Tetramethylpyrazine ameliorates depression by inhibiting TLR4-NLRP3 inflammasome signal pathway in mice
Tetramethylpyrazine ameliorates depression by inhibiting TLR4-NLRP3 inflammasome signal pathway in mice
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DOI：
10.1007/s00213-019-05210-6
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发表时间：
2019-07-01
影响因子：
3.4
通讯作者：
Jiang, Sheng
中科院分区：
文献类型：
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作者：
Fu, Songnian;Wang, Jiangtao;Jiang, Sheng
抑郁症是一种常见而严重的精神疾病，同时也是一种炎症性疾病。Toll样受体4（TLR 4）作为一种模式识别受体，在神经炎症反应中起重要作用。核巧酸结合和寡聚化结构域样受体家族含化巧蛋白结构域3（NLRP 3）炎性体作为TLR 4下游的重要信号分子起作用，并且可促进炎性细胞因子如白细胞介素-1 β（IL-1 β）的成熟。川芎嗪（TMP）是一种具有神经保护作用的天然化合物，但其抗抑郁样作用的机制尚不清楚。在本研究中，我们假设TMP改善抑郁症可能是通过抑制TLR 4-NF-κ B-NLRP 3信号通路。我们的研究结果表明，慢性不可预测的轻度应激（CNOS），诱导减少蔗糖偏好和增加不动时间显着逆转TMP和氟西汀。此外，我们还发现，TNS诱导的促炎细胞因子的上调; TLR 4和NLRP 3相关蛋白在前额叶皮层和海马中被TMP显著抑制。TMP还具有较强的抗氧化作用，并能提高血清和脑组织中的单胺水平，如提高血清中SOD和GSH-Px的活性，降低MDA的活性，升高血清和脑组织中5-HT和NE的含量。此外，用Cli-095（TLR 4抑制剂）处理也显著抑制了CNS诱导的抑郁样行为。以上结果提示，川芎嗪对BRAS小鼠具有潜在的抗抑郁作用，其分子机制可能与抑制脑内TLR 4-NF-kappa B-NLRP 3信号通路有关。
Depression is a common but serious mental illness; meanwhile, it is also an inflammatory disorder. Toll-like receptor 4 (TLR4), as the pattern recognition receptor, has been shown to play a vital role in neuroinflammation. The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome acts as an important signaling molecule downstream of TLR4 and can promote the maturation of inflammatory cytokines, such as interleukin-1 beta (IL-1 beta). Tetramethylpyrazine (TMP) is a natural compound with neuroprotective effects but with unknown mechanisms on its antidepressant-like effect. In this study, we hypothesized that TMP ameliorates depression may be through the inhibition of the TLR4-NF-kappa B-NLRP3 signal pathway. Our results have shown that chronic unpredictable mild stress (CUMS) that induced the decreased sucrose preference and increased immobile time was prominently reversed by TMP and fluoxetine. Additionally, we also found that CUMS induced the upregulation of proinflammatory cytokines; TLR4 and NLRP3-associated proteins were significantly suppressed by TMP in the prefrontal cortex and hippocampus. TMP also exhibited potent antioxidant effects and increased the monoamine levels in the serum and brain, such as increasing the activity of SOD and GSH-Px, and reducing the activity of MDA in the serum, and elevating the 5-HT and NE concentration in the serum and brain. Moreover, treatment with Cli-095 (TLR4 inhibitor) also markedly inhibited CUMS-induced depression-like behaviors. Taken together, our findings suggested that TMP exerted a potential antidepressant-like effect in CUMS mice, and the molecular mechanisms may relate to inhibit the TLR4-NF-kappa B-NLRP3 signaling pathway in the brain.