Thiamine preserves mitochondrial function in a rat model of traumatic brain injury,preventing inactivation of the 2-oxoglutarate dehydrogenase complex |
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Authors: | Garik V. Mkrtchyan Muammer Üçal Andrea Müllebner Sergiu Dumitrescu Martina Kames Rudolf Moldzio Marek Molcanyi Samuel Schaefer Adelheid Weidinger Ute Schaefer Juergen Hescheler Johanna Catharina Duvigneau Heinz Redl Victoria I. Bunik Andrey V. Kozlov |
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Affiliation: | 1. Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria;2. Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia;3. Department of Neurosurgery, Medical University Graz, Graz, Austria;4. Institute for Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, Austria;5. Institute of Neurophysiology, Medical Faculty, University of Cologne, Cologne, Germany;6. Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Moscow, Russia |
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Abstract: | Background and purposeBased 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 approachInterventional 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 resultsIncreased 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 implicationsOur 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. |
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Keywords: | ER endoplasmic reticulum iNOS inducible nitric oxide synthase OGDHC 2-oxoglutarate dehydrogenase complex PDH pyruvate dehydrogenase TBI traumatic brain injury ThDP thiamine diphosphate TNF tumor necrosis factor Thiamine Traumatic brain injury (TBI) Mitochondria TCA cycle 2-Oxoglutarate dehydrogenase complex Neuroinflammation |
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