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Metabolomic Analyses of Brain Tissue in Sepsis Induced by Cecal Ligation Reveal Specific Redox Alterations-Protective Effects of the Oxygen Radical Scavenger Edaravone.

Hara, Naomi ; Chijiiwa, Miyuki ; Yara, Miki ; Ishida, Yusuke ; Ogiwara, Yukihiko ; Inazu, Masato ; Kuroda, Masahiko ; Karlsson, Michael LU ; Sjövall, Fredrik LU orcid and Elmer, Eskil LU orcid , et al. (2015) In Shock 44(6). p.578-584
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Shock
volume
44
issue
6
pages
578 - 584
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:26529662
  • wos:000365673700010
  • scopus:84947867395
  • pmid:26529662
ISSN
1540-0514
DOI
10.1097/SHK.0000000000000465
language
English
LU publication?
yes
id
5e8c117e-330c-4f20-9520-58f9b7c344e9 (old id 8243438)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/26529662?dopt=Abstract
date added to LUP
2016-04-01 10:21:55
date last changed
2022-04-04 17:23:18
@article{5e8c117e-330c-4f20-9520-58f9b7c344e9,
  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 &lt; 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 &lt; 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.}},
  author       = {{Hara, Naomi and Chijiiwa, Miyuki and Yara, Miki and Ishida, Yusuke and Ogiwara, Yukihiko and Inazu, Masato and Kuroda, Masahiko and Karlsson, Michael and Sjövall, Fredrik and Elmer, Eskil and Uchino, Hiroyuki}},
  issn         = {{1540-0514}},
  language     = {{eng}},
  number       = {{6}},
  pages        = {{578--584}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Shock}},
  title        = {{Metabolomic Analyses of Brain Tissue in Sepsis Induced by Cecal Ligation Reveal Specific Redox Alterations-Protective Effects of the Oxygen Radical Scavenger Edaravone.}},
  url          = {{http://dx.doi.org/10.1097/SHK.0000000000000465}},
  doi          = {{10.1097/SHK.0000000000000465}},
  volume       = {{44}},
  year         = {{2015}},
}