Laboratory of Pharmacology, Faculty of Pharmacy and Research Institute of Pharmaceutical Sciences, Musashino University.
Biol Pharm Bull. 2022;45(3):301-308. doi: 10.1248/bpb.b21-00841.
Neuroinflammation induced by activated microglia is a key feature of neurodegenerative diseases such as Alzheimer's disease. The natural flavonoid 3',4',7-trihydroxyflavone protects nerve cells from oxidative stress-mediated apoptosis and inhibits the aggregation of amyloid β protein in vitro. However, little is known about its effects on microglial activation. In this study, we investigated the effects of 3',4',7-trihydroxyflavone on lipopolysaccharide (LPS)- or interferon-γ (IFN-γ)-induced neuroinflammatory responses in MG6 microglial cells. 3',4',7-Trihydroxyflavone inhibited LPS- or IFN-γ-mediated nitric oxide (NO) generation and the upregulation of inducible NO synthase (iNOS) in MG6 cells. 3',4',7-Trihydroxyflavone also suppressed LPS- or IFN-γ-mediated phosphorylation of signal transducer and activator of transcription 1 (STAT1), which is crucial for iNOS expression. LPS stimulation induced rapid phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK) in MG6 cells. 3',4',7-Trihydroxyflavone significantly inhibited the LPS-mediated phosphorylation of JNK, but not that of ERK and p38 MAPK. The inhibitory effect of 3',4',7-trihydroxyflavone on NO generation was mimicked by pharmacological inhibition of the JNK signaling pathway with SP600125. Furthermore, SP600125 significantly inhibited LPS- or IFN-γ-mediated phosphorylation of STAT1 in MG6 cells. These results suggest that 3',4',7-trihydroxyflavone exerts anti-neuroinflammatory effects via inhibition of the JNK-STAT1 pathway in microglia.
小胶质细胞激活引起的神经炎症是阿尔茨海默病等神经退行性疾病的一个关键特征。天然类黄酮 3',4',7-三羟基黄酮能保护神经细胞免受氧化应激介导的细胞凋亡，并抑制体外淀粉样β蛋白的聚集。然而，其对小胶质细胞激活的影响知之甚少。在这项研究中，我们研究了 3',4',7-三羟基黄酮对 LPS 或 IFN-γ诱导的 MG6 小胶质细胞神经炎症反应的影响。3',4',7-三羟基黄酮抑制 LPS 或 IFN-γ介导的一氧化氮（NO）生成和诱导型一氧化氮合酶（iNOS）的上调。3',4',7-三羟基黄酮还抑制 LPS 或 IFN-γ介导的信号转导和转录激活因子 1（STAT1）的磷酸化，这对 iNOS 表达至关重要。LPS 刺激诱导 MG6 细胞中 c-Jun N 端激酶（JNK）、p38 丝裂原活化蛋白激酶（p38 MAPK）和细胞外信号调节激酶（ERK）的快速磷酸化。3',4',7-三羟基黄酮显著抑制 LPS 介导的 JNK 磷酸化，但不抑制 ERK 和 p38 MAPK 的磷酸化。SP600125 抑制 JNK 信号通路可模拟 3',4',7-三羟基黄酮对 NO 生成的抑制作用。此外，SP600125 显著抑制 LPS 或 IFN-γ介导的 MG6 细胞中 STAT1 的磷酸化。这些结果表明，3',4',7-三羟基黄酮通过抑制小胶质细胞中的 JNK-STAT1 通路发挥抗炎作用。
