In vivo1H‐[13C]‐NMR spectroscopy of cerebral metabolism

Graaf, Robin A. de; Mason, Graeme F.; Patel, Anant B.; Behar, Kevin L.; Rothman, Douglas L.

doi:10.1002/nbm.847

Cited by 133 publications

(151 citation statements)

References 81 publications

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“…8,14,15 Models of brain metabolism used to estimate fluxes from 13 C time courses have dealt with this problem by either inclusion of a dilution flux (V dil(Gln) , V ex , or V dil ) at the level of glutamine 5,7,12,13,[16][17][18] or astroglial acetyl-CoA 6 derived from nonlabeled precursors. The presence of the glutamine-C4 dilution, and its incorporation into the metabolic model was recently shown to be critical for the accurate determination of the glutamate-glutamine cycle rate in NMR studies using [1][2][3][4][5][6][7][8][9][10][11][12][13] C]/ [1,6-13 C 2 ]glucose. 15 Thus, it is critical to better define the source of the astroglial glutamine dilution, allowing refinement of the metabolic models to estimate cerebral fluxes in 13 C-labeling studies, while exploring alternate 13 C-labeled substrates that might be exploited to study astrocytic and neuronal function in vivo.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Cerebral Glutamine Uptake from Blood in the Mouse Brain: Implications for Metabolic Modeling of¹³C NMR Data

Bagga

Behar

Mason

et al. 2014

J Cereb Blood Flow Metab

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13 C Nuclear Magnetic Resonance (NMR) studies of rodent and human brain using [1-13 C]/[1,6-13 C 2 ]glucose as labeled substrate have consistently found a lower enrichment (B25% to 30%) of glutamine-C4 compared with glutamate-C4 at isotopic steady state. The source of this isotope dilution has not been established experimentally but may potentially arise either from blood/brain exchange of glutamine or from metabolism of unlabeled substrates in astrocytes, where glutamine synthesis occurs. In this study, the contribution of the former was evaluated ex vivo using 1 H-[ 13 C]-NMR spectroscopy together with intravenous infusion of [U-13 C 5 ]glutamine for 3, 15, 30, and 60 minutes in mice. 13 C labeling of brain glutamine was found to be saturated at plasma glutamine levels 41.0 mmol/L. Fitting a blood-astrocyte-neuron metabolic model to the 13 C enrichment time courses of glutamate and glutamine yielded the value of glutamine influx, V Gln(in) , 0.036±0.002 mmol/g per minute for plasma glutamine of 1.8 mmol/L. For physiologic plasma glutamine level (B0.6 mmol/L), V Gln(in) would be B0.010 mmol/g per minute, which corresponds to B6% of the glutamine synthesis rate and rises to B11% for saturating blood glutamine concentrations. Thus, glutamine influx from blood contributes at most B20% to the dilution of astroglial glutamine-C4 consistently seen in metabolic studies using [1-13 C]glucose. Keywords: glutamate; neurotransmitter; nuclear magnetic resonance spectroscopy INTRODUCTION Glucose, the primary source of energy in the mature brain, is mainly oxidized in neurons to support neuronal firing, and the release and recycling of neurotransmitters, glutamate, and GABA, through the neuron-astrocyte glutamate-glutamine and GABAglutamine cycles. The metabolic pathways comprising these cycles have been revealed in vivo by 13 C Nuclear Magnetic Resonance (NMR) spectroscopy combined with infusions of 13 C-labeled substrates, 1,2 permitting detailed investigation of the metabolism of glucose and alternative substrates in the brain.A consistent finding in NMR studies of rodent and human brain metabolism using [1-13 C] or [1,6-13 C 2 ]glucose as precursor is the lower fractional 13 C enrichment of brain glutamate and glutamine at isotopic steady state compared with blood glucose, 3-5 revealing the presence of constant 'dilutional' flows of unlabeled substrates into the respective tricarboxylic acid (TCA) cycles of neurons and astroglia. For glutamate, this dilution amounts to 25% to 30% in rodents 5,6 (B14% in human brain 7 ) of the theoretical maximum expected from the 13 C-labeled glucose, and is thought to arise within neurons mainly from metabolism of blood-borne substrates such as lactate or ketone bodies and within the brain from glutamine produced in astrocytes through the glutamate-glutamine cycle. [8][9][10] In addition to the glutamate-C4 dilution (relative to glucose-C1), 13 C enrichment of glutamine-C4 is further B20% to 30% less than that of glutamate-C4 at isotopic steady state. 4,5,[11][12][13] As the majority of...

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Section: Introductionmentioning

confidence: 99%

Characterization of Cerebral Glutamine Uptake from Blood in the Mouse Brain: Implications for Metabolic Modeling of¹³C NMR Data

Bagga

Behar

Mason

et al. 2014

J Cereb Blood Flow Metab

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“…MRS has become a major tool in the non-invasive characterization of brain tumor metabolism in vivo and in vitro. A highly versatile technique, MRS allows measurements of the concentrations of many neurochemicals, including the kinetics of single enzyme-catalyzed reactions such as LDH (Xu et al, 2007) or creatine kinase (Smith et al, 1997), as well as the rates of entire metabolic pathways, such as the TCA cycle and the glutamate/glutamine neurotransmitter cycle (Sibson et al, 2001;de Graaf et al, 2003). MRS is commonly employed with several stable (non-radioactive) isotopes of biological importance such as 1 H, 13 C, 15 N, and 31 P, allowing investigation of many aspects of cellular metabolism.…”

Section: Metabolism Metabolic and Other Functional Roles Of Astrocytementioning

confidence: 99%

Glioblastoma: Current Chemotherapeutic Status and Need for New Targets and Approaches

Jain¹,

Lai²,

Chowdhury³

et al. 2011

Brain Tumors - Current and Emerging Therapeutic Strategies

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“…13 C NMR spectroscopy combined with metabolic modeling is a unique tool to measure tricarboxylic acid (TCA) cycle rate in vivo (1,2). The measurement relies on the intravenous infusion of a 13 C-enriched substrate, typically glucose labeled at C1 and/or C6, and on the detection by NMR spectroscopy of the progressive incorporation of 13 C at glutamate C3 and C4 positions.…”

mentioning

confidence: 99%

Simplified ¹³C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivo

Valette

Boumezbeur

Hantraye

et al. 2009

Magnetic Resonance in Med

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13 C NMR spectroscopy is a unique tool to measure the cerebral tricarboxylic acid (TCA) cycle rate in vivo. The measurement relies on metabolic modeling of glutamate C3 and C4 enrichment time courses during a 13 C-glucose intravenous infusion. Usual metabolic models require the plasma glucose and 13 Cglucose time courses as input functions, as well as the knowledge of Michaelis-Menten kinetics parameters governing passage through the blood-brain barrier. It is shown in the present work that, when using an infusion protocol yielding a rapidly stable plasma glucose fractional enrichment, metabolic modeling can be simplified in such a manner that this additional information on input function and glucose transport is no longer required, significantly simplifying the measurement of cerebral TCA cycle rate in vivo. 13 C NMR spectroscopy combined with metabolic modeling is a unique tool to measure tricarboxylic acid (TCA) cycle rate in vivo (1,2). The measurement relies on the intravenous infusion of a 13 C-enriched substrate, typically glucose labeled at C1 and/or C6, and on the detection by NMR spectroscopy of the progressive incorporation of 13 C at glutamate C3 and C4 positions. These measured enrichments are related to the TCA cycle flux (V TCA ) using a metabolic model, which is a set of differential equations describing the temporal evolution of 13 C enrichments, depending on the concentration and enrichment time courses of the infused substrates and on metabolic parameters such as fluxes and transport kinetics. In particular, the passage of glucose through the blood-brain barrier and the amount of 13 C-glucose available inside the brain are calculated based on (i) assumed values of the MichaelisMenten parameters; and (ii) the time courses of glucose concentration and fractional enrichment (FE), which impose blood sampling throughout the experiment followed by glucose concentration measurement and 13 C enrichment determination. However, the knowledge of Michaelis-Menten parameters is not straightforward since they might vary between species, tissues, and pathologic conditions, such as diabetes (3). In addition, the experimental burden associated with glycemia and 13 C-glucose plasma measurements, which generally require specific processing and acquisition on a high-resolution NMR or mass spectrometer, complicates significantly the already complex 13 C experiment, especially for small animals like mice due to their limited blood volume.In this context, the goal of the present work was to investigate whether the knowledge of experimental plasma glucose and 13 C-glucose time courses, and a parametered description of the blood-brain barrier transport using Michaelis-Menten kinetics, are actually required for the determination of V TCA by 13 C NMR spectroscopy. It is demonstrated that, under experimental conditions where an adequate infusion protocol yields a rapidly and reasonably stable plasma glucose FE, the FE of the brain pyruvate/lactate pool as simulated using metabolic modeling rapidly reaches a plateau and...

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In vivo¹H‐[¹³C]‐NMR spectroscopy of cerebral metabolism

Cited by 133 publications

References 81 publications

Characterization of Cerebral Glutamine Uptake from Blood in the Mouse Brain: Implications for Metabolic Modeling of¹³C NMR Data

Characterization of Cerebral Glutamine Uptake from Blood in the Mouse Brain: Implications for Metabolic Modeling of¹³C NMR Data

Glioblastoma: Current Chemotherapeutic Status and Need for New Targets and Approaches

Simplified ¹³C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivo

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In vivo1H‐[13C]‐NMR spectroscopy of cerebral metabolism

Cited by 133 publications

References 81 publications

Characterization of Cerebral Glutamine Uptake from Blood in the Mouse Brain: Implications for Metabolic Modeling of13C NMR Data

Characterization of Cerebral Glutamine Uptake from Blood in the Mouse Brain: Implications for Metabolic Modeling of13C NMR Data

Glioblastoma: Current Chemotherapeutic Status and Need for New Targets and Approaches

Simplified 13C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivo

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In vivo¹H‐[¹³C]‐NMR spectroscopy of cerebral metabolism

Characterization of Cerebral Glutamine Uptake from Blood in the Mouse Brain: Implications for Metabolic Modeling of¹³C NMR Data

Characterization of Cerebral Glutamine Uptake from Blood in the Mouse Brain: Implications for Metabolic Modeling of¹³C NMR Data

Simplified ¹³C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivo