Acetate and fluoroacetate as possible markers for glial metabolism in vivo

Muir, David; Berl, S.; Clarke, Donald D.

doi:10.1016/0006-8993(86)90231-3

Cited by 135 publications

(127 citation statements)

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“…Therefore, NAA can supply both acetate and oxaloacetate to the TCA cycle for energy production (Nadler and Cooper, 1972a), at least in oligodendrocytes where ASPA is present. Glial cells preferentially utilize acetate for energy production through the TCA cycle, as opposed to neurons (Bluml et al, 2002;Hassel et al, 1995;Muir et al, 1986) suggesting that oligodendrocytes could make substantial use of NAA-derived acetate for energy production when myelination is complete. It has also been proposed that NAA could act as a reservoir of glutamate in the brain, wherein NAA is converted to aspartate in oligodendrocytes, which could then be converted to glutamate through the TCA cycle with favorable energetics (Clark et al, 2006).…”

Section: Fate Of Naa In Oligodendrocytes After Postnatal Myelinationmentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,179

1,087

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Section: Fate Of Naa In Oligodendrocytes After Postnatal Myelinationmentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,179

1,087

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“…Acetate serves as a 'reporter molecule' for astrocytic oxidative metabolism due to its cell-type specificity, as shown in a histochemical study by Muir et al (1986); acetate-derived label was highly localized in astrocytes compared with neurons in cerebellar cortex, cerebral cortex, and retinal Figure 7 Metabolism and energetics of glutamate and glutamine oxidation in astrocytes. Astrocytic glutamate can be converted to aketoglutarate, metabolized in the TCA cycle to malate, which exits the TCA cycle to the cytoplasm, and decarboxylated by cytosolic malic enzyme to pyruvate, which subsequently can be converted to acetyl CoA, catalyzed by PDH, and metabolized in the TCA cycle.…”

Section: Determination Of Oxidative Activity In Astrocytes Via Three mentioning

confidence: 99%

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

Hertz

Peng

Dienel

2006

J Cereb Blood Flow Metab

511

568

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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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“…4 Radioligands of the 18-kDa translocator protein, particularly [ 11 C]PK11195, have been used extensively for imaging upregulated expression of translocator protein in glia during neuroinflammation. 5,6 However, it does not directly measure glial metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…4,7 Mouse astrocytes express both MCT1 and MCT4 isoforms, the latter of which is thought to be primarily involved in efflux of lactate, and a subpopulation of rat astrocytes also express MCT2. 8 Activated microglia in rats have been shown to upregulate MCT1 and MCT2 expression after ischemia.…”

Section: Introductionmentioning

confidence: 99%

“…9 Radiotracers of glial acetate metabolism have been used in the past, primarily for autoradiography of naïve rodent brain, and include [ 3 H] and [ 11 C] labeled acetate. 4,10 [ 14 C]acetate has been used in vitro in astrocyte cultures to measure uptake, 11 and has also been used for autoradiography in a rat model of short-term middle cerebral artery occlusion (MCAo)-a reduction in uptake was attributed to transient depression of glial metabolism in the model. 12 Similar studies have also examined the incorporation of radiolabeled carbon from [ 14 C]acetate into metabolites to examine changes in astrocyte metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of 2-[¹⁸F]fluoroacetate Kinetics in Rodent Models of Cerebral Hypoxia–Ischemia

Ouyang

Tinianow²,

Cherry

et al. 2014

J Cereb Blood Flow Metab

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Glia account for 90% of human brain cells and have a significant role in brain homeostasis. Thus, specific in vivo imaging markers of glial metabolism are potentially valuable. In the brain, 2-fluoroacetate is selectively taken up by glial cells and becomes metabolically trapped in the tricarboxylic acid cycle. Recent work in rodent brain injury models demonstrated elevated lesion uptake of 2-[ 18 F]fluoroacetate ([ 18 F]FACE), suggesting possible use for specifically imaging glial metabolism. To assess this hypothesis, we evaluated [ 18 F]FACE kinetics in rodent models of cerebral hypoxia-ischemia at 3 and 24 hours post insult. Lesion uptake was significantly higher at 30 minutes post injection (Po0.05). An image-based method for input function estimation using cardiac blood was validated. Analysis of whole blood showed no significant metabolites and plasma activity concentrations of B50% that of whole blood. Kinetic models describing [ 18 F]FACE uptake were developed and quantitatively compared. Elevated [ 18 F]FACE uptake was found to be driven primarily by K 1 /k 2 rather than k 3 , but changes in the latter were detectable. The two-tissue irreversible uptake model (2T3k) was found to be necessary and sufficient for modeling [ 18 F]FACE uptake. We conclude that kinetic modeling of [ 18 F]FACE uptake represents a potentially useful tool for interrogation of glial metabolism.

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Acetate and fluoroacetate as possible markers for glial metabolism in vivo

Cited by 135 publications

References 6 publications

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

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

Evaluation of 2-[¹⁸F]fluoroacetate Kinetics in Rodent Models of Cerebral Hypoxia–Ischemia

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Acetate and fluoroacetate as possible markers for glial metabolism in vivo

Cited by 135 publications

References 6 publications

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

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

Evaluation of 2-[18F]fluoroacetate Kinetics in Rodent Models of Cerebral Hypoxia–Ischemia

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Evaluation of 2-[¹⁸F]fluoroacetate Kinetics in Rodent Models of Cerebral Hypoxia–Ischemia