SS-31 Improves Cognitive Function in Sepsis-Associated Encephalopathy by Inhibiting the Drp1-NLRP3 Inflammasome Activation

• Published in: Neuromolecular medicine Vol. 25; no. 2; pp. 230 - 241
• Main Authors: Zhong, Lanlan, Ren, Xingshu, Ai, Yuhang, Liu, Zhiyong
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2023; Springer Nature B.V
• Subjects: ATP; Biomedical and Life Sciences; Biomedicine; Cecum; Cognition; Cognitive ability; Dynamin; Dynamins - metabolism; Encephalopathy; Hippocampus; Humans; Inflammasomes; Inflammation; Internal Medicine; Lipopolysaccharides; Microglia; Mitochondria; Neurology; Neurosciences; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Oligomerization; Reactive oxygen species; Sepsis; Sepsis-Associated Encephalopathy - drug therapy; Hippocampal; Mitochondria; Sepsis-associated encephalopathy; NLRP3 inflammasome; Drp1; Microglia
• ISSN: 1535-1084; 1559-1174
• DOI: 10.1007/s12017-022-08730-1

Neuroinflammation and microglial activation are involved in the pathogenesis of sepsis-associated encephalopathy (SAE). Mitochondrial dynamics emerged as a new player in the regulation of immunological processes. In this study, we aimed at exploring the effects of mitochondrial-targeted antioxidant peptide SS-31 on cognitive function in mice with SAE. In mice, SS-31 was intraperitoneally administered for seven consecutive days after cecal ligation and puncture surgery. SS-31 improved cognitive performance and survival rate of mice and alleviated hippocampal inflammation, reactive oxygen species production, and excessive mitochondrial fission. The increase of nucleotide-binding oligomerization domain 3 (NLRP3) and phosphorylated dynamin-related protein 1 (Drp1) ser616 in microglia was attenuated by SS-31. In vitro, the microglial cell line BV-2 was pre-treated with SS-31, followed by lipopolysaccharide/adenosine triphosphate induction. SS-31 effectively decreased the activation of NLRP3 inflammasome, mitochondrial translocation of Drp1, excessive mitochondrial fission, and mitochondrial membrane recruitment of gasdermin-D N-terminal (GSDMD-N). Similarly, knockdown of Drp1 inhibited the activation of NLRP3 inflammasome. SS-31 improved survival rate and cognitive functions of mice with SAE, related to mitochondrial fission protein Drp1 to inhibiting activation of NLRP3 inflammasome.