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.

神经炎症和小胶质细胞激活参与脓毒症相关脑病（SAE）的发病机制。线粒体动力学成为免疫过程调节中的新参与者。在本研究中，我们旨在探讨线粒体靶向抗氧化肽 SS-31 对 SAE 小鼠认知功能的影响。在小鼠中，盲肠结扎和穿刺手术后，连续 7 天腹腔注射 SS-31。SS-31 改善了小鼠的认知能力和存活率，并减轻了海马炎症、活性氧产生和线粒体过度裂变。SS-31 减弱了小胶质细胞中核苷酸结合寡聚化结构域 3 (NLRP3) 和磷酸化动力相关蛋白 1 (Drp1) ser616 的增加。体外，小胶质细胞系 BV-2 用 SS-31 预处理，然后进行脂多糖/三磷酸腺苷诱导。SS-31 有效降低 NLRP3 炎性体的激活、Drp1 的线粒体易位、过度的线粒体裂变以及gasdermin-D N 末端 (GSDMD-N) 的线粒体膜募集。同样，Drp1 的敲除抑制了 NLRP3 炎性体的激活。SS-31提高SAE小鼠的存活率和认知功能，与线粒体裂变蛋白Drp1抑制NLRP3炎症小体的激活有关。以及gasdermin-D N 末端（GSDMD-N）的线粒体膜募集。同样，Drp1 的敲除抑制了 NLRP3 炎性体的激活。SS-31提高SAE小鼠的存活率和认知功能，与线粒体裂变蛋白Drp1抑制NLRP3炎症小体的激活有关。以及gasdermin-D N 末端（GSDMD-N）的线粒体膜募集。同样，Drp1 的敲除抑制了 NLRP3 炎性体的激活。SS-31提高SAE小鼠的存活率和认知功能，与线粒体裂变蛋白Drp1抑制NLRP3炎症小体的激活有关。