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Updated: Aug 23, 2025
Evaluation of a Reliable Biomarker in a Cecal Ligation and Puncture-Induced Mouse Model of Sepsis
Published on: December 9, 2022
SS-31 Improves Cognitive Function in Sepsis-Associated Encephalopathy by Inhibiting the Drp1-NLRP3 Inflammasome
Lanlan Zhong1,2, Xingshu Ren1,2, Yuhang Ai1,2
1Department of Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People's Republic of China.
Abstract:
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.
Insights
Mitochondrial-targeted antioxidant SS-31 improved survival and cognitive function in sepsis-associated encephalopathy (SAE) mice. It reduced neuroinflammation by inhibiting mitochondrial fission protein Drp1 and NLRP3 inflammasome activation.
Area of Science:
- Neuroscience
- Immunology
- Mitochondrial Biology
Background:
- Sepsis-associated encephalopathy (SAE) involves neuroinflammation and microglial activation.
- Mitochondrial dynamics play a role in regulating immune responses.
Purpose of the Study:
- To investigate the effects of the mitochondrial-targeted antioxidant peptide SS-31 on cognitive function in a mouse model of SAE.
- To explore the underlying mechanisms involving mitochondrial dynamics and inflammasome activation.
Main Methods:
- Mice underwent cecal ligation and puncture surgery to induce SAE, followed by intraperitoneal administration of SS-31.
- In vitro studies used the BV-2 microglial cell line treated with SS-31 and stimulated with lipopolysaccharide/adenosine triphosphate.
- Assessed cognitive performance, survival rates, hippocampal inflammation, reactive oxygen species (ROS), mitochondrial fission, NLRP3 inflammasome activation, Drp1, and GSDMD-N.
Main Results:
- SS-31 administration improved cognitive performance and survival rates in SAE mice.
- SS-31 treatment reduced hippocampal inflammation, ROS production, and excessive mitochondrial fission.
- SS-31 attenuated the increase in NLRP3 and phosphorylated Drp1 (ser616) in microglia and inhibited NLRP3 inflammasome activation, Drp1 translocation, and GSDMD-N recruitment in vitro.
- Knockdown of Drp1 also inhibited NLRP3 inflammasome activation.
Conclusions:
- SS-31 demonstrates neuroprotective effects in SAE by improving survival and cognitive function.
- The therapeutic benefits of SS-31 are linked to its ability to inhibit mitochondrial fission protein Drp1, thereby suppressing NLRP3 inflammasome activation and neuroinflammation.
