Barbiturates and Oxidative Phosphorylation

Biochemical Journal (Impact Factor: 4.4). 08/1960; 76(1):47-56. DOI: 10.1042/bj0760047
Source: PubMed
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    • "Barbiturates inhibit mitochondrial respiration [51]. Although effects of barbiturates on oxidative phosphorylation have not been recognized previously as physiologically relevant in neurons, we speculated that transiently elevated AMP/ATP ratios might lead to induction of AMPK, a kinase that can activate eEF2K through phosphorylation at Ser398 [19], and thus might be responsible for the inhibitory Thr56 phosphorylation of eEF2. "
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    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.
    Full-text · Article · Oct 2013 · PLoS ONE
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    • "Barbiturates are widely used as anesthetics and to some extent are applied as protective agents, such as during and after anoxic events (Yatsu et al., 1972; Steen et al., 1978; Amakawa et al., 1996; Kobayashi et al., 2007) or traumatic brain injuries (Huynh et al., 2009, and references therein), which can be ascribed to their function as central nervous system depressants, mainly by binding g-aminobutyric acid type A (GABA A ) receptors and possibly interacting with glutamate receptors (Marszalec and Narahashi, 1993). Additionally, barbiturates have been shown to depress energy metabolism by, e.g., inhibiting the oxidation of NADH in the respiratory chain (Aldridge and Parker, 1960; Chance et al., 1963), glucose transport at the blood–brain barrier (BBB; Haspel et al., 1999), and cerebral glucose utilization (Strang and Bachelard, 1973; Sokoloff et al., 1977). Therefore, investigation of the effect of barbiturates in vivo in animal models might potentially help in understanding their particular pharmacological roles. "
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    ABSTRACT: Barbiturates are regularly used as an anesthetic for animal experimentation and clinical procedures and are frequently provided with solubilizing compounds, such as ethanol and propylene glycol, which have been reported to affect brain function and, in the case of (1)H NMR experiments, originate undesired resonances in spectra affecting the quantification. As an alternative, thiopental can be administrated without any solubilizing agents. The aim of the study was to investigate the effect of deep thiopental anesthesia on the neurochemical profile consisting of 19 metabolites and on glucose transport kinetics in vivo in rat cortex compared with alpha-chloralose using localized (1)H NMR spectroscopy. Thiopental was devoid of effects on the neurochemical profile, except for the elevated glucose at a given plasma glucose level resulting from thiopental-induced depression of glucose consumption at isoelectrical condition. Over the entire range of plasma glucose levels, steady-state glucose concentrations were increased on average by 48% +/- 8%, implying that an effect of deep thiopental anesthesia on the transport rate relative to cerebral glucose consumption ratio was increased by 47% +/- 8% compared with light alpha-chloralose-anesthetized rats. We conclude that the thiopental-induced isoelectrical condition in rat cortex significantly affected glucose contents by depressing brain metabolism, which remained substantial at isoelectricity.
    Full-text · Article · Feb 2010 · Journal of Neuroscience Research
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    • "Barbiturates are known to depress metabolism by inhibiting the oxidation of NADH in the respiratory chain (Aldridge and Parker, 1960; Chance and Hollunger, 1963). In cell cultures, barbiturates have been shown to reduce neuronal glutamate release and to inhibit astrocytic glutamate uptake (Qu et al., 1999; Swanson and Seid, 1998). "
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    ABSTRACT: The effect of deep barbiturate anesthesia on brain glucose transport, TCA cycle flux, and aspartate, glutamate, and glutamine metabolism was assessed in the rat brain using 13C nuclear magnetic resonance spectroscopy at 9.4 T in conjunction with [1-13C] glucose infusions. Brain glucose concentrations were elevated, consistent with a twofold reduced cerebral metabolic rate for glucose (CMRglc) compared with light alpha-chloralose anesthesia. Using a mathematical model of neurotransmitter metabolism, several metabolic reaction rates were extracted from the rate of label incorporation. Total oxidative glucose metabolism, CMRglc(ox), was 0.33 +/- 0.03 micromol x g(-1) x min(-1). The neuronal TCA cycle rate was similar to that in the glia, 0.35 +/- 0.03 micromol x g(-1) x min(-1) and 0.26 +/- 0.06 micromol x g(-1) x min(-1), respectively, suggesting that neuronal energy metabolism was mainly affected. The rate of pyruvate carboxylation was 0.03 +/- 0.01 micromol x g(-1) x min(-1). The exchange rate between cytosolic glutamate and mitochondrial 2-oxoglutarate, Vx, was equal to the rate of neuronal pyruvate dehydrogenase flux. This indicates that Vx is coupled to CMRglc(ox), implying that the malate-aspartate shuttle is the major mechanism that facilitates label exchange across the inner mitochondrial membrane. The apparent rate of glutamatergic neurotransmission, V(NT), was 0.04 +/- 0.01 micromol x g x min, consistent with strong reductions in electrical activity. However, the rates of cerebral oxidative glucose metabolism and glutamatergic neurotransmission, CMRglc(ox)/V(NT), did not correlate with a 1:1 stoichiometry.
    Full-text · Article · Dec 2002 · Journal of Cerebral Blood Flow & Metabolism
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