S100B/RAGE/Ceramide signaling pathway is involved in sepsis-associated encephalopathy

• Published in: Life sciences (1973) Vol. 277; p. 119490
• Main Authors: Zhang, Lina, Jiang, Yuan, Deng, Songyun, Mo, Yunan, Huang, Yan, Li, Wenchao, Ge, Chenglong, Ren, Xinshu, Zhang, Haisong, Zhang, Xiaolei, Peng, Qianyi, Liu, Zhiyong, Huang, Li, Zhou, Fan, Ai, Yuhang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.07.2021; Elsevier BV
• Subjects: Apoptosis; Brain; Brain damage; Brain injury; Calcium-binding protein; Cecum; Ceramide; Cognitive ability; Complications; Damage accumulation; Drp1; Encephalopathy; Head injuries; Hippocampus; Impairment; In vivo methods and tests; Inhibitors; Kinases; Mitochondria; Mitochondrial dynamics; Protein B; RAGE; S100B; S100b protein; Sepsis; Sepsis-associated encephalopathy; Signal transduction; Signaling; siRNA; Traumatic brain injury; mdivi-1; CLP; Mitochondrial dynamics; i.p; RAGE; S100B; MAPK; Drp1; NF-κB; SAE; ROS; Ceramide; Sepsis-associated encephalopathy
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119490

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.