Suppression of the RAC1/MLK3/p38 Signaling Pathway by β-Elemene Alleviates Sepsis-Associated Encephalopathy in Mice

被引:25
|
作者
Pan, Cailong [1 ]
Si, Yanna [1 ]
Meng, Qinghai [2 ]
Jing, Ling [1 ]
Chen, Lu [3 ]
Zhang, Yong [1 ]
Bao, Hongguang [1 ]
机构
[1] Nanjing Med Univ, Nanjing Hosp 1, Dept Anesthesiol, Nanjing, Jiangsu, Peoples R China
[2] Nanjing Univ Chinese Med, Sch Pharm, Nanjing, Jiangsu, Peoples R China
[3] Nanjing Med Univ, Dept Pharmacol, Jiangsu Key Lab Neurodegenerat, Nanjing, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
beta-elemene; sepsis-associated encephalopathy; RAC1; MLK3; p38MAPK; microglia; BREAST-CANCER CELLS; COGNITIVE IMPAIRMENT; RAC1; ACTIVATION; INFLAMMATION; INHIBITION; EXPRESSION; MIGRATION; MODEL; LUNG;
D O I
10.3389/fnins.2019.00358
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
It is still difficult to treat sepsis-associated encephalopathy (SAE) which is a diffuse brain dysfunction caused by sepsis, with excessive activation of microglia as one of the main mechanisms. Ras-related C3 botulinum toxin substrate 1 (RAC1) is proven to be a key molecule in the inflammatory signaling network. By using microglial cell line BV-2 and a mouse model of cecal ligation puncture (CLP), we herein evaluated the effects of beta-elemene, an extract of Curcuma zedoaria Rosc., on RAC1 signaling in microglia. beta-Elemene decreased the expressions of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-6] and attenuated translocation of nuclear factor-kappa B (NF-kappa B) p65 from the cytosol to the nucleus in BV-2 cells after lipopolysaccharide (LPS) treatment. It also inhibited the activation of RAC1, mixed-lineage protein kinase 3 (MLK3) and p38 mitogen-activated protein kinase (MAPK). The phosphorylation of the RAC1 Ser71 site was increased by beta-elemene. Moreover, the learning and memory abilities of CLP mice in the water maze test and fear conditioning test were improved after beta-elemene treatment. It reduced the expression of the microglial marker IBA1, significantly increased RAC1 Ser71 phosphorylation, and suppressed the RAC1/MLK3/p38 signaling activation and inflammatory response in the hippocampus. In conclusion, beta-elemene effectively alleviated SAE in mice and inhibited the RAC1/MLK3/p38 signaling pathway in microglia, and might be an eligible potential candidate for SAE treatment.
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页数:13
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