Abstract
Multiple sclerosis (MS) is a neurodegenerative disorder characterized by periodic neuronal demyelination, which leads to a range of symptoms and eventually to disability. The goal of this research was to use UPLC-Orbitrap/MS to identify validated biomarkers and explore the metabolic mechanisms of MS in mice. Thirty-two C57BL/6 male mice were randomized into two groups that were fed either normal food or 0.2% CPZ for 11 weeks. The mouse demyelination model was assessed by LFB and the expression of MBP by immunofluorescence and immunohistochemistry. The metabolites of the corpus callosum were quantified using UPLC-Orbitrap/MS. The mouse pole climbing experiment was used to assess coordination ability. Multivariate statistical analysis was adopted for screening differential metabolites, and the ingenuity pathway analysis (IPA) was used to reveal the metabolite interaction network. We successfully established the demyelination model. The CPZ group slowly lost weight and showed an increased pole climbing time during feeding compared to the CON group. A total of 81 metabolites (VIP > 1 and P < 0.05) were determined to be enriched in 24 metabolic pathways; 41 metabolites were markedly increased, while 40 metabolites were markedly decreased in the CPZ group. The IPA results revealed that these 81 biomarker metabolites were associated with neuregulin signaling, PI3K-AKT signaling, mTOR signaling, and ERK/MAPK signaling. KEGG pathway analysis showed that two significantly different metabolic pathways were enriched, namely, the glycerophospholipid and sphingolipid metabolic pathways, comprising a total of nine biomarkers. Receiver operating characteristic analysis showed that the metabolites (e.g., PE (16 : 0/22 : 6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)), PC (18 : 0/22 : 4(7Z, 10Z, 13Z, 16Z)), cytidine 5′-diphosphocholine, PS (18 : 0/22 : 6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)), glycerol 3-phosphate, SM (d18 : 0/16 : 1(9Z)), Cer (d18:1/18 : 0), galabiosylceramide (d18:1/18 : 0), and GlcCer (d18:1/18 : 0)) have good discrimination ability for the CPZ group. In conclusion, the differential metabolites have great potential to serve as biomarkers of demyelinating diseases. In addition, we identified metabolic pathways associated with CPZ-induced demyelination pathogenesis, which provided a new perspective for understanding the relationship between metabolites and CNS demyelination pathogenesis.
Highlights
Multiple sclerosis (MS) is a multifactorial autoimmunity disease of the central nervous system (CNS) that is characterized by the loss of oligodendrocytes and myelin sheaths in the white matter tracts [1]
Immunohistochemistry, immunofluorescence, and western blotting were used to detect MBP and glial fibrillary acidic protein (GFAP) expression and combined with behavioral testing to explore the successful establishment of the demyelination model
Immunohistochemistry revealed that the expression of MBP in the CPZ group was significantly reduced compared to that in the CON group, and the expression of GFAP in the CPZ group was increased (Figures 1(c) and 1(d))
Summary
Multiple sclerosis (MS) is a multifactorial autoimmunity disease of the central nervous system (CNS) that is characterized by the loss of oligodendrocytes and myelin sheaths in the white matter tracts [1]. Muscle spasms, ataxia, paraparesis or hemiparesis, vision loss, pain, and cognitive deficits [3]. These clinical deficits have a major economic impact on medical and health care systems. As a multifactorial disease, the exact pathological mechanism of MS is not known, and the diagnosis of MS remains a challenge [4]. It is important to identify efficient biomarkers of MS using new methods to make diagnosis easier and more reliable
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