Orexin‐A Attenuates the Inflammatory Response in Sepsis‐Associated Encephalopathy by Modulating Oxidative Stress and Inhibiting the ERK / NF ‐ κB Signaling Pathway in Microglia and Astrocytes

作者：Jing Guo, Dexun Kong, Junchi Luo, Tao Xiong, Fang Wang, Mei Deng, Zhuo Kong, Sha Yang, Jingjing Da, Chaofei Chen, Jinhai Lan, Liangzhao Chu, Guoqiang Han, Jian Liu, Ying Tan, Jiqin Zhang · 发表于：CNS Neuroscience & Therapeutics · 年份：2024 · DOI：10.1111/cns.70096 · 被引用次数：19 · 研究领域：Sleep and Wakefulness Research、Obstructive Sleep Apnea Research、Neuroscience of respiration and sleep

BACKGROUND: Oxidative stress-induced inflammation is a major pathogenic mechanism in sepsis-associated encephalopathy (SAE). We hypothesized that regulation of reactive oxygen species (ROS) by the neuropeptide orexin-A could prevent SAE-induced oxidative stress and inflammation. Therefore, the aim of this study was to investigate the effects of orexin-A on oxidative stress and inflammation in SAE in mice. METHODS: Adult male mice were treated with orexin-A (250 μg/kg, intranasal administration) to establish a cecal ligation perforation (CLP) model. We performed behavioral tests, observed neuronal damage in the hippocampal region, measured the levels of ROS, NOX2, and observed the structure of mitochondria by transmission electron microscopy. We then examined the inflammatory factors TNF-α and IL-1β, the activation of microglia and astrocytes, the expression of ERK/NF-κB, C3, and S100A10, and the presence of A1 type astrocytes and A2 type astrocytes. RESULTS: Orexin-A treatment improved cognitive performance in CLP-induced SAE mice, attenuated neuronal apoptosis in the hippocampal region, ameliorated ROS levels and the extent of mitochondrial damage, and reduced protein expression of NOX2 in hippocampal tissue. In addition, orexin-A treatment significantly reduced microglia and astrocyte activation, inhibited the levels of P-ERK and NF-κB, and reduced the release of IL-1β and TNF-α, which were significantly increased after CLP. Finally, Orexin-A treatment significantly decreas...