title: Metabolomic Analyses of Brain Tissue in Sepsis Induced by Cecal Ligation Reveal Specific Redox Alterations--Protective Effects of the Oxygen Radical Scavenger Edaravone.
abstract: The pathophysiology of sepsis-associated encephalopathy (SAE) is complex and remains incompletely elucidated. Dysregulated reactive oxygen species (ROS) production and mitochondrial-mediated necrotic-apoptotic pathway have been proposed as part of the pathogenesis. The present study aimed at analyzing the preventive effect of the free radical scavenger edaravone on sepsis-induced brain alterations. Sepsis was induced by cecal ligation and puncture (CLP) and the mice were divided into three groups-CLP vehicle (CLPV), CLP and edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one) (CLPE), and sham-operated (Sham). Mice in CLPV and CLPE were injected with saline or edaravone intraperitoneally at a dose of 10 mg/kg twice daily. The treatments were initiated 4 days prior to the surgical procedure. Mortality, histological changes, electron microscopy (EM), and expression of Bcl-2 family genes (Bcl-2 and Bax) were analyzed in selected brain regions. CLPE showed significant improvement in survival compared with CLPV 18 h postinduction of sepsis (P < 0.05). At the same time point, pathohistological analysis also showed marked reduction of neuronal cell death in both parietal cortex and hippocampus in the CLPE (P < 0.05). RT-PCR and immunoblotting directed at the Bcl-2 family revealed increased Bax mRNA levels in hippocampus at 12 h in CLPV as well as an increased Bax/Bcl-2 protein ratio, changes that were significantly suppressed in CLPE. In conclusion, our study suggests that sepsis induced by cecal ligation alters cerebral redox status and supports a proapoptotic phenotype. The free radical scavenger edavarone reduces mortality of septic mice and protects against sepsis-induced neuronal cell death.
authors.affiliation: *Department of Anesthesiology †Institute of Medical Science ‡Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan §Mitochondrial Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Naomi
authors.initials: N
authors.lastname: Hara
authors.forename: Miyuki
authors.initials: M
authors.lastname: Chijiiwa
authors.forename: Miki
authors.initials: M
authors.lastname: Yara
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ishida
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Ogiwara
authors.forename: Masato
authors.initials: M
authors.lastname: Inazu
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kuroda
authors.forename: Michael
authors.initials: M
authors.lastname: Karlsson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Sjovall
authors.forename: Eskil
authors.initials: E
authors.lastname: Elmér
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchino
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017209:Apoptosis; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002432:Cecum / Q000601:surgery; D016923:Cell Death; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D008026:Ligation; D055432:Metabolomics; D051379:Mice; D008854:Microscopy, Electron; D009474:Neurons / Q000473:pathology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D016133:Polymerase Chain Reaction; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000503:physiopathology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D016166:Free Radical Scavengers; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D000077553:Edaravone; D010100:Oxygen; D000983:Antipyrine