Type 1 astrocytes (A1), which are highly proinflammatory and neurotoxic, are prevalent in multiple sclerosis (MS). In addition, in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), immune cells must cross the blood-brain barrier (BBB) and infiltrate into the parenchyma of the central nervous system (CNS) in order to induce neurological deficits. We have previously reported that treatment of EAE with matrine (MAT), a quinazine alkaloid derived from Sophorae Flavescens, effectively inhibited CNS inflammation and promoted neuroregeneration. However, the impact of MAT treatment on astrocyte phenotype is not known. In the present study, we showed that MAT treatment inhibited the generation of neurotoxic A1 astrocytes and promoted neuroprotective A2 astrocytes in the CNS of EAE, most likely by inhibiting production of the A1-inducing cytokine cocktail. MAT also downregulated the expression of vascular endothelial growth factor-A (VEGF-A) and upregulated tight junction proteins Claudin 5 and Occludin, thus protecting the BBB from CNS inflammation-induced damage. Moreover, MAT treatment promotes the formation of astrocyte tight junctions at glia limitans, thereby limiting parenchymal invasion of the CNS by immune cells. Taken together, the inhibition of A1 astrogliogenesis, and the dual effects on the BBB and astrocytic glia limitans, may be the mechanisms whereby MAT significantly improves EAE clinical scores and neuroprotection.

1 型星形胶质细胞 (A1) 具有高度促炎和神经毒性，在多发性硬化症 (MS) 中普遍存在。此外，在 MS 及其动物模型实验性自身免疫性脑脊髓炎 (EAE) 中，免疫细胞必须穿过血脑屏障 (BBB) 并渗透到中枢神经系统 (CNS) 的实质中以诱导神经功能缺损。我们之前曾报道用苦参碱 (MAT) 治疗 EAE，这是一种从苦参中提取的喹嗪生物碱，有效抑制中枢神经系统炎症，促进神经再生。然而，MAT 治疗对星形胶质细胞表型的影响尚不清楚。在本研究中，我们发现 MAT 治疗抑制了神经毒性 A1 星形胶质细胞的产生，并促进了 EAE 的 CNS 中的神经保护性 A2 星形胶质细胞，很可能是通过抑制 A1 诱导细胞因子混合物的产生。MAT 还下调血管内皮生长因子-A (VEGF-A) 的表达并上调紧密连接蛋白 Claudin 5 和 Occludin，从而保护 BBB 免受 CNS 炎症诱导的损伤。此外，MAT 治疗促进胶质细胞边界处星形胶质细胞紧密连接的形成，从而限制免疫细胞对中枢神经系统的实质侵袭。总之，抑制 A1 星形胶质细胞生成，