title: Mitochondria-Targeted Peptide Reverses Mitochondrial Dysfunction and Cognitive Deficits in Sepsis-Associated Encephalopathy.
abstract: Sepsis-associated encephalopathy (SAE) is associated with increased mortality, morbidity, and long-term cognitive impairments. Its pathophysiology remains to be determined and an effective pharmacologic treatment is lacking. The goal of this study was to investigate the effects of the mitochondria-targeted peptide SS-31 on mitochondrial function and cognitive deficits in SAE mice. C57BL/6 male mice were randomly divided into sham, sham + SS-31, cecal ligation and puncture (CLP), and CLP + SS-31 groups. Peptide SS-31 (5 mg/kg) was intraperitoneally administrated immediately after operation and afterwards once daily for six consecutive days. Surviving mice were subjected to behavioral tests and the hippocampus was collected for biochemical analysis 7 days after operation. The results showed that CLP resulted in high mortality rate and cognitive deficits, representative characteristics of SAE. A physiological mechanistic investigation revealed that mitochondrial function of hippocampus was severely impaired, coupled with reactive oxygen species (ROS) generation, triggering neuronal apoptosis and inflammation. Notably, administration of peptide SS-31 protected the integrity of mitochondria, reversed the mitochondrial dysfunction, inhibited the apoptosis resulting from the release of cytochrome c, diminished the response of inflammation, and ultimately reversed the behavior deficits in the SAE mice. In conclusion, our data demonstrate that daily treatment with mitochondria-targeted peptide SS-31 reduces mortality rate and ameliorates cognitive deficits, which is possibly through a mechanism of reversing mitochondrial dysfunction and partial inhibition of neuronal apoptosis and inflammation in the hippocampus of the SAE mice.
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 210093, Nanjing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Zhang
authors.forename: Shuangying
authors.initials: S
authors.lastname: Hao
authors.forename: Ming
authors.initials: M
authors.lastname: Jia
authors.forename: Muhuo
authors.initials: M
authors.lastname: Ji
authors.forename: Lili
authors.initials: L
authors.lastname: Qiu
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Sun
authors.forename: Jianjun
authors.initials: J
authors.lastname: Yang
authors.forename: Kuanyu
authors.initials: K
authors.lastname: Li
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002432:Cecum; D003072:Cognition Disorders / Q000150:complications* / Q000188:drug therapy*; D004579:Electron Transport / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008026:Ligation; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D011677:Punctures; D017382:Reactive Oxygen Species / Q000378:metabolism; D065166:Sepsis-Associated Encephalopathy / Q000150:complications* / Q000188:drug therapy*; D016019:Survival Analysis
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D010455:Peptides; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate