In Vivo Microdialysis of Endogenous and 13C-labeled TCA Metabolites in Rat Brain: Reversible and Persistent Effects of Mitochondrial Inhibition and Transient Cerebral Ischemia
| Autor: | Troels Halfeld Nielsen, Jan Bert Gramsbergen, Carl-Henrik Nordström, Frantz Rom Poulsen, Kevin Heebøll Nygaard, Axel Forsse, Nils J. Færgeman, Jesper F. Havelund |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Fumaric acid Microdialysis Endocrinology Diabetes and Metabolism Ischemia lcsh:QR1-502 Pharmacology Biochemistry Article cerebral ischemia lcsh:Microbiology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine energy metabolism mitochondrial dysfunction medicine Extracellular micro-dialysis Molecular Biology lc-ms biology Succinate dehydrogenase medicine.disease malonate reperfusion Citric acid cycle 030104 developmental biology Malonate chemistry endothelin-1 biology.protein 13c-labeled succinate tricarboxylic acid cycle 13C-labeled succinate Malic acid 030217 neurology & neurosurgery |
| Zdroj: | Metabolites, Vol 9, Iss 10, p 204 (2019) Metabolites Volume 9 Issue 10 Havelund, J F, Nygaard, K H, Nielsen, T H, Nordström, C-H, Poulsen, F R, Færgeman, N J, Forsse, A & Gramsbergen, J B 2019, ' In Vivo Microdialysis of Endogenous and 13C-labeled TCA Metabolites in Rat Brain : Reversible and Persistent Effects of Mitochondrial Inhibition and Transient Cerebral Ischemia ', Metabolites, vol. 9, no. 10, 204 . https://doi.org/10.3390/metabo9100204 |
| ISSN: | 2218-1989 |
| Popis: | Cerebral micro-dialysis allows continuous sampling of extracellular metabolites, including glucose, lactate and pyruvate. Transient ischemic events cause a rapid drop in glucose and a rise in lactate levels. Following such events, the lactate/pyruvate (L/P) ratio may remain elevated for a prolonged period of time. In neurointensive care clinics, this ratio is considered a metabolic marker of ischemia and/or mitochondrial dysfunction. Here we propose a novel, sensitive microdialysis liquid chromatography-mass spectrometry (LC-MS) approach to monitor mitochondrial dysfunction in living brain using perfusion with 13C-labeled succinate and analysis of 13C-labeled tricarboxylic acid cycle (TCA) intermediates. This approach was evaluated in rat brain using malonate-perfusion (10&ndash 50 mM) and endothelin-1 (ET-1)-induced transient cerebral ischemia. In the malonate model, the expected changes upon inhibition of succinate dehydrogenase (SDH) were observed, i.e., an increase in endogenous succinate and decreases in fumaric acid and malic acid. The inhibition was further elaborated by incorporation of 13C into specific TCA intermediates from 13C-labeled succinate. In the ET-1 model, increases in non-labeled TCA metabolites (reflecting release of intracellular compounds) and decreases in 13C-labeled TCA metabolites (reflecting inhibition of de novo synthesis) were observed. The analysis of 13C incorporation provides further layers of information to identify metabolic disturbances in experimental models and neuro-intensive care patients. |
| Databáze: | OpenAIRE |
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