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

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.