title: The tricarboxylic acid cycle activity in cultured primary astrocytes is strongly accelerated by the protein tyrosine kinase inhibitor tyrphostin 23.
abstract: Tyrphostin 23 (T23) is a well-known inhibitor of protein tyrosine kinases and has been considered as potential anti-cancer drug. T23 was recently reported to acutely stimulate the glycolytic flux in primary cultured astrocytes. To investigate whether T23 also affects the tricarboxylic acid (TCA) cycle, we incubated primary rat astrocyte cultures with [U-13C]glucose in the absence or the presence of 100 μM T23 for 2 h and analyzed the13C metabolite pattern. These incubation conditions did not compromise cell viability and confirmed that the presence of T23 doubled glycolytic lactate production. In addition, T23-treatment strongly increased the molecular carbon labeling of the TCA cycle intermediates citrate, succinate, fumarate and malate, and significantly increased the incorporation of13C-labelling into the amino acids glutamate, glutamine and aspartate. These results clearly demonstrate that, in addition to glycolysis, also the mitochondrial TCA cycle is strongly accelerated after exposure of astrocytes to T23, suggesting that a protein tyrosine kinase may be involved in the regulation of the TCA cycle in astrocytes.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: hohnholt@uni-bremen.de.
authors.forename: Michaela C
authors.initials: MC
authors.lastname: Hohnholt
authors.affiliation: Centre for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, PO. Box 330440, D-28334 Bremen, Germany; Centre for Environmental Research and Sustainable Technology, Leobener Strasse, D-28359 Bremen, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Blumrich
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Science, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Helle S
authors.initials: HS
authors.lastname: Waagepetersen
authors.affiliation: Centre for Biomolecular Interactions Bremen, Faculty 2 (Biology/Chemistry), University of Bremen, PO. Box 330440, D-28334 Bremen, Germany; Centre for Environmental Research and Sustainable Technology, Leobener Strasse, D-28359 Bremen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dringen
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002952:Citric Acid Cycle / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017208:Rats, Wistar; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D020032:Tyrphostins; D001224:Aspartic Acid; D018698:Glutamic Acid; D005947:Glucose; C060641:tyrphostin A23
keywords: Astrocytes; Lactate; Metabolism; Tricarboxylic acid cycle; Tyrphostins