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Research ArticleNeuropharmacology

Carbimazole Is an Inhibitor of Protein Synthesis and Protects from Neuronal Hypoxic Damage In Vitro

Cornelius Lehane, Timo Guelzow, Simone Zenker, Anika Erxleben, Christian I. Schwer, Bernd Heimrich, Hartmut Buerkle and Matjaz Humar
Journal of Pharmacology and Experimental Therapeutics December 2013, 347 (3) 781-793; DOI: https://doi.org/10.1124/jpet.113.205989
Cornelius Lehane
Department of Anesthesiology and Critical Care Medicine (C.L., C.I.S., H.B., M.H.) and Department of General Neurosurgery, Cellular Neurophysiology (T.G.), University Medical Center Freiburg, Freiburg, Germany; and Department of Anatomy and Cell Biology (S.Z., B.H.) and Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences (A.E.), Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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Timo Guelzow
Department of Anesthesiology and Critical Care Medicine (C.L., C.I.S., H.B., M.H.) and Department of General Neurosurgery, Cellular Neurophysiology (T.G.), University Medical Center Freiburg, Freiburg, Germany; and Department of Anatomy and Cell Biology (S.Z., B.H.) and Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences (A.E.), Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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Simone Zenker
Department of Anesthesiology and Critical Care Medicine (C.L., C.I.S., H.B., M.H.) and Department of General Neurosurgery, Cellular Neurophysiology (T.G.), University Medical Center Freiburg, Freiburg, Germany; and Department of Anatomy and Cell Biology (S.Z., B.H.) and Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences (A.E.), Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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Anika Erxleben
Department of Anesthesiology and Critical Care Medicine (C.L., C.I.S., H.B., M.H.) and Department of General Neurosurgery, Cellular Neurophysiology (T.G.), University Medical Center Freiburg, Freiburg, Germany; and Department of Anatomy and Cell Biology (S.Z., B.H.) and Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences (A.E.), Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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Christian I. Schwer
Department of Anesthesiology and Critical Care Medicine (C.L., C.I.S., H.B., M.H.) and Department of General Neurosurgery, Cellular Neurophysiology (T.G.), University Medical Center Freiburg, Freiburg, Germany; and Department of Anatomy and Cell Biology (S.Z., B.H.) and Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences (A.E.), Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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Bernd Heimrich
Department of Anesthesiology and Critical Care Medicine (C.L., C.I.S., H.B., M.H.) and Department of General Neurosurgery, Cellular Neurophysiology (T.G.), University Medical Center Freiburg, Freiburg, Germany; and Department of Anatomy and Cell Biology (S.Z., B.H.) and Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences (A.E.), Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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Hartmut Buerkle
Department of Anesthesiology and Critical Care Medicine (C.L., C.I.S., H.B., M.H.) and Department of General Neurosurgery, Cellular Neurophysiology (T.G.), University Medical Center Freiburg, Freiburg, Germany; and Department of Anatomy and Cell Biology (S.Z., B.H.) and Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences (A.E.), Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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Matjaz Humar
Department of Anesthesiology and Critical Care Medicine (C.L., C.I.S., H.B., M.H.) and Department of General Neurosurgery, Cellular Neurophysiology (T.G.), University Medical Center Freiburg, Freiburg, Germany; and Department of Anatomy and Cell Biology (S.Z., B.H.) and Pharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences (A.E.), Albert-Ludwigs-University of Freiburg, Freiburg, Germany
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Abstract

Oxygen deprivation during ischemic or hemorrhagic stroke results in ATP depletion, loss of ion homeostasis, membrane depolarization, and excitotoxicity. Pharmacologic restoration of cellular energy supply may offer a promising concept to reduce hypoxic cell injury. In this study, we investigated whether carbimazole, a thionamide used to treat hyperthyroidism, reduces neuronal cell damage in oxygen-deprived human SK-N-SH cells or primary cortical neurons. Our results revealed that carbimazole induces an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) that was associated with a marked inhibition of global protein synthesis. Translational inhibition resulted in significant bioenergetic savings, preserving intracellular ATP content in oxygen-deprived neuronal cells and diminishing hypoxic cellular damage. Phosphorylation of eEF2 was mediated by AMP-activated protein kinase and eEF2 kinase. Carbimazole also induced a moderate calcium influx and a transient cAMP increase. To test whether translational inhibition generally diminishes hypoxic cell damage when ATP availability is limiting, the translational repressors cycloheximide and anisomycin were used. Cycloheximide and anisomycin also preserved ATP content in hypoxic SK-N-SH cells and significantly reduced hypoxic neuronal cell damage. Taken together, these data support a causal relation between the pharmacologic inhibition of global protein synthesis and efficient protection of neurons from ischemic damage by preservation of high-energy metabolites in oxygen-deprived cells. Furthermore, our results indicate that carbimazole or other translational inhibitors may be interesting candidates for the development of new organ-protective compounds. Their chemical structure may be used for computer-assisted drug design or screening of compounds to find new agents with the potential to diminish neuronal damage under ATP-limited conditions.

Footnotes

    • Received April 30, 2013.
    • Accepted September 17, 2013.
  • This work was supported by the Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Germany.

  • dx.doi.org/10.1124/jpet.113.205989.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 347 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 3
1 Dec 2013
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Research ArticleNeuropharmacology

Carbimazole Induces Phosphorylation of eEF2

Cornelius Lehane, Timo Guelzow, Simone Zenker, Anika Erxleben, Christian I. Schwer, Bernd Heimrich, Hartmut Buerkle and Matjaz Humar
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 781-793; DOI: https://doi.org/10.1124/jpet.113.205989

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Research ArticleNeuropharmacology

Carbimazole Induces Phosphorylation of eEF2

Cornelius Lehane, Timo Guelzow, Simone Zenker, Anika Erxleben, Christian I. Schwer, Bernd Heimrich, Hartmut Buerkle and Matjaz Humar
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 781-793; DOI: https://doi.org/10.1124/jpet.113.205989
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