Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.

Uchino, HiroyukiTokyo Medical University(Swepub:lu)extLU-1443 (författare)
Elmér, EskilLund University,Lunds universitet,Klinisk neurofysiologi,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Mitokondriell Medicin,Forskargrupper vid Lunds universitet,Clinical Neurophysiology,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Mitochondrial Medicine,Lund University Research Groups(Swepub:lu)expb-eel (författare)
Ogihara, YukihikoTokyo Medical University (författare)
Fujita, Hidetoshi (författare)
Sekine, ShusukeTokyo Medical University (författare)
Ishida, YusukeTokyo Medical University (författare)
Saiki, IwaoTokyo Medical University (författare)
Shibata, ShoichiroTokyo Medical University (författare)
Kawachi, AyaTokyo Medical University (författare)
Tokyo Medical UniversityKlinisk neurofysiologi (creator_code:org_t)

Ingår i:International Journal of Molecular Sciences: MDPI AG23:21661-65961422-0067

Av författaren/redakt...: Kobayashi, Takay ...; Uchino, Hiroyuki; Elmér, Eskil; Ogihara, Yukihik ...; Fujita, Hidetosh ...; Sekine, Shusuke; visa fler...; Ishida, Yusuke; Saiki, Iwao; Shibata, Shoichi ...; Kawachi, Aya; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Kirurgi

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Neurovetenskaper

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