bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival
Authors: Niizuma Kuniyasu , Endo Hidenori , Chan Pak H. 
Published: April 2009

AbstractMitochondria are the powerhouse of the cell. Their primary physiological function is to generate adenosine triphosphate through oxidative phosphorylation via the electron transport chain. Reactive oxygen species generated from mitochondria have been implicated in acute brain injuries such as stroke and neurodegeneration. Recent studies have shown that mitochondrially‐formed oxidants are mediators of molecular signaling, which is implicated in the mitochondria‐dependent apoptotic pathway that involves pro‐ and antiapoptotic protein binding, the release of cytochrome c, and transcription‐independent p53 signaling, leading to neuronal death. Oxidative stress and the redox state of ischemic neurons are also implicated in the signaling pathway that involves phosphatidylinositol 3‐kinase/Akt and downstream signaling, which lead to neuronal survival. Genetically modified mice or rats that over‐express or are deficient in superoxide dismutase have provided strong evidence in support of the role of mitochondrial dysfunction and oxidative stress as determinants of neuronal death/survival after stroke and neurodegeneration.
Functional significance of brain glycogen in sustaining glutamatergic neurotransmission
Authors: Sickmann Helle M. , Walls Anne B. , Schousboe Arne , Bouman Stephan D. , Waagepetersen Helle S. 
Published: April 2009

AbstractThe involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present unclear. The significance of glycogen in fueling glutamate uptake into astrocytes was specifically addressed in cultured astrocytes. Moreover, the objective was to elucidate whether glycogen derived energy is important for maintaining glutamatergic neurotransmission, induced by repetitive exposure to NMDA in co‐cultures of cerebellar neurons and astrocytes. In the astrocytes it was shown that uptake of the glutamate analogue d‐[3H]aspartate was impaired when glycogen degradation was inhibited irrespective of the presence of glucose, signifying that energy derived from glycogen degradation is important for the astrocytic compartment. By inhibiting glycogen degradation in co‐cultures it was evident that glycogen provides energy to sustain glutamatergic neurotransmission, i.e. release and uptake of glutamate. The relocation of glycogen derived lactate to the neuronal compartment was investigated by employing d‐lactate, a competitive substrate for the monocarboxylate transporters. Neurotransmitter release was affected by the presence of d‐lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment.
AMPK in the brain: its roles in energy balance and neuroprotection
Authors: Ronnett Gabriele V. , Ramamurthy Santosh , Kleman Amy M. , Landree Leslie E. , Aja Susan 
Published: April 2009

AbstractAdenosine monophosphate‐activated protein kinase (AMPK) senses metabolic stress and integrates diverse physiological signals to restore energy balance. Multiple functions are indicated for AMPK in the CNS. While all neurons sense their own energy status, some integrate neuro‐humoral signals to assess organismal energy balance. A variety of disease states may involve AMPK, so determining the underlying mechanisms is important. We review the impact of altered AMPK activity under physiological (hunger, satiety) and pathophysiological (stroke) conditions, as well as therapeutic manipulations of AMPK that may improve energy balance.
The rate‐limiting step for glucose transport into the hypothalamus is across the blood–hypothalamus interface
Authors: Poitry‐Yamate Carol , Lei HongXia , Gruetter Rolf 
Published: April 2009

AbstractSpecialized glucosensing neurons are present in the hypothalamus, some of which neighbor the median eminence, where the blood–brain barrier has been reported leaky. A leaky blood–brain barrier implies high tissue glucose levels and obviates a role for endothelial glucose transporters in the control of hypothalamic glucose concentration, important in understanding the mechanisms of glucose sensing We therefore addressed the question of blood–brain barrier integrity at the hypothalamus for glucose transport by examining the brain tissue‐to‐plasma glucose ratio in the hypothalamus relative to other brain regions. We also examined glycogenolysis in hypothalamus because its occurrence is unlikely in the potential absence of a hypothalamus–blood interface. Across all regions the concentration of glucose was comparable at a given plasma glucose concentration and was a near linear function of plasma glucose. At steady‐state, hypothalamic glucose concentration was similar to the extracellular hypothalamic glucose concentration reported by others. Hypothalamic glycogen fell at a rate of ∼1.5 μmol/g/h and remained present in substantial amounts. We conclude for the hypothalamus, a putative primary site of brain glucose sensing that: the rate‐limiting step for glucose transport into brain cells is at the blood–hypothalamus interface, and that glycogenolysis is consistent with a substantial blood ‐to‐ intracellular glucose concentration gradient.
Redox dependence and compartmentation of [13C]pyruvate in the brain of deuterated rats bearing implanted C6 gliomas
Authors: Rodrigues Tiago B. , López‐Larrubia Pilar , Cerdán Sebastián 
Published: April 2009

AbstractWe investigated the redox dependence and compartmentation of the pyruvate pool in the brain of partially deuterated rats bearing C6 gliomas. Adult male Wistar rats implanted with C6 cells drunk 2H2O (50% v/v) or tap water for 9 days before they were infused with solutions containing [1‐13C]glucose and [2‐13C]pyruvate or [U‐13C3]lactate. Their brains were fixed with high‐power focused microwaves and biopsies prepared from the contralateral, ipsilateral, and tumor regions. 13C NMR analysis of the extracts allowed the determination of the relative amounts of [13C]lactate isotopomers derived from infused glucose or monocarboxylates. The relative amounts of [3‐13C]lactate derived from glucose to the [2‐13C] or [U‐13C3]lactate isotopomers derived from monocarboxylates decreased in the order contralateral > ipsilateral > tumor regions, revealing a progressive reduction in glycolysis for regions containing increasing endogenous lactate concentrations. Cortical astrocytes depicted similar reductions in glycolysis when incubated with [1,2‐13C2]glucose and increasing concentrations of [3‐13C]lactate. Deuterated animals bearing C6 tumors, infused with [1‐13C]glucose and [2‐13C]pyruvate, showed different deuterium enrichments in the methyl groups of cerebral [3‐13C] and [2‐13C]lactate, revealing a slow mixing of the [3‐13C] and [2‐13C]pyruvate precursors in the 2H exchange timescale of their methyl groups. Together, these evidences reveal the role of the redox state of the pyruvate pool derived from monocarboxylates in the modulation of cerebral glycolytic flux in vivo and in vitro.
Mitochondrial glutathione uptake: characterization in isolated brain mitochondria and astrocytes in culture
Authors: Wadey Alison L. , Muyderman Hakan , Kwek Perrin T. , Sims Neil R. 
Published: April 2009

AbstractGlutathione in the mitochondria is an important determinant of cellular responses to oxidative stress. Mitochondrial glutathione is maintained by uptake from the cytosol, a process that has been little studied in brain cells. In the present study, measurements using isolated rat brain mitochondria showed a rapid uptake of [3H]‐glutathione that was strongly influenced by the mitochondrial glutathione content. [3H]‐glutathione incorporated into the mitochondria was not rapidly released. Uptake was inhibited by substrates and inhibitors for several known mitochondrial anion transporters. Citrate, isocitrate and benzene‐1,2,3‐tricarboxylate were particularly effective inhibitors, suggesting a possible role for a tricarboxylate carrier in the glutathione transport. The properties of uptake differed greatly from those reported previously for mitochondria from kidney and liver. In astrocytes in primary culture, diethylmaleate or hydrogen peroxide treatment resulted in depletion of cytosolic and mitochondrial glutathione. The pattern of restoration of glutathione content in the presence of glutathione precursors following treatment with diethylmaleate was consistent with uptake into mitochondria being controlled primarily by the glutathione gradient between the cytosol and mitochondria. However, following hydrogen peroxide treatment, recovery of glutathione in the mitochondria initially preceded comparable proportional restoration in the cytosol, suggesting the possibility of additional controls on glutathione uptake in some conditions.
The ketogenic diet has no effect on the expression of spike‐and‐wave discharges and nutrient transporters in genetic absence epilepsy rats from Strasbourg
Authors: Nehlig Astrid , Dufour Franck , Klinger Marianne , Willing Lisa B. , Simpson Ian A. , Vannucci Susan J. 
Published: April 2009

AbstractThe genetic absence epilepsy rat from Strasbourg is considered an isomorphic, predictive, and homologous model of typical childhood absence epilepsy. It is characterized by the expression of spike‐and‐wave discharges (SWDs) in the thalamus and cortex. The ketogenic diet (KD) is successfully used in humans and animals with various types of seizures, but was not effective in children with intractable atypical absence epilepsy. Here, we studied its potential impact on the occurrence of SWDs in genetic absence epilepsy rat from Strasbourg. Rats were fed the KD for 3 weeks during which they were regularly subjected to the electroencephalographic recording of SWDs. The KD did not influence the number and duration of SWDs despite a 15–22% decrease in plasma glucose levels and a large increase in β‐hydroxybutyrate levels. Likewise, the KD did not affect the level of expression of the blood–brain barrier glucose transporter GLUT1 or of the monocarboxylate transporters, MCT1 and MCT2. This report extends the observation in humans that the KD does not appear to show effectiveness in intractable atypical absence epilepsy to this model of typical childhood absence epilepsy which responds to specific antiepileptic drugs.
What learning in day‐old chickens can teach a neurochemist: focus on astrocyte metabolism
Authors: Hertz Leif , Gibbs Marie E. 
Published: April 2009

AbstractThe learning process sets in motion a prolonged, reproducible, and complicated pattern of brain activation, which provides information about biochemical reactions in activated brain. Study of this pattern during one‐trial aversive bead discrimination in day‐old chick is facilitated by precise timing of sequential metabolic events occurring between a 10‐s learning period, in which the chicks learn to associate a red bead with aversive taste, and memory consolidation, indicated by unwillingness to peck at untainted red beads while freely pecking at corresponding blue beads. Inhibition of learning by metabolic inhibitors and restoration of memory by specific substrates at specific times allow determination of specific metabolic events and their neuronal or astrocytic localization. Downstream metabolism of glycogen and of glucose to pyruvate/lactate is segregated into separate pools. Glucose metabolism via pyruvate dehydrogenation provides energy in both neurons and astrocytes and may include gap junction‐mediated lactate transport into astrocytes. A key role is played by glycogenolysis, stimulated by β2‐adrenergic and/or 5‐HT2‐receptor stimulation along with α2‐adrenergic stimulation of glycogen synthesis. The importance of glycogen reflects that it selectively supports de novo synthesis of transmitter glutamate by combined pyruvate dehydrogenation and carboxylation in astrocytes.
Neuronal glucose but not lactate utilization is positively correlated with NMDA‐induced neurotransmission and fluctuations in cytosolic Ca2+levels
Authors: Bak Lasse K. , Walls Anne B. , Schousboe Arne , Ring Avi , Sonnewald Ursula , Waagepetersen Helle S. 
Published: April 2009

AbstractAlthough the brain utilizes glucose for energy production, individual brain cells may to some extent utilize substrates derived from glucose. Thus, it has been suggested that neurons consume extracellular lactate during synaptic activity. However, the precise role of lactate for fuelling neuronal activity is still poorly understood. Recently, we demonstrated that glucose metabolism is up‐regulated in cultured glutamatergic neurons during neurotransmission whereas that of lactate is not. Here, we show that utilization of glucose but not lactate correlates with NMDA‐induced neurotransmitter glutamate release in cultured cerebellar neurons from mice. Pulses of NMDA at 30, 100, and 300 μM, leading to a progressive increase in both cytosolic [Ca2+] and release of glutamate, increased uptake and metabolism of glucose but not that of lactate as evidenced by mass spectrometric measurement of13C incorporation into intracellular glutamate. In this manuscript, a cascade of events for the preferential neuronal utilization of glucose during neurotransmission is suggested and discussed in relation to our current understanding of neuronal energy metabolism.
Mild reduction in the activity of the α‐ketoglutarate dehydrogenase complex elevates GABA shunt and glycolysis
Authors: Shi Qingli , Risa Øystein , Sonnewald Ursula , Gibson Gary E. 
Published: April 2009

AbstractDiminished energy metabolism and reduced activity of brain α‐ketoglutarate dehydrogenase complex (KGDHC) occur in a number of neurodegenerative diseases. The relation between diminished KGDHC activity and altered energy metabolism is unknown. The present study tested whether a reduction in the KGDHC activity would alter cellular metabolism by comparing metabolism of [U‐13C]glucose in a human embryonic kidney cell line (E2k100) to one in which the KGDHC activity was about 70% of control (E2k67). After a 2 h incubation of the cells with [U‐13C]glucose, the E2k67 cells showed a greater increase in 13C labeling of alanine compared with the E2k100 cells. This suggested an increase in glycolysis. Furthermore, an increase in labeled lactate after 12 h incubation supported the suggestion of an increased glycolysis in the E2k67 cells. Increased GABA shunt in the E2k67 cells was indicated by increased 13C labeling of GABA at both 2 and 12 h compared with the control cells. GABA concentration as determined by HPLC was also increased in the E2k67 cells compared with the control cells. However, the GABA shunt was not sufficient to normalize metabolism in the E2k67 cells compared with control at 2 or 12 h. However, by 24 h metabolism had normalized (i.e. labeling was similar in E2k67 and E2k100). Thus, the data are consistent with an enhanced glycolysis and GABA shunt in response to a mild reduction in KGDHC. Our findings indicate that a mild change in KGDHC activity can lead to large changes in metabolism. The changes may maintain normal energy metabolism but make the cells more vulnerable to perturbations such as occur with oxidants.
Synaptic and extrasynaptic GABA transporters as targets for anti‐epileptic drugs
Authors: Madsen Karsten K. , Clausen Rasmus P. , Larsson Orla M. , Krogsgaard‐Larsen Povl , Schousboe Arne , Steve White H. 
Published: April 2009

AbstractInhibition of the GABA transporter subtype GAT1 by the clinically available anti‐epileptic drug tiagabine has proven to be an effective strategy for the treatment of some patients with partial seizures. In 2005, the investigational drug EF1502 was described as possessing activity at both GAT1 and BGT‐1. When combined with the GAT1 selective inhibitor tiagabine, EF1502 was found to possess a synergistic anti‐convulsant action in the Frings audiogenic seizure‐susceptible mouse model of reflex epilepsy. This effect was subsequently attributed to inhibition of BGT‐1. In this study, the anti‐convulsant effect of the GAT2/3 inhibitor SNAP‐5114 was assessed in the Frings audiogenic seizure‐susceptible mouse alone, and in combination with tiagabine and EF1502. The results showed that SNAP‐5114 produced a synergistic anti‐convulsant effect in combination with EF1502 but not when used in combination with tiagabine. These findings support anatomical evidence that GAT2/3 are most likely located at the synapse in close proximity to GAT1; whereas BGT‐1 is located some distance away from the synapse and GAT1 and GAT2/3. Lastly, EF1502 and tiagabine were evaluated alone, and in combination, in the corneal kindled mouse model of partial epilepsy. The results of this evaluation provide further evidence in support of a role for BGT‐1 in the control of seizure activity. In addition, they suggest that the combined inhibition of GAT1 and BGT‐1 may afford some advantage over inhibiting either transporter alone.
Altered fatty acid metabolism and composition in cultured astrocytes under hyperammonemic conditions
Authors: Gottschalk Sven , Zwingmann Claudia 
Published: April 2009

Abstract In vitro
1H‐ and 13C‐NMR spectroscopy was used to investigate the effect of ammonia on fatty acid synthesis and composition in cultured astrocytes. Cells were incubated 3 and 24 h with 5 mM ammonia in the presence or absence of the glutamine synthetase inhibitor methionine sulfoximine. An increase of de novo synthesized fatty acids and the glycerol subunit of lipids was observed after 3 h treatment with ammonia (35% and 40% over control, respectively), the initial time point examined. Both parameters further increased significantly to 85% and 60% over control after 24 h ammonia treatment. Three hours incubation with ammonia increased the synthesis of diacylglycerides, while formation of triacylglycerides was decreased (40% over and 15% under control, respectively). The degradation of fatty acids was not affected by ammonia treatment. Furthermore, ammonia caused alterations in the composition of fatty acids, e.g. increased mono‐ and decreased polyunsaturated fatty acids (85% over and 15% under control concentrations, respectively). The decrease of polyunsaturated fatty acids was even more pronounced in isolated astrocytic mitochondria (39% lower than controls). Our results suggest ammonia‐induced abnormalities in astrocytic membranes, which may be related to astrocytic mitochondrial dysfunction in hyperammonemic states. Most of the observed effects of ammonia on fatty acid synthesis and composition were ameliorated when glutamine synthetase was inhibited by methionine sulfoximine, supporting a pathological role of glutamine in ammonia toxicity. This study further emphasizes the importance of investigating the relative contribution of exogenous ammonia, effects of glutamine and of glutamine‐derived ammonia on astrocytes and astrocytic mitochondria.
The in vivo neuron‐to‐astrocyte lactate shuttle in human brain: evidence from modeling of measured lactate levels during visual stimulation
Authors: Mangia Silvia , Simpson Ian A. , Vannucci Susan J. , Carruthers Anthony 
Published: April 2009

AbstractFunctional magnetic resonance spectroscopy (fMRS) allows the non‐invasive measurement of metabolite concentrations in the human brain, including changes induced by variations in neurotransmission activity. However, the limited spatial and temporal resolution of fMRS does not allow specific measurements of metabolites in different cell types. Thus, the analysis of fMRS data in the context of compartmentalized metabolism requires the formulation and application of mathematical models. In the present study we utilized the mathematical model introduced by Simpson et al. (2007) to gain insights into compartmentalized metabolism in vivo from the fMRS data obtained in humans at ultra high magnetic field by Mangia et al. (2007a). This model simulates brain glucose and lactate levels in a theoretical cortical slice. Using experimentally determined concentrations and catalytic activities for the respective transporter proteins, we calculate inflow and export of glucose and lactate in endothelium, astrocytes, and neurons. We then vary neuronal and astrocytic glucose and lactate utilization capacities until close correspondence is observed between in vivo and simulated glucose and lactate levels. The results of the simulations indicate that, when literature values of glucose transport capacity are utilized, the fMRS data are consistent with export of lactate by neurons and import of lactate by astrocytes, a mechanism that can be referred to as a neuron‐to‐astrocyte lactate shuttle. A shuttle of lactate from astrocytes to neurons could be simulated, but this required the astrocytic glucose transport capacity to be increased by 12‐fold, and required that neurons not respond to activation with increased glycolysis, two conditions that are not supported by current literature.
Ciliary neurotrophic factor fused to a protein transduction domain retains full neuroprotective activity in the absence of cytokine‐like side effects
Authors: Rezende Alexandre C. , Peroni Daniele , Vieira Andrè S. , Rogerio Fabio , Talaisys Rafael L. , Costa Fabio T. M. , Langone Francesco , Skaper Stephen D. , Negro Alessandro 
Published: April 2009

AbstractCiliary neurotrophic factor (CNTF) is a multifunctional cytokine that can regulate the survival and differentiation of many types of developing and adult neurons. CNTF prevents the degeneration of motor neurons after axotomy and in mouse mutant progressive motor neuronopathy, which has encouraged trials of CNTF for human motor neuron disease. Given systemically, however, CNTF causes severe side effects, including cachexia and a marked immune response, which has limited its clinical application. The present work describes a novel approach for administering recombinant human CNTF (rhCNTF) while conserving neurotrophic activity and avoiding deleterious side effects. rhCNTF was fused to a protein transduction domain derived from the human immunodeficiency virus‐1 TAT (transactivator) protein. The resulting fusion protein (TAT‐CNTF) crosses the plasma membrane within minutes and displays a nuclear localization. TAT‐CNTF was equipotent to rhCNTF in supporting the survival of cultured chicken embryo dorsal root ganglion neurons. Local or subcutaneous administration of TAT‐CNTF, like rhCNTF rescued motor neurons from death in neonatal rats subjected to sciatic nerve transection. In contrast to subcutaneous rhCNTF, which caused a 20–30% decrease in body weight in neonatal rats between postnatal days 2 and 7 together with a considerable fat mobilization in brown adipose tissue, TAT‐CNTF lacked such side effects. Together, these results indicate that rhCNTF fused with the protein transduction domain/TAT retains neurotrophic activity in the absence of CNTFs cytokine‐like side effects and may be a promising candidate for the treatment of motor neuron and other neurodegenerative diseases.