Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China.
Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
Life Sci. 2021 Jul 15;277:119490. doi: 10.1016/j.lfs.2021.119490. Epub 2021 Apr 13.
Sepsis-associated encephalopathy (SAE) is one of the most common complications of sepsis, and it might lead to long-term cognitive dysfunction and disability. This study aimed to explore the role of S100 calcium binding protein B (S100B)/RAGE/ceramide signaling pathway in SAE.
FPS-ZM1 (an inhibitor of RAGE), myriocin and GW4869 (an inhibitor of ceramide) were used to explore the role of S100B/RAGE/ceramide in acute brain injury and long-term cognitive impairment in sepsis. In addition, Mdivi-1 (inhibitor of Drp1) and Drp1 siRNA were utilized to assess the effects of C2-ceramide on neuronal mitochondria, and to explore the specific underlying mechanism in C2 ceramide-induced death of HT22 mouse hippocampal neuronal cells.
Western blot analysis showed that sepsis significantly up-regulated S100B and RAGE. Nissl staining and Morris water maze (MWM) test revealed that inhibition of RAGE with FPS-ZM1 markedly attenuated cecal ligation and puncture (CLP)-induced brain damage and cognitive dysfunction. Furthermore, FPS-ZM1 relieved sepsis-induced C2-ceramide accumulation and abnormal mitochondrial dynamics. Moreover, inhibition of ceramide also showed similar protective effects both in vivo and in vitro. Furthermore, Mdivi-1 and Drp1 siRNA significantly reduced C2-ceramide-induced neuronal mitochondrial fragmentation and cell apoptosis in vitro.
This study confirmed that S100B regulates mitochondrial dynamics through RAGE/ceramide pathway, in addition to the role of this pathway in acute brain injury and long-term cognitive impairment during sepsis.
脓毒症相关性脑病（SAE）是脓毒症最常见的并发症之一，可导致长期认知功能障碍和残疾。本研究旨在探讨 S100 钙结合蛋白 B（S100B）/RAGE/神经酰胺信号通路在 SAE 中的作用。
采用 FPS-ZM1（RAGE 抑制剂）、曲古抑菌素 A 和 GW4869（神经酰胺抑制剂）探讨 S100B/RAGE/神经酰胺在脓毒症急性脑损伤和长期认知障碍中的作用。此外，采用 Mdivi-1（Drp1 抑制剂）和 Drp1 siRNA 评估 C2-神经酰胺对神经元线粒体的影响，并探讨 C2 神经酰胺诱导 HT22 小鼠海马神经元细胞死亡的具体潜在机制。
Western blot 分析表明，脓毒症显著上调 S100B 和 RAGE。Nissl 染色和 Morris 水迷宫（MWM）试验显示，用 FPS-ZM1 抑制 RAGE 可显著减轻盲肠结扎穿孔（CLP）诱导的脑损伤和认知功能障碍。此外，FPS-ZM1 减轻了脓毒症引起的 C2-神经酰胺积累和异常线粒体动力学。此外，神经酰胺抑制剂在体内和体外也表现出类似的保护作用。此外，Mdivi-1 和 Drp1 siRNA 显著减少了 C2 神经酰胺诱导的神经元线粒体碎片化和细胞凋亡。
本研究证实 S100B 通过 RAGE/神经酰胺通路调节线粒体动力学，该通路在脓毒症期间急性脑损伤和长期认知障碍中起作用。
