Neuronal-astrocytic and cytosolic-mitochondrial metabolite trafficking during brain activation, hyperammonemia and energy deprivation

Hertz, Leif; Yu, Albert Cheung-Hoi; Kala, Geeta; Schousboe, Arne

doi:10.1016/s0197-0186(00)00012-7

Cited by 103 publications

(67 citation statements)

References 168 publications

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“…The finding of a large fraction of activity-dependent glucose uptake in neurons requires an alternative explanation of the 1:1 relationship. Two alternate mechanisms have been postulated, one involving the coupling of neuronal glycolysis (or glycolytic ATP) to vesicular loading of glutamate (37,38) and another involving the coupling of neuronal glutamate formed from glutamine to redox movements into mitochondria via the malate aspartate shuttle (39,40). Glutamate accumulation into synaptic vesicles is driven by a H + electrochemical gradient produced by a vacuolar (H + )-ATPase, the energetic cost of which was estimated to be ∼0.33 ATP/glutamate (26).…”

Section: Discussionmentioning

confidence: 99%

Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle

Patel

Lai

Chowdhury

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

170

158

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Previous 13C magnetic resonance spectroscopy experiments have shown that over a wide range of neuronal activity, approximately one molecule of glucose is oxidized for every molecule of glutamate released by neurons and recycled through astrocytic glutamine. The measured kinetics were shown to agree with the stoichiometry of a hypothetical astrocyte-to-neuron lactate shuttle model, which predicted negligible functional neuronal uptake of glucose. To test this model, we measured the uptake and phosphorylation of glucose in nerve terminals isolated from rats infused with the glucose analog, 2-fluoro-2-deoxy-D-glucose (FDG) in vivo. The concentrations of phosphorylated FDG (FDG 6P ), normalized with respect to known neuronal metabolites, were compared in nerve terminals, homogenate, and cortex of anesthetized rats with and without bicuculline-induced seizures. The increase in FDG 6P in nerve terminals agreed well with the increase in cortical neuronal glucose oxidation measured previously under the same conditions in vivo, indicating that direct uptake and oxidation of glucose in nerve terminals is substantial under resting and activated conditions. These results suggest that neuronal glucose-derived pyruvate is the major oxidative fuel for activated neurons, not lactate-derived from astrocytes, contradicting predictions of the original astrocyte-to-neuron lactate shuttle model under the range of study conditions. neuroenergetics | glutamate−glutamine cycle | neuronal glucose phosphorylation | synaptoneurosomes | 2-fluorodeoxyglucose M etabolic and neurophysiological research has experimentally related brain energy consumption, in the form of glucose oxidation, to the brain work supporting neuronal firing. Carbon-13 magnetic resonance spectroscopy (MRS) measurements (1, 2) of the associated fluxes in cerebral cortex of anesthetized rats over a range of electrical activity revealed, surprisingly, a near 1:1 relationship (in molar equivalent units) between increments in the glutamate−glutamine neurotransmitter cycle and neuronal glucose oxidation. Subsequent studies of rat and human cerebral cortex have been consistent with this finding (3, 4). The near 1:1 flux relation was consistent with a cellular/ molecular model, originally proposed by Pellerin and Magistretti (5), and subsequently expanded to include the glutamate/glutamine cycle (1, 6). Evidence for the astrocyte-to-neuron lactate shuttle (ANLS) model is summarized in ref. 7. In this model (Fig. 1A), glutamate released from neurons is taken up by astrocytes and converted to glutamine using ATP derived from glycolysis. Lactate produced by this process is transferred to neurons where oxidation occurs. This ANLS model predicts a 1:1 relationship between increments in astrocytic glutamate uptake and glycolysis. Glycolytically derived ATP might provide for more rapid clearance of glutamate from the synaptic cleft into astrocyte processes devoid of mitochondria (8).The ANLS hypothesis has been challenged on biochemical, in vivo, in situ, and in vitro experimental a...

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Section: Discussionmentioning

confidence: 99%

Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle

Patel

Lai

Chowdhury

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

170

158

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“…The large contribution of ketone bodies to TCA cycle flux in neurons places testable limits on models of neuroenergetics which propose glucose metabolism as an integral part of the mechanism of glutamatergic/GABAergic neurotransmission. 8,26,38 …”

Section: Discussionmentioning

confidence: 99%

“…25,26,38 In the models involving obligatory coupling of glial glycolysis (and transfer of the lactate produced by glycolysis to the neurons), the predicted relationship between DV pdhN and DV cyc ranges from 1:1 to 2:1, depending on whether Gln synthesis also requires glycolytic ATP, or the extent to which glial glucose oxidation is altered by activity. 39 An alternative model of Glu neurotransmitter synthesis from astroglial Gln was described in Hertz et al, 38 and more recently by Lund et al, 26 which would produce a flux ratio of 1:1 between DV pdhN and DV cyc (i.e., 0.5:1 between neuronal glucose oxidation and glutamate cycling). In this model the synthesis of neurotransmitter Glu from Gln is indirect, with mitochondrial formation of a-KG from Gln (deamidation by glutaminase in the mitochondrial membrane, Glu entry into the mitochondrial matrix by exchange with Asp, and transamination to a-KG), efflux of a-KG to cytoplasm in exchange with malate, and transamination of a-KG back to Glu.…”

Section: Implications Of Ketone Body Oxidation For Models Of Neuroenementioning

confidence: 99%

The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

Chowdhury

Jiang

Rothman

et al. 2014

J Cereb Blood Flow Metab

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The capacity of ketone bodies to replace glucose in support of neuronal function is unresolved. Here, we determined the contributions of glucose and ketone bodies to neocortical oxidative metabolism over a large range of brain activity in rats fasted 36 hours and infused intravenously with [2,4-13 C 2 ]-D-b-hydroxybutyrate (BHB). Three animal groups and conditions were studied: awake ex vivo, pentobarbital-induced isoelectricity ex vivo, and halothane-anesthetized in vivo, the latter data reanalyzed from a recent study. Rates of neuronal acetyl-CoA oxidation from ketone bodies (V acCoA-kbN ) and pyruvate (V pdhN ), and the glutamateglutamine cycle (V cyc ) were determined by metabolic modeling of 13 C label trapped in major brain amino acid pools. V acCoA-kbN increased gradually with increasing activity, as compared with the steeper change in tricarboxylic acid (TCA) cycle rate (V tcaN ), supporting a decreasing percentage of neuronal ketone oxidation: B100% (isoelectricity), 56% (halothane anesthesia), 36% (awake) with the BHB plasma levels achieved in our experiments (6 to 13 mM). In awake animals ketone oxidation reached saturation for blood levels 417 mM, accounting for 62% of neuronal substrate oxidation, the remainder (38%) provided by glucose. We conclude that ketone bodies present at sufficient concentration to saturate metabolism provides full support of basal (housekeeping) energy needs and up to approximately half of the activity-dependent oxidative needs of neurons. Keywords: 13 C isotopes; glucose utilization; glutamate/glutamine cycle; ketone body utilization; neuroenergetics; nuclear magnetic resonance spectroscopy INTRODUCTIONThe adult mammalian brain shows a remarkably high utilization of glucose compared with other potential fuel substrates, such as lactate or ketone bodies. Brain consumption of alternate substrates is limited by transport from the blood, and factors which alter membrane transport alter the rate of consumption. Under fasting conditions, starvation, or diets high in fats, blood ketone body levels rise, increasing their cerebral rate of consumption. The extent to which ketone bodies can support the different aspects of brain function, once transport is no longer limiting, has not been clearly established. Ketone bodies are metabolized by neurons and astrocytes in vitro and in vivo, 1-3 and like glucose, neuronal (glutamatergic) oxidation dominates quantitatively in vivo, 3,4 reflecting the relatively larger volume fraction of neurons compared with glial cells. Despite extensive study to ascertain the role of ketone bodies in neural function, basic unanswered questions persist about their involvement, and that of glucose, in the energy requirements associated with neurotransmission.Previous studies from our laboratory using 13 C magnetic resonance spectroscopy (MRS) with [1-13 C]glucose reported a linear relationship between neuronal oxidation of glucose in the tricarboxylic acid (TCA) cycle and glutamate (Glu)-glutamine (Gln) cycling flux over a large range of brain activity, 5-7...

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“…Edema cerebral se ha observado tanto en sobredosis como en terapias crónicas mantenidas con dosis supraterapeúticas 80 . Se describe a las 48-72 horas de la ingestión 81 y su mecanismo de formación es controvertido, implicando a los metabolitos en la génesis del mismo 82 , la hiperamoniemia coincidente 80 o la estimulación de los receptores NMDA 83 .…”

Section: Intoxicación Agudaunclassified

Intoxicaciones medicamentosas (II): Analgésicos y anticonvulsivantes

Munné

Banuelos

Izura

et al. 2003

Anales Sis San Navarra

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RESUMENEn este segundo capítulo sobre Intoxicaciones Medicamentosas Agudas abordamos dos grupos de sustancias de enorme trascendencia desde el punto de vista de su uso y morbimortalidad. Dentro del grupo de los anagésicos-antiinflamatorios desarrollamos el paracetamol y los salicilatos, de enorme disponibilidad para la población. En cuanto a los anticonvulsivantes, aunque están poco implicados en el conjunto de las intoxicaciones medicamentosas agudas, sus efectos pueden ser graves. Nos ceñimos a cuatro fármacos: ácido valproico, fenobarbital, carbamacepina, y fenitoína. Finalmente dedicamos un apartado a la isoniacida, fármaco que, con el rebrote de la tuberculosis, presenta interés toxicológico.Palabras clave. Intoxicación aguda. Paracetamol. Anticonvulsivantes. Fenitoína. Isoniacida. ABSTRACTIn this second chapter on Acute Drugs Poisoning we deal with two groups of substances of great transcendence from the point of view of their use and morbidity/mortality. Within the group of analgesic-antiinflammatory drugs we consider paracetamol and the salicylates, which are easily available to the population. With respect to the anticonvulsants, although they are barely involved in the ensemble of acute drug poisonings, their effects can be serious. We concentrate on four drugs: valproic acid, phenobarbitol, carbamacepine, and phenytoin. Finally, a section is dedicated to isoniazid, a drug that, with the renewed incidence of tuberculosis, is of toxicological interest.

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Neuronal-astrocytic and cytosolic-mitochondrial metabolite trafficking during brain activation, hyperammonemia and energy deprivation

Cited by 103 publications

References 168 publications

Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle

Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle

The Contribution of Ketone Bodies to Basal and Activity-Dependent Neuronal Oxidation in Vivo

Intoxicaciones medicamentosas (II): Analgésicos y anticonvulsivantes

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