Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation
Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation
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DOI：
10.1046/j.1460-9568.2002.02290.x
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发表时间：
2002-12-01
影响因子：
3.4
通讯作者：
Jeng, KCG
中科院分区：
文献类型：
--
作者：
Wang, MJ;Lin, WW;Jeng, KCG
由小胶质细胞激活介导的中枢神经系统炎症反应是神经退行性疾病发展的早期阶段的关键事件。水飞蓟素是从水飞蓟中提取的一种多酚类黄酮类化合物，具有抗炎、细胞保护和抗癌作用。在本研究中，我们首先研究了水飞蓟素对内毒素诱导的中脑混合神经元-神经胶质细胞毒性的神经保护作用。结果表明，水飞蓟素显著抑制内毒素诱导的小胶质细胞活化和肿瘤坏死因子-α、一氧化氮(NO)等炎症介质的产生，减轻对多巴胺能神经元的损伤。因此，我们进一步研究了水飞蓟素抑制小胶质细胞活化的机制。以内毒素刺激的BV-2细胞为小胶质细胞激活模型，研究诱导型一氧化氮合酶(INOS)的产生。水飞蓟素以剂量依赖方式显著降低内毒素诱导的亚硝酸盐、诱导型一氧化氮合酶基因和蛋白水平。此外，内毒素可诱导p38丝裂原活化蛋白激酶(MAPK)和c-jun氨基末端激酶的激活，但不能诱导细胞外信号调节激酶的激活。选择性p38MAPK抑制剂SB203580可抑制内毒素诱导的NO生成。这些结果表明，p38MAPK信号通路参与了内毒素诱导的NO生成。但水飞蓟素不能抑制p38MAPK的激活。而水飞蓟素能有效抑制脂多糖诱导的超氧化物歧化和核因子-kappaB的活化。提示水飞蓟素对小胶质细胞活化的抑制作用是通过抑制核因子-kappaB的激活而实现的。
An inflammatory response in the central nervous system mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Silymarin is a polyphenolic flavanoid derived from milk thistle that has anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we first investigated the neuroprotective effect of silymarin against lipopolysaccharide (LPS)-induced neurotoxicity in mesencephalic mixed neuron-glia cultures. The results showed that silymarin significantly inhibited the LPS-induced activation of microglia and the production of inflammatory mediators, such as tumour necrosis factor-alpha and nitric oxide (NO), and reduced the damage to dopaminergic neurons. Therefore, the inhibitory mechanisms of silymarin on microglia activation were studied further. The production of inducible nitric oxide synthase (iNOS) was studied in LPS-stimulated BV-2 cells as a model of microglia activation. Silymarin significantly reduced the LPS-induced nitrite, iNOS mRNA and protein levels in a dose-dependent manner. Moreover, LPS could induce the activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase but not extracellular signal-regulated kinase. The LPS-induced production of NO was inhibited by the selective p38 MAPK inhibitor SB203580. These results indicated that the p38 MAPK signalling pathway was involved in the LPS-induced NO production. However, the activation of p38 MAPK was not inhibited by silymarin. Nevertheless, silymarin could effectively reduce LPS-induced superoxide generation and nuclear factor kappaB (NF-kappaB) activation. It suggests that the inhibitory effect of silymarin on microglia activation is mediated through the inhibition of NF-kappaB activation.