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

Abstract

AIMS:

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.

MAIN METHODS:

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.

KEY FINDINGS:

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.

SIGNIFICANCE:

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.

• Authors: Lina Zhang, Yuan Jiang, Songyun Deng, Yunan Mo, Yan Huang, Wenchao Li, Chenglong Ge, Xinshu Ren, Haisong Zhang, Xiaolei Zhang, Qianyi Peng, Zhiyong Liu, Li Huang, Fan Zhou, Yuhang Ai
• Journal: Life sciences (Life Sci) Vol. 277 Pg. 119490 (Jul 15 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 33862114 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Ceramides
• Receptor for Advanced Glycation End Products
• S100 Calcium Binding Protein beta Subunit
• S100b protein, mouse

Topics

• Animals
• Apoptosis (drug effects)
• Brain (metabolism)
• Brain Diseases (complications, metabolism)
• Brain Injuries (metabolism)
• Ceramides (metabolism)
• Cognitive Dysfunction (metabolism)
• Disease Models, Animal
• Hippocampus (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mitochondria (drug effects)
• Neurons (metabolism)
• Receptor for Advanced Glycation End Products (metabolism)
• S100 Calcium Binding Protein beta Subunit (metabolism)
• Sepsis (complications)
• Sepsis-Associated Encephalopathy (complications, metabolism, physiopathology)
• Signal Transduction