The inflammatory mediator high-mobility group box 1 (HMGB1)-induced signaling pathway has been shown to play an important role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophorae flavescens, has the capacity to effectively suppress EAE. However, the impact of MAT treatment on HMGB1-induced signaling is not known. In the present study, we show that MAT treatment alleviated disease severity of ongoing EAE, reduced inflammatory infiltration and demyelination, and reduced the production of inflammatory factors including TNF-α, IL-6, and IL-1β in the CNS. Moreover, MAT administration significantly reduced the protein and RNA expression of HMGB1 and TLR4 in the spinal cord, particularly in astrocytes and microglia/infiltrating macrophages. The expression of MyD88 and TRAF6, and the phosphorylation of NF-κB p65, was also down-regulated after MAT treatment. In contrast, the level of IκB-α, an inhibitory molecule for NF-κB activation, was significantly increased. Furthermore, the direct inhibitory effect of MAT on HMGB1/TLR4/NF-κB signaling in macrophages was further confirmed in vitro. Taken together, these findings demonstrate that MAT treatment alleviated CNS inflammatory demyelination and activation of astrocytes and microglia/macrophages in EAE rats, and that the mechanism underlying these effects may be closely related to modulation of HMGB1/TLR4/NF-κB signaling pathway.

中文翻译：

---

在实验性自身免疫性脑脊髓炎中苦参碱对 CNS HMGB1/TLR4/NF-κB 信号通路的调节

炎症介质高迁移率族框 1 (HMGB1) 诱导的信号通路已被证明在多发性硬化症 (MS) 及其动物模型实验性自身免疫性脑脊髓炎 (EAE) 的发病机制中发挥重要作用。苦参碱 (MAT) 是一种来源于苦参根的喹诺西啶生物碱成分，具有有效抑制 EAE 的能力。然而，MAT 处理对 HMGB1 诱导的信号传导的影响尚不清楚。在本研究中，我们表明 MAT 治疗减轻了正在进行的 EAE 的疾病严重程度，减少了炎症浸润和脱髓鞘，并减少了中枢神经系统中炎症因子（包括 TNF-α、IL-6 和 IL-1β）的产生。此外，MAT 给药显着降低了脊髓中 HMGB1 和 TLR4 的蛋白质和 RNA 表达，特别是在星形胶质细胞和小胶质细胞/浸润性巨噬细胞中。MyD88 和 TRAF6 的表达以及 NF-κB p65 的磷酸化在 MAT 处理后也被下调。相比之下，NF-κB 激活的抑制分子 IκB-α 的水平显着增加。此外，MAT对巨噬细胞中HMGB1/TLR4/NF-κB信号传导的直接抑制作用在体外得到进一步证实。总之，这些发现表明，MAT 治疗减轻了 EAE 大鼠中枢神经系统炎症脱髓鞘和星形胶质细胞和小胶质细胞/巨噬细胞的活化，并且这些作用的潜在机制可能与 HMGB1/TLR4/NF-κB 信号通路的调节密切相关。MAT 处理后也下调。相比之下，NF-κB 激活的抑制分子 IκB-α 的水平显着增加。此外，MAT对巨噬细胞中HMGB1/TLR4/NF-κB信号传导的直接抑制作用在体外得到进一步证实。总之，这些发现表明，MAT 治疗减轻了 EAE 大鼠中枢神经系统炎症脱髓鞘和星形胶质细胞和小胶质细胞/巨噬细胞的活化，并且这些作用的潜在机制可能与 HMGB1/TLR4/NF-κB 信号通路的调节密切相关。MAT 处理后也下调。相比之下，NF-κB 激活的抑制分子 IκB-α 的水平显着增加。此外，MAT对巨噬细胞中HMGB1/TLR4/NF-κB信号传导的直接抑制作用在体外得到进一步证实。总之，这些发现表明，MAT 治疗减轻了 EAE 大鼠中枢神经系统炎症脱髓鞘和星形胶质细胞和小胶质细胞/巨噬细胞的活化，并且这些作用的潜在机制可能与 HMGB1/TLR4/NF-κB 信号通路的调节密切相关。