title: Thiopental inhibits global protein synthesis by repression of eukaryotic elongation factor 2 and protects from hypoxic neuronal cell death.
abstract: Ischemic and traumatic brain injury is associated with increased risk for death and disability. The inhibition of penumbral tissue damage has been recognized as a target for therapeutic intervention, because cellular injury evolves progressively upon ATP-depletion and loss of ion homeostasis. In patients, thiopental is used to treat refractory intracranial hypertension by reducing intracranial pressure and cerebral metabolic demands; however, therapeutic benefits of thiopental-treatment are controversially discussed. In the present study we identified fundamental neuroprotective molecular mechanisms mediated by thiopental. Here we show that thiopental inhibits global protein synthesis, which preserves the intracellular energy metabolite content in oxygen-deprived human neuronal SK-N-SH cells or primary mouse cortical neurons and thus ameliorates hypoxic cell damage. Sensitivity to hypoxic damage was restored by pharmacologic repression of eukaryotic elongation factor 2 kinase. Translational inhibition was mediated by calcium influx, activation of the AMP-activated protein kinase, and inhibitory phosphorylation of eukaryotic elongation factor 2. Our results explain the reduction of cerebral metabolic demands during thiopental treatment. Cycloheximide also protected neurons from hypoxic cell death, indicating that translational inhibitors may generally reduce secondary brain injury. In conclusion our study demonstrates that therapeutic inhibition of global protein synthesis protects neurons from hypoxic damage by preserving energy balance in oxygen-deprived cells. Molecular evidence for thiopental-mediated neuroprotection favours a positive clinical evaluation of barbiturate treatment. The chemical structure of thiopental could represent a pharmacologically relevant scaffold for the development of new organ-protective compounds to ameliorate tissue damage when oxygen availability is limited.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Christian I
authors.initials: CI
authors.lastname: Schwer
authors.forename: Cornelius
authors.initials: C
authors.lastname: Lehane
authors.forename: Timo
authors.initials: T
authors.lastname: Guelzow
authors.forename: Simone
authors.initials: S
authors.lastname: Zenker
authors.forename: Karl M
authors.initials: KM
authors.lastname: Strosing
authors.forename: Sashko
authors.initials: S
authors.lastname: Spassov
authors.forename: Anika
authors.initials: A
authors.lastname: Erxleben
authors.forename: Bernd
authors.initials: B
authors.lastname: Heimrich
authors.forename: Hartmut
authors.initials: H
authors.lastname: Buerkle
authors.forename: Matjaz
authors.initials: M
authors.lastname: Humar
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D054736:Elongation Factor 2 Kinase / Q000378:metabolism; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D020652:Peptide Elongation Factor 2 / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects*; D013874:Thiopental / Q000494:pharmacology*
chemical_list: D006993:Hypnotics and Sedatives; D020652:Peptide Elongation Factor 2; D054736:Elongation Factor 2 Kinase; D013874:Thiopental; D010100:Oxygen