Abstract
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 β-elemene, an extract of Curcuma zedoaria Rosc., on RAC1 signaling in microglia. β-Elemene decreased the expressions of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6] and attenuated translocation of nuclear factor-κB (NF-κB) 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 β-elemene. Moreover, the learning and memory abilities of CLP mice in the water maze test and fear conditioning test were improved after β-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, β-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.
Highlights
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis. Sonneville et al (2017) recently reported that 53% of septic patients had sepsis-associated encephalopathy (SAE) in intensive care unit (ICU), and SAE was associated with higher mortality rate, more consumption of ICU resources and longer hospital stay
Β-elemene suppressed the activation of related C3 botulinum toxin substrate 1 (RAC1), mixedlineage protein kinase 3 (MLK3), p38 mitogen-activated protein kinase (MAPK), and NF-kB p65, as well as significantly decreased the expressions of pro-inflammatory cytokines in BV-2 cells and the hippocampus of mice
Compared with the cecal ligation puncture (CLP) group, β-elemene lowered the expression of the microglial marker IBA1 and increased the phosphorylation of RAC1 in the hippocampus
Summary
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis. Sonneville et al (2017) recently reported that 53% of septic patients had SAE in intensive care unit (ICU), and SAE was associated with higher mortality rate, more consumption of ICU resources and longer hospital stay. The mechanism of SAE is still unclear, and the treatment outcomes remain unsatisfactory, thereby urgently requiring new therapies. It is well-documented that neuroinflammation played a key role in the onset and progression of SAE (Semmler et al, 2008; Piva et al, 2015). GTP binding of RAC1 is reduced through phosphorylation at Ser site (Kwon et al, 2000), which decreases the binding of RAC1 to MLK3 and negatively regulates its downstream MAPK signaling pathway in the rat hippocampus, mitigating cerebral ischemic injury (Zhang et al, 2006). We hypothesized that β-elemene relieved CLP-induced cognitive dysfunction by suppressing the RAC1/MLK3/p38 signal pathway to inhibit microglial activation. The findings provide new insights into the clinical effects of β-elemene on SAE and the mechanism
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