High Extracellular K<sup>+</sup>Levels Stimulate Acetate Oxidation in Brain Slices from Well and Malnourished Rats

Schweigert, Ingrid Dalira; Roehrig, Cíntia; Costa, Fabiane da; Scheibel, Fernando; Gottfried, Carmen; Rotta, Liane Nanci; Gonçalves, Carlos Alberto; Souza, Diogo O.; Perry, Marcos L. S.

doi:10.1023/b:nere.0000029568.27684.0d

Cited by 4 publications

(3 citation statements)

References 26 publications

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“…We investigated the in vitro effect of these metabolites added separately or combined on glucose utilization, lactate generation, glucose and acetate oxidation, as well as on key enzyme activities involved in energy metabolism in brain of developing rats. The control values obtained in the various parameters analyzed in rat cerebral cortex were similar to those found by other investigators (Leighton et al, 1985;Toyomizu et al, 1999;Rasia-Filho et al, 2002;Sgaravatti et al, 2003;Reis de Assis et al, 2004;Schweigert et al, 2004;Rosa et al, 2005;Schuck et al, 2007a,b).…”

Section: Marquessupporting

confidence: 90%

Evidence for a synergistic action of glutaric and 3‐hydroxyglutaric acids disturbing rat brain energy metabolism

Ferreira

Tonin

Schuck

et al. 2007

Intl J of Devlp Neuroscience

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Glutaric acidemia type I is an inherited metabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric and 3-hydroxyglutaric acids in the brain tissue of the affected patients. Considering that a toxic role was recently postulated for quinolinic acid in the neuropathology of glutaric acidemia type I, in the present work we investigated whether the combination of quinolinic acid with glutaric or 3-hydroxyglutaric acids or the mixture of glutaric plus 3-hydroxyglutaric acids could alter brain energy metabolism. The parameters evaluated in cerebral cortex from young rats were glucose utilization, lactate formation and (14)CO(2) production from labeled glucose and acetate, as well as the activities of pyruvate dehydrogenase and creatine kinase. We first observed that glutaric (5 mM), 3-hydroxyglutaric (1 mM) and quinolinic acids (0.1 microM) per se did not alter these parameters. Similarly, no change of these parameters occurred when combining glutaric with quinolinic acids or 3-hydroxyglutaric with quinolinic acids. In contrast, co-incubation of glutaric plus 3-hydroxyglutaric acids increased glucose utilization, decreased (14)CO(2) generation from glucose, inhibited pyruvate dehydrogenase activity as well as total and mitochondrial creatine kinase activities. The glutaric plus 3-hydroxyglutaric acids-induced inhibitory effects on creatine kinase were prevented by the antioxidants glutathione and catalase plus superoxide dismutase, indicating the participation of reactive oxygen species. Our data indicate a synergic action of glutaric and 3-hydroxyglutaric acids disturbing energy metabolism in cerebral cortex of young rats.

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Section: Marquessupporting

confidence: 90%

Evidence for a synergistic action of glutaric and 3‐hydroxyglutaric acids disturbing rat brain energy metabolism

Ferreira

Tonin

Schuck

et al. 2007

Intl J of Devlp Neuroscience

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“…Acetate oxidation also increases after behavioural training (Dienel et al, 2003), in reactive cells responding to stab wound injury (Cetin et al, 2003), in gliotic brain tumours (Dienel et al, 2001b), in experimental epilepsy (Hosoi et al, 2010), and is altered after ischaemia (Hosoi et al, 2007) and by NMDA ( N -methyl- D -aspartate) receptor activity (Hirose et al, 2009). Elevated extracellular [K + ] enhances acetate oxidation in brain slices (Schweigert et al, 2004), suggesting that uptake of K + released during neuronal activity stimulates astrocytic respiration in adult brain. Thus, astrocytic energetics during excitatory neurotransmission is not described solely by glycolytic metabolism of blood-borne glucose, and the astrocyte-to-neuron lactate shuttle is incomplete because it does not include astrocytic oxidative or glycogenolytic metabolism during activation.…”

Section: Brain Activation In Normal Conscious Subjectsmentioning

confidence: 99%

Fueling and Imaging Brain Activation

2012

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Metabolic signals are used for imaging and spectroscopic studies of brain function and disease and to elucidate the cellular basis of neuroenergetics. The major fuel for activated neurons and the models for neuron–astrocyte interactions have been controversial because discordant results are obtained in different experimental systems, some of which do not correspond to adult brain. In rats, the infrastructure to support the high energetic demands of adult brain is acquired during postnatal development and matures after weaning. The brain's capacity to supply and metabolize glucose and oxygen exceeds demand over a wide range of rates, and the hyperaemic response to functional activation is rapid. Oxidative metabolism provides most ATP, but glycolysis is frequently preferentially up-regulated during activation. Underestimation of glucose utilization rates with labelled glucose arises from increased lactate production, lactate diffusion via transporters and astrocytic gap junctions, and lactate release to blood and perivascular drainage. Increased pentose shunt pathway flux also causes label loss from C1 of glucose. Glucose analogues are used to assay cellular activities, but interpretation of results is uncertain due to insufficient characterization of transport and phosphorylation kinetics. Brain activation in subjects with low blood-lactate levels causes a brain-to-blood lactate gradient, with rapid lactate release. In contrast, lactate flooding of brain during physical activity or infusion provides an opportunistic, supplemental fuel. Available evidence indicates that lactate shuttling coupled to its local oxidation during activation is a small fraction of glucose oxidation. Developmental, experimental, and physiological context is critical for interpretation of metabolic studies in terms of theoretical models.

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“…In contrast, oxidative decarboxylation of [U-14 C]glucose by cerebellar granule neurons is unaltered by doubling [K + ] e from 5 to 10 mmol/L, whereas it is greatly stimulated by further increases ( Figure 11A). Oxygen consumption by brain slices also increases with elevated [K + ] e when either glucose or pyruvate is the substrate, and this effect must involve astrocytic activation, because excess K + greatly increases oxidative decarboxylation of [ 14 C]acetate in brain slices (Gonda and Quastel, 1966;Schweigert et al, 2004). Bull and Cummins (1973) obtained evidence that elevated [K + ] e stimulates brain slice respiration by two different systems, one inhibited by omission of Ca 2 + , the other by ouabain.…”

Section: Fuel For Regulation Of Extracellular K + Concentration By Asmentioning

confidence: 99%

Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

Hertz

Peng

Dienel

2007

J Cereb Blood Flow Metab

526

573

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Astrocytic energy demand is stimulated by K + and glutamate uptake, signaling processes, responses to neurotransmitters, Ca 2 + fluxes, and filopodial motility. Astrocytes derive energy from glycolytic and oxidative pathways, but respiration, with its high-energy yield, provides most adenosine 5 0 triphosphate (ATP). The proportion of cortical oxidative metabolism attributed to astrocytes (B30%) in in vivo nuclear magnetic resonance (NMR) spectroscopic and autoradiographic studies corresponds to their volume fraction, indicating similar oxidation rates in astrocytes and neurons. Astrocyte-selective expression of pyruvate carboxylase (PC) enables synthesis of glutamate from glucose, accounting for two-thirds of astrocytic glucose degradation via combined pyruvate carboxylation and dehydrogenation. Together, glutamate synthesis and oxidation, including neurotransmitter turnover, generate almost as much energy as direct glucose oxidation. Glycolysis and glycogenolysis are essential for astrocytic responses to increasing energy demand because astrocytic filopodial and lamellipodial extensions, which account for 80% of their surface area, are too narrow to accommodate mitochondria; these processes depend on glycolysis, glycogenolysis, and probably diffusion of ATP and phosphocreatine formed via mitochondrial metabolism to satisfy their energy demands. High glycogen turnover in astrocytic processes may stimulate glucose demand and lactate production because less ATP is generated when glucose is metabolized via glycogen, thereby contributing to the decreased oxygen to glucose utilization ratio during brain activation. Generated lactate can spread from activated astrocytes via low-affinity monocarboxylate transporters and gap junctions, but its subsequent fate is unknown. Astrocytic metabolic compartmentation arises from their complex ultrastructure; astrocytes have high oxidative rates plus dependence on glycolysis and glycogenolysis, and their energetics is underestimated if based solely on glutamate cycling. Keywords: acetate; glucose metabolism; glutamate; neurotransmitters; potassium; pyruvate carboxylation Introduction Astrocytes are More Than HousekeepersRecent studies in many different fields have shown much more active roles of astrocytes in brain function than previously portrayed by their traditionally ascribed 'bystander or housekeeping' functions. Emerging roles of astrocytes include their interactions with the vasculature, neurons, and other astrocytes via signaling, biosynthetic, and transport processes to regulate blood flow, modulate impulse transmission, and synthesize and degrade glucose-derived neurotransmitters, for example, glutamate and g-aminobutyric acid (GABA) (Takano et al, 2006;Hertz and Zielke, 2004;Volterra and Meldolesi, 2005). All of these processes are energyrequiring or dependent on energy-related metabolic pathways, thereby directly linking astrocyte functions, energetics, and metabolite fluxes.The narrow astrocytic surface extensions (lamellae and filopodia, also called peripheral ast...

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High Extracellular K⁺Levels Stimulate Acetate Oxidation in Brain Slices from Well and Malnourished Rats

Cited by 4 publications

References 26 publications

Evidence for a synergistic action of glutaric and 3‐hydroxyglutaric acids disturbing rat brain energy metabolism

Evidence for a synergistic action of glutaric and 3‐hydroxyglutaric acids disturbing rat brain energy metabolism

Fueling and Imaging Brain Activation

Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

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High Extracellular K+Levels Stimulate Acetate Oxidation in Brain Slices from Well and Malnourished Rats

Cited by 4 publications

References 26 publications

Evidence for a synergistic action of glutaric and 3‐hydroxyglutaric acids disturbing rat brain energy metabolism

Evidence for a synergistic action of glutaric and 3‐hydroxyglutaric acids disturbing rat brain energy metabolism

Fueling and Imaging Brain Activation

Energy Metabolism in Astrocytes: High Rate of Oxidative Metabolism and Spatiotemporal Dependence on Glycolysis/Glycogenolysis

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High Extracellular K⁺Levels Stimulate Acetate Oxidation in Brain Slices from Well and Malnourished Rats