Energy Metabolism in Cortical Synaptic Terminals from Weanling and Mature Rat Brain: Evidence for Multiple Compartments of Tricarboxylic Acid Cycle Activity

McKenna, Mary C.; Tildón, J. Tyson; Stevenson, Joseph; Hopkins, Irene B.

doi:10.1159/000112122

Cited by 83 publications

(76 citation statements)

References 46 publications

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“…As the interest in alternative metabolic substrates for metabolic therapy grows, it becomes increasingly important to document both cerebral uptake and metabolism of these substrates under various cerebral pathological states. Previous studies utilizing in vivo models have only demonstrated substrate uptake (Hawkins et al 1971;Chen et al 2000); studies demonstrating both substrate uptake and oxidation have been limited to in vitro experiments (Brandt et al 1984;Yu et al 1984;LopesCardozo et al 1986;McKenna et al 1986McKenna et al , 1994Edmond et al 1987;Westergaard et al 1994;Waniewski and Martin 1998). The present study applied a modified in vivo approach to measure both cerebral uptake and metabolism of the alternative substrate bHB and demonstrate the value of such an approach in studying cerebral injury.…”

Section: Discussionmentioning

confidence: 65%

“…In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al 1986a), lactate (Brandt et al 1984;McKenna et al 1994), glutamine/glutamate (Yu et al 1984;McKenna et al 1994), citrate (Westergaard et al 1994), malate (McKenna et al 1994(McKenna et al , 1990, b-hydroxybutyrate (bHB) (Edmond et al 1987;McKenna et al 1994), acetoacetate (Lopes-Cardozo et al 1986;Waniewski and Martin 1998), as well as octanoate and palmitate (Edmond et al 1987). However, ketone bodies such as bHB are the only endogenously circulating alternative substrates that have been shown significantly to supplement cerebral metabolism (Owen et al 1967;Hawkins et al 1971;Dahlquist and Persson 1976).…”

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confidence: 99%

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Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Prins

Lee

Fujima

et al. 2004

Journal of Neurochemistry

100

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There is growing evidence of the brain's ability to increase its reliance on alternative metabolic substrates under conditions of energy stress such as starvation, hypoxia and ischemia. We hypothesized that following traumatic brain injury (TBI), which results in immediate changes in energy metabolism, the adult brain increases uptake and oxidation of the alternative substrate b-hydroxybutyrate (bHB). Arterio-venous differences were used to determine global cerebral uptake of bHB and production of 14 CO 2 from [ 14 C]3-bHB 3 h after controlled cortical impact (CCI) injury. Quantitative bioluminescence was used to assess regional changes in ATP concentration. As expected, adult sham and CCI animals with only endogenously available bHB showed no significant increase in cerebral uptake of bHB or 14 CO 2 production. Increasing arterial bHB concentrations 2.9-fold with 3 h of bHB infusion failed to increase cerebral uptake of bHB or 14 CO 2 production in adult sham animals. Only CCI animals that received a 3-h bHB infusion showed an 8.5-fold increase in cerebral uptake of bHB and greater than 10.7-fold increase in 14 CO 2 production relative to sham bHB-infused animals. The TBI-induced 20% decrease in ipsilateral cortical ATP concentration was alleviated by 3 h of bHB infusion beginning immediately after CCI injury. Keywords: alternative substrates, b-hydroxybutyrate, metabolism, traumatic brain injury. Although glucose remains the primary cerebral metabolic substrate under normal conditions, there are many physiological states during which the brain's reliance on glucose shifts to alternative substrates (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976;Kries and Ross 1992;Vannucci and Vannucci 2000). In vitro studies have documented uptake and oxidation of 14 C-labeled glycerol (McKenna et al. 1986a) (Edmond et al. 1987). However, ketone bodies such as bHB are the only endogenously circulating alternative substrates that have been shown significantly to supplement cerebral metabolism (Owen et al. 1967;Hawkins et al. 1971;Dahlquist and Persson 1976). In normally fed adult mammals bHB metabolism comprises less than 3% of total cerebral metabolism and bHB is present in low circulating concentrations (0.1 mM) with negligible uptake into the brain (Hawkins et al. 1971). However, upon increasing bHB arterial concentrations by starvation for 2 days or more, cerebral uptake is significantly enhanced (Hawkins et al. 1971). Increased cerebral uptake of bHB has also been shown during development (Hawkins et al. 1971;Dahlquist and Persson 1976), following starvation (Owen et al. 1967) and in diabetes (Kries and Ross 1992). The brain's ability to increase its reliance on bHB appears to be a common form of cerebral metabolic adaptation under conditions of insufficient glucose availability and developmental increases in cerebral energy demand.The evidence for the use of bHB by the brain under conditions of cerebral metabolic stress suggests a role for this alternative substrate in cerebral metabolism after ...

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Section: Discussionmentioning

confidence: 65%

mentioning

confidence: 99%

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Prins

Lee

Fujima

et al. 2004

Journal of Neurochemistry

100

View full text Add to dashboard Cite

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“…Regarding the energy substrates that might be concerned, lactate has attracted much attention recently. Lactate has been shown to be a preferential oxidative substrate for neurons both in vitro (McKenna et al, 1993(McKenna et al, , 1994 and in vivo (Hyder et al, 2006;Serres et al, 2005 Figure 7 Putative signaling pathways leading to translational activation and enhanced MCT2 protein synthesis after BDNF treatment in cultured cortical neurons. BDNF and TrkB can activate distinct signal transduction pathways involving specific kinases leading to translation initiation.…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor Enhances the Expression of the Monocarboxylate Transporter 2 through Translational Activation in Mouse Cultured Cortical Neurons

Robinet

Pellerin

2009

J Cereb Blood Flow Metab

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MCT2 is the predominant neuronal monocarboxylate transporter allowing lactate use as an alternative energy substrate. It is suggested that MCT2 is upregulated to meet enhanced energy demands after modifications in synaptic transmission. Brain-derived neurotrophic factor (BDNF), a promoter of synaptic plasticity, significantly increased MCT2 protein expression in cultured cortical neurons (as shown by immunocytochemistry and western blot) through a translational regulation at the synaptic level. Brain-derived neurotrophic factor can cause translational activation through different signaling pathways. Western blot analyses showed that p44/p42 mitogen-activated protein kinase (MAPK), Akt, and S6 were strongly phosphorylated on BDNF treatment. To determine by which signal transduction pathway(s) BDNF mediates its upregulation of MCT2 protein expression, the effect of specific inhibitors for p38 MAPK, phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK), p44/p42 MAPK (ERK), and Janus kinase 2 (JAK2) was evaluated. It could be observed that the BDNF-induced increase in MCT2 protein expression was almost completely blocked by all inhibitors, except for JAK2. These data indicate that BDNF induces an increase in neuronal MCT2 protein expression by a mechanism involving a concomitant stimulation of PI3K/Akt/mTOR/S6, p38 MAPK, and p44/p42 MAPK. Moreover, our observations suggest that changes in MCT2 expression could participate in the process of synaptic plasticity induced by BDNF.

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“…[1,2-C]glucose and [1-C]glucose probe predominately neuronal metabolism whereas [1,2-C]acetate probes primarily astrocytic metabolism [5]. Our aims were to analyse: (1) if the utilisation, cycling and incorporation of [ C]glucose would be lower; (2) if the relative proportion of [ C]glucose metabolised via the pentose phosphate and pyruvate carboxylation pathways would be larger; (3) the different transfers of substrate between the cellular compartments in the neonatal versus the adult brain.…”

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confidence: 99%

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

et al. 2013

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Glucose and acetate metabolism and the synthesis of amino acid neurotransmitters, anaplerosis, glutamate-glutamine cycling and the pentose phosphate pathway (PPP) have been extensively investigated in the adult, but not the neonatal rat brain. To do this, 7 day postnatal (P7) rats were injected with [1-C]glucose and [1,2-C]acetate and sacrificed 5, 10, 15, 30 and 45 min later. Adult rats were injected and sacrificed after 15 min. To analyse pyruvate carboxylation and PPP activity during development, P7 rats received [1,2-C]glucose and were sacrificed 30 min later. Brain extracts were analysed using Hand C-NMR spectroscopy. The neonatal brain contained lower levels of glutamate, aspartate and N-acetylaspartate but similar levels of GABA and glutamine compared to adults. Metabolism of [1-C]glucose at the acetyl CoA stage was reduced much more than that of [1,2-C]acetate. The transfer of glutamate from neurons to astrocytes was greatly reduced while transfer of glutamine from astrocytes to glutamatergic neurons was relatively higher compared to adults. However, transport of glutamine from astrocytes to GABAergic neurons was lower. Using [1,2-C]glucose it could be shown that despite much lower pyruvate carboxylation, relatively more pyruvate from glycolysis was directed towards anaplerosis than pyruvate dehydrogenation in astrocytes compared to reports from the adult brain. Moreover, the ratio of PPP/glucose metabolism was higher in P7 compared to adult brain. Our findings indicate that only the part of the glutamateglutamine cycle that transfers glutamine from astrocytes to neurons is operating in the After uptake into the cell, glucose (via pyruvate from glycolysis) and acetate can be converted to the TCA cycle substrate acetyl CoA. It has been reported that glucose oxidation is lower and that the average time the metabolites stay in the TCA cycle before conversion to substances such as neurotransmitters glutamate and thereafter γ-amino butyric acid (GABA) is longer in the neonatal compared to the adult brain [7]. This is in part attributed to the low levels of enzymes for pyruvate metabolism and oxidative glucose metabolism in the postnatal period [8].Pyruvate carboxylase, the brain's exclusive anaplerotic enzyme [9], is present in astrocytes only [10], and is of major importance for glial metabolic support of neurotransmission. Pyruvate carboxylase content is low in the neonatal period and increases 15-fold up to young adult age (postnatal day 30-40) when the level reaches a plateau [8].Most of the glutamate in the brain is found in neurons and is released into the synapse after depolarisation [11]. The ability of astrocytes to take up glutamate from the synapse and convert it into glutamine by the astrocyte specific enzyme glutamine synthetase [12] is vital for normal metabolic homeostasis and as a defence mechanism against excitotoxicity [13]. The subsequent transfer of glutamine from astrocytes to neurons for deamidation to glutamate closes the glutamate-

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Energy Metabolism in Cortical Synaptic Terminals from Weanling and Mature Rat Brain: Evidence for Multiple Compartments of Tricarboxylic Acid Cycle Activity

Cited by 83 publications

References 46 publications

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats

Brain-Derived Neurotrophic Factor Enhances the Expression of the Monocarboxylate Transporter 2 through Translational Activation in Mouse Cultured Cortical Neurons

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

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