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首页> 外文期刊>Neuroscience: An International Journal under the Editorial Direction of IBRO >GABA TRANSPORT AND NEUROINFLAMMATION ARE COUPLED IN MULTIPLE SCLEROSIS: REGULATION OF THE GABA TRANSPORTER-2 BY GANAXOLONE
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GABA TRANSPORT AND NEUROINFLAMMATION ARE COUPLED IN MULTIPLE SCLEROSIS: REGULATION OF THE GABA TRANSPORTER-2 BY GANAXOLONE

机译：GABA运输和神经炎在多发性硬化症中耦合：甘那酮对GABA TRANSPORTER-2的调节

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Interactions between neurotransmitters and the immune system represent new prospects for understanding neuroinflammation and associated neurological disease. GABA is the chief inhibitory neurotransmitter but its actions on immune pathways in the brain are unclear. In the present study, we investigated GABAergic transport in conjunction with neuroinflammation in models of multiple sclerosis (MS). Protein and mRNA levels of y-amino butyric acid transporter 2 (GAT-2) were examined in cerebral white matter from MS and control (Non-MS) patients, in cultured human macrophages, microglia and astrocytes, and in spinal cords from mice with and without experimental autoimmune encephalomyelitis (EAE) using western blotting, immunocytochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). GABA levels were measured by HPLC. The GAT-2's expression was increased in MS patients' (n = 6) white matter, particularly in macrophage lineage cells, compared to Non-MS patients (n = 6) (p < 0.05). Interferon-gamma (IFN-gamma) stimulation of human macrophage lineage cells induced GAT-2 expression and reduced extracellular GABA levels (p < 0.05) but soluble GABA treatment suppressed HLA-DRalpha, GAT-2 and XBP-1ls expression in stimulated macrophage lineage cells (p < 0.05). Similarly, the synthetic allopregnanolone analog, ganaxolone (GNX), repressed GAT-2, JAK-1 and STAT-1 expression in activated macrophage lineage cells (p < 0.05). In vivo GNX treatment reduced Gat-2, Cd3epsilon, MhcU, and Xbp-1/s expression in spinal cords following EAE induction (p < 0.05), which was correlated with improved neurobehavioral outcomes and reduced neuroinflammation, demyelination and axonal injury. These findings highlight altered GABAergic transport through GAT-2 induction during neuroinflammation. GABA transport and neuroinflammation are closely coupled but regulated by GNX, pointing to GABAergic pathways as therapeutic targets in neuroinflammatory diseases.
机译：神经递质与免疫系统之间的相互作用代表了理解神经炎症和相关神经疾病的新前景。 GABA是主要的抑制性神经递质，但它对大脑免疫途径的作用尚不清楚。在本研究中，我们研究了多发性硬化症（MS）模型中GABA能转运与神经炎症的关系。在MS和对照组（Non-MS）患者的脑白质，培养的人巨噬细胞，小胶质细胞和星形胶质细胞以及小鼠脊髓脊髓中，检测了y-氨基丁酸转运蛋白2（GAT-2）的蛋白质和mRNA水平。而无需使用Western印迹，免疫细胞化学和定量实时聚合酶链反应（qRT-PCR）进行实验性自身免疫性脑脊髓炎（EAE）。通过HPLC测量GABA水平。与非MS患者（n = 6）相比，MS患者（n = 6）白质，尤其是巨噬细胞谱系细胞中GAT-2的表达增加（p <0.05）。干扰素-γ（IFN-γ）刺激人类巨噬细胞谱系细胞诱导了GAT-2表达并降低了细胞外GABA水平（p <0.05），但是可溶性GABA处理抑制了刺激的巨噬细胞谱系中HLA-DRalpha，GAT-2和XBP-1ls的表达。细胞（p <0.05）。相似地，合成的Allopregnanolone类似物ganaxolone（GNX）抑制了活化巨噬细胞谱系细胞中的GAT-2，JAK-1和STAT-1表达（p <0.05）。体内GNX治疗降低了EAE诱导后脊髓中Gat-2，Cd3epsilon，MhcU和Xbp-1 / s的表达（p <0.05），这与神经行为改善，神经炎症，脱髓鞘和轴突损伤减少有关。这些发现强调了神经炎症过程中通过GAT-2诱导改变的GABA能转运。 GABA转运和神经炎症密切相关，但受GNX调控，指出GABA能途径是神经炎性疾病的治疗靶标。

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