Mkrtchyan, Garik V., Uecal, Muammer, Muellebner, Andrea, Dumitrescu, Sergiu, Kames, Martina, Moldzio, Rudolf, Molcanyi, Marek, Schaefer, Samuel, Weidinger, Adelheid, Schaefer, Ute, Hescheler, Juergen, Duvigneau, Johanna Catharina, Redl, Heinz, Bunik, Victoria I. and Kozlov, Andrey V. (2018). Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex. Biochim. Biophys. Acta-Bioenerg., 1859 (9). S. 925 - 932. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 0006-3002

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Abstract

Background and purpose: Based on the fact that traumatic brain injury is associated with mitochondrial dysfunction we aimed at localization of mitochondrial defect and attempted to correct it by thiamine. Experimental approach: Interventional controlled experimental animal study was used. Adult male Sprague-Dawley rats were subjected to lateral fluid percussion traumatic brain injury. Thiamine was administered 1 h prior to trauma; cortex was extracted for analysis 4 h and 3 d after trauma. Key results: Increased expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor receptor 1 (TNF-R1) by 4 h was accompanied by a decrease in mitochondrial respiration with glutamate but neither with pyruvate nor succinate. Assays of TCA cycle flux-limiting 2-oxoglutarate dehydrogenase complex (OGDHC) and functionally linked enzymes (glutamate dehydrogenase, glutamine synthetase, pyruvate dehydrogenase, malate dehydrogenase and malic enzyme) indicated that only OGDHC activity was decreased. Application of the OGDHC coenzyme precursor thiamine rescued the activity of OGDHC and restored mitochondrial respiration. These effects were not mediated by changes in the expression of the OGDHC sub-units (E1k and E3), suggesting post-translational mechanism of thiamine effects. By the third day after TBI, thiamine treatment also decreased expression of TNF-R1. Specific markers of unfolded protein response did not change in response to thiamine. Conclusion and implications: Our data point to OGDHC as a major site of damage in mitochondria upon traumatic brain injury, which is associated with neuroinflammation and can be corrected by thiamine. Further studies are required to evaluate the pathological impact of these findings in clinical settings.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mkrtchyan, Garik V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uecal, MuammerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muellebner, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dumitrescu, SergiuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kames, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moldzio, RudolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Molcanyi, MarekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, SamuelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weidinger, AdelheidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schaefer, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hescheler, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duvigneau, Johanna CatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Redl, HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bunik, Victoria I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kozlov, Andrey V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-175300
DOI: 10.1016/j.bbabio.2018.05.005
Journal or Publication Title: Biochim. Biophys. Acta-Bioenerg.
Volume: 1859
Number: 9
Page Range: S. 925 - 932
Date: 2018
Publisher: ELSEVIER SCIENCE BV
Place of Publication: AMSTERDAM
ISSN: 0006-3002
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; NITRIC-OXIDE; ER STRESS; INFLAMMATORY RESPONSE; OXIDATIVE STRESS; MOLECULAR-MECHANISMS; GLUTAMATE RELEASE; CELL-SURVIVAL; DYSFUNCTIONMultiple languages
Biochemistry & Molecular Biology; BiophysicsMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17530

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