocyte precursor cells to mature oligodendrocytes consistent with their role in remyelination, where their failure to differentiate and remyelinate axons is thought to be an important cause of the demyelination seen in MS. 6,7,9,10 In a phase 1, double-blind, placebo-controlled, singleascending-dose study of rHIgM22 in people with clinically stable MS, doses of 0.025 to 2.0 mg/kg were well tolerated and demonstrated dose proportionality in pharmacokinetics. There were minimal, infrequent, adverse events (AEs) attributed to rHIgM22: mainly headaches and mild infusion-type reactions (pruritus, arthralgia, flushing).…”

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells

“…Human monoclonal antibodies and human immunoglobulin (Ig)Ms can promote remyelination and significantly raise the levels of myelinated axons in MS preclinical models [65], with effects that seem driven by decreasing astrocyte aSMase and increasing the S1P/ceramide ratio [66]. These natural human monoclonal antibodies have been found to be safe in over 70 patients with severe deficits from MS [67].…”