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.