Abstract：
Sepsis-associated encephalopathy (SAE) is a severe complication that affects the central nervous system and is a leading cause of increased morbidity and mortality in intensive care units. Psoralidin (PSO), a coumarin compound isolated from the traditional Chinese medicine Psoralea corylifolia L., can penetrate the blood-brain barrier and has various pharmacological activities, including anti-inflammation, anti-oxidation and anti-depression. This study aims to explore whether PSO alleviates SAE and delve into the underlying mechanisms. We found that PSO treatment significantly reduced sepsis scores, aspartate transaminase (AST) and aspartate transaminase (LDH), while increased anal temperature and neurological scores in CLP-injured mice. Moreover, PSO treatment ameliorated sepsis-associated cognitive impairment, mood, anxiety disorders, inhibited inflammatory responses, as well as attenuated endoplasmic reticulum stress (ERS). These results were also validated in vitro experiments, PSO treatment reduced ROS, inflammation response, and attenuated ERS in LPS-injured N2a cells. Importantly, tunicamycin (TUN), as ERS agonist, significantly reversed the protective effect of PSO on LPS-injured N2a cells, as evidenced by increased expression levels of IL-6, NLRP3, CHOP, and ATF6. Likewise, ATF6 overexpression also reversed the protective effect of PSO. In conclusion, these results confirmed that PSO has a protective effect on SAE, which was largely attributed to neuroinflammation and ERS. These findings provide new insights into the neuroprotective role of PSO and suggest that PSO is a new therapeutic intervention of SAE.
摘要：
脓毒症相关性脑病（SAE）是一种严重的并发症，影响中枢神经系统，是重症监护病房发病率和死亡率增加的主要原因。补骨脂素（PSO），一种从中药补骨脂中分离出的香豆素化合物，能穿透血脑屏障，具有多种药理活性，包括抗炎，抗氧化和抗抑郁。本研究旨在探讨PSO是否缓解SAE，并深入研究其潜在机制。我们发现PSO治疗显著降低了脓毒症评分，天冬氨酸转氨酶（AST）和天冬氨酸转氨酶（LDH），而CLP损伤小鼠的肛门温度和神经系统评分升高。此外，PSO治疗改善脓毒症相关认知障碍，心情,焦虑症,抑制炎症反应，以及改善内质网应激（ERS）。这些结果也在体外实验中得到了验证，PSO处理减少了ROS，炎症反应，和改善LPS损伤的N2a细胞中的ERS。重要的是,衣霉素（TUN），作为ERS激动剂，显著逆转PSO对LPS损伤的N2a细胞的保护作用，如IL-6、NLRP3、CHOP、ATF6同样，ATF6过表达也逆转了PSO的保护作用。总之,这些结果证实了PSO对SAE具有保护作用，这主要归因于神经炎症和ERS。这些发现为PSO的神经保护作用提供了新的见解，并表明PSO是SAE的一种新的治疗干预措施。
