Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai R&D Center for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, Shanghai R&D Center for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
J Ethnopharmacol. 2022 Nov 15;298:115622. doi: 10.1016/j.jep.2022.115622. Epub 2022 Aug 11.
Radix Astragali is a traditional Chinese medicine with various pharmacological effects. Total astragalosides (TA), the main effective ingredients in Radix Astragali, exert properties including anti-oxidative stress, anti-neuroinflammation, and neuroprotection. We previously found that TA alleviated experimental autoimmune encephalomyelitis (EAE) progression, a widely used animal model of multiple sclerosis (MS). As a chronic demyelination disease, MS generally manifests myelin loss and fails to myelin regeneration. Regulation of oligodendrocyte progenitor cells (OPCs) differentiation and remyelination is the fundamental strategy for MS treatment. However, whether TA could directly promote OPCs differentiation and remyelination is still unknown.
This study was aimed to investigate pro-differentiation and myelin regeneration effects of TA on OPCs and Cuprizone (CPZ)-induced demyelination mice, an animal model of MS, and to explore mechanism underlying from regulation of OPCs differentiation and maturation.
Mice were orally given CPZ (400 mg/kg) daily for 4 weeks to induce myelin loss, and then treated with TA (25 and 50 mg/kg) daily for 1 week. Cell proliferation assay, Western blot, RT-PCR, immunocytochemistry and immunohistochemistry were performed to explore the mechanisms. The role of TA in oligodendrocyte differentiation and maturation was evaluated using MO3.13, a human oligodendrocytic hybrid cell line.
TA was shown to mitigate behavioral impairment in CPZ-induced mice. It markedly ameliorated myelin loss and enhanced remyelination in the corpus callosum of mice, evidenced by increased expression of myelin basic protein (MBP) and the number of CC1 newly generated oligodendrocytes (OLs). TA also enhanced the expression of MBP at both mRNA and protein levels in MO3.13 cells. In CPZ-induced mice and MO3.13 cells, TA remarkably promoted the activation of GSK3β, repressed the phosphorylation of β-catenin, reduced the expression of transcription factor 4 and inhibitor of DNA binding 2. The agonist of β-catenin, SKL2001, partially abolished the pro-differentiation effect of TA in MO3.13 cells.
Taken together, we clarified that TA could effectively enhance the differentiation and maturation of OPCs and accelerate remyelination in CPZ-induced mice through inhibition of Wnt/β-catenin signaling pathway. This study provides new insight into the beneficial effect of TA in the treatment of MS.
黄芪是一种具有多种药理作用的中药。黄芪总皂苷（TA）是黄芪的主要有效成分，具有抗氧化应激、抗神经炎症和神经保护作用。我们之前发现，TA 可减轻实验性自身免疫性脑脊髓炎（EAE）的进展，EAE 是多发性硬化症（MS）的一种广泛应用的动物模型。作为一种慢性脱髓鞘疾病，MS 通常表现为髓鞘丢失和无法再生髓鞘。调节少突胶质前体细胞（OPC）分化和髓鞘再生是 MS 治疗的基本策略。然而，TA 是否能直接促进 OPC 分化和髓鞘再生尚不清楚。
本研究旨在探讨 TA 对少突胶质前体细胞（OPC）的促分化和髓鞘再生作用，以及对 CPZ 诱导的脱髓鞘小鼠（MS 的动物模型）的作用，并从调节 OPC 分化和成熟的角度探讨其作用机制。
用 400mg/kg 的 CPZ 每日灌胃 4 周诱导髓鞘丢失，然后用 25 和 50mg/kg 的 TA 每日灌胃 1 周。通过细胞增殖实验、Western blot、RT-PCR、免疫细胞化学和免疫组织化学等方法探讨机制。用 MO3.13（一种人少突胶质杂交细胞系）评估 TA 在少突胶质细胞分化和成熟中的作用。
TA 可减轻 CPZ 诱导的小鼠的行为障碍。它显著改善了 CPZ 诱导的小鼠胼胝体中的髓鞘丢失和髓鞘再生，表现为髓鞘碱性蛋白（MBP）的表达增加和新生成的少突胶质细胞（OLs）的 CC1 数量增加。TA 还能增强 MO3.13 细胞中 MBP 的 mRNA 和蛋白水平的表达。在 CPZ 诱导的小鼠和 MO3.13 细胞中，TA 明显促进 GSK3β 的激活，抑制β-catenin 的磷酸化，降低转录因子 4 和 DNA 结合抑制因子 2 的表达。β-catenin 的激动剂 SKL2001 部分消除了 TA 在 MO3.13 细胞中的促分化作用。
综上所述，我们阐明了 TA 可通过抑制 Wnt/β-catenin 信号通路，有效促进 CPZ 诱导的小鼠 OPC 的分化和成熟，并加速髓鞘再生。本研究为 TA 治疗 MS 的有益作用提供了新的见解。
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