Therapeutic effect of combination vitamin D3 and siponimod on remyelination and modulate microglia activation in cuprizone mouse model of multiple sclerosis

Abstract

Stimulation of remyelination is critical for the treatment of multiple sclerosis (MS) to alleviate symptoms and protect the myelin sheath from further damage. The current study aimed to investigate the possible therapeutic effects of combining vitamin D3 (Vit D3) and siponimod (Sipo) on enhancing remyelination and modulating microglia phenotypes in the cuprizone (CPZ) demyelination mouse model. The study was divided into two stages; demyelination (first 5 weeks) and remyelination (last 4 weeks). In the first 5 weeks, 85 mice were randomly divided into two groups, control (n = 20, standard rodent chow) and CPZ (n = 65, 0.3% CPZ mixed with chow for 6 weeks, followed by 3 weeks of standard rodent chow). At week 5, the CPZ group was re-divided into four groups (n = 14) for remyelination stages; untreated CPZ (0.2 ml of CMC orally), CPZ+Vit D3 (800 IU/kg Vit D3 orally), CPZ+Sipo (1.5 mg/kg Sipo orally), and CPZ+Vit D3 (800 IU/kg Vit D3) + Sipo (1.5 mg/kg Sipo orally). Various behavioral tasks were performed to evaluate motor performance. Luxol Fast Blue (LFB) staining, the expression level of myelin basic protein (MBP), and M1/M2 microglia phenotype genes were assessed in the corpus callosum (CC). The results showed that the combination of Vit D3 and Sipo improved behavioral deficits, significantly promoted remyelination, and modulated expression levels of microglia phenotype genes in the CC at early and late remyelination stages. These results demonstrate for the first time that a combination of Vit D3 and Sipo can improve the remyelination process in the cuprizone (CPZ) mouse model by attenuating the M1 microglia phenotype. This may help to improve the treatment of MS patients.

Vitamin D Supplementation: Effect on Cytokine Profile in Multiple Sclerosis

“…However, it is possible to hypothesize a synergistic effect for other DMTs as well. In a murine model, the combination of vitamin D and Siponimod modulated the expression levels of microglia phenotype genes at the early and late remyelination stages [74]. In pwMS treated with Ocrelizumab, vitamin D serum levels of < 30 ng/mL were associated with a higher likelihood of early B cell reappearance at the six-month follow-up [18].…”

Modulation of Gut Microbiome Community Mitigates Multiple Sclerosis in a Mouse Model: The Promising Role of Palmaria palmata Alga as a Prebiotic

“…In the late 1960s, cuprizone-induced demyelination was first seen in Swiss mice [3]. Cuprizone is a copper chelator that produces demyelination in the mouse central nervous system (CNS), mainly in the corpus callosum (CC), by triggering oligodendrocyte death and activation of microglia and astrocytes inside demyelinating lesions [4]. Demyelination appears three weeks after the commencement of the cuprizone administration.…”

“…Scientists have, therefore, focused a lot of research on developing safe and effective neuroprotective medicines [1,6]. Adaptogens are plant-based medical and nutritional supplements that improve living organisms' adaptation, resilience, and survival without harming the body's homeostasis [4]. In this regard, seaweed may be a source of neuroprotective adaptogens [1].…”