半合成的基于异荭草素的糖原合酶激酶-3β抑制剂在脂多糖激活的小胶质细胞中的抗神经炎症作用,ACS Chemical Neuroscience

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半合成的基于异荭草素的糖原合酶激酶-3β抑制剂在脂多糖激活的小胶质细胞中的抗神经炎症作用
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2021-12-16 , DOI: 10.1021/acschemneuro.1c00537
Meng Xu ₁ , Megan J Lantz ₂ , Robert A Nichols ₂ , Qing X Li ₁

Affiliation

神经炎症有助于几种神经退行性疾病的发病机制。糖原合酶激酶-3β (GSK-3β) 调节促炎细胞因子的释放并促进免疫细胞的炎症反应。小胶质细胞是中枢神经系统的常驻单核免疫细胞。在这里，我们研究了 (2 S ,3 S ,4 R ,5 R ,6 S )-6-(2-(3,4-dimethoxyphenyl)-5,7-dimethoxy-4-oxo- 4 H -chromen-6-yl)-3,4,5-trihydroxy- N -(( S )-1,1,1-trifluoropropan-2-yl)tetrahydro-2 H-pyran-2-carboxamide (TFGF-18)，一种半合成的 GSK-3β 抑制剂，可激活自发永生化 SIM-A9 小胶质细胞和小鼠皮质小胶质细胞的脂多糖 (LPS)。相对于 LPS 处理对照组，2.5 μM 浓度的 TFGF-18 在 SIM-A9 细胞中分别抑制 LPS 诱导的一氧化氮产生 56.3% 和促炎细胞因子 TNF-α 和 IL-1β 28.3% 和 59.2%。用 2.5 μM 浓度的 TFGF-18 预处理小鼠原代小胶质细胞导致 LPS 刺激后 24 小时 TNF-α+ 小胶质细胞减少 58.7%。在划痕试验中预处理 TFGF-18 后，LPS 激活的 SIM-A9 细胞的迁移也减少了 26.7%。对信号通路的分析表明，TFGF-18 导致 LPS 诱导的 GSK-3β 活化和 p65/NF-κB 活性的抑制。此外，SIM-A9 与 SH-SY5Y 神经母细胞瘤细胞的共培养显示在体外抑制 TFGF-18 对小胶质细胞介导的神经毒性。研究结果表明 TFGF-18 通过调节 GSK-3β 和下游 p65/NF-κB 信号传导对 LPS 诱导的小胶质细胞活化具有强烈的抑制作用。结果表明 TFGF-18 通过其抗神经炎症作用在神经保护中发挥潜在作用。

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Anti-Neuroinflammatory Effects of a Semi-Synthetic Isoorientin-Based Glycogen Synthase Kinase-3β Inhibitor in Lipopolysaccharide-Activated Microglial Cells

Neuroinflammation contributes to the pathogenesis of several neurodegenerative disorders. Glycogen synthase kinase-3β (GSK-3β) regulates the release of proinflammatory cytokines and promotes inflammatory responses in immune cells. Microglia are the resident mononuclear immune cells of the central nervous system. Here, we investigated the anti-neuroinflammatory effects of (2S,3S,4R,5R,6S)-6-(2-(3,4-dimethoxyphenyl)-5,7-dimethoxy-4-oxo-4H-chromen-6-yl)-3,4,5-trihydroxy-N-((S)-1,1,1-trifluoropropan-2-yl)tetrahydro-2H-pyran-2-carboxamide (TFGF-18), a semisynthetic GSK-3β inhibitor, in lipopolysaccharide (LPS) activation of spontaneously immortalized SIM-A9 microglial cells and of mouse cortical microglia. TFGF-18 at 2.5 μM concentration inhibited LPS-induced production of nitric oxide by 56.3% and the proinflammatory cytokines TNF-α and IL-1β by 28.3 and 59.2% in SIM-A9 cells, respectively, relative to the LPS treatment control group. Pretreatment of mouse primary microglial cells with TFGF-18 at 2.5 μM concentration led to a reduction of 58.7% in TNF-α+ microglial cells at 24 h post-LPS stimulation. The migration of LPS-activated SIM-A9 cells was also reduced by 26.7% with pretreatment of TFGF-18 in a scratch assay. Analyses of signaling pathways demonstrated that TFGF-18 led to the suppression of LPS-induced GSK-3β activation and p65/NF-κB activity. Furthermore, the co-culture of SIM-A9 with SH-SY5Y neuroblastoma cells showed the suppression of TFGF-18 to microglia-mediated neurotoxicity in vitro. The findings indicate strong inhibitory effects of TFGF-18 on LPS-induced microglia activation via regulation of GSK-3β and downstream p65/NF-κB signaling. The results suggest a potential role of TFGF-18 in neuroprotection via its anti-neuroinflammatory effect.

更新日期：2022-01-05

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