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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 67 (1996), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Vigabatrin is a novel antiepileptic drug designed to control seizures by raising brain γ-aminobutyric acid (GABA) concentrations. Seizure control is not improved significantly when the daily dose is increased beyond 50 mg/kg. Serial, in vivo measurements of GABA levels in human occipital lobe were made using 1H NMR spectroscopy before and after the start of vigabatrin treatment. We used a 2.1-T magnetic resonance imagerspectrometer and an 8-cm surface coil to examine serially a 14-cm3 volume in the occipital lobe of 26 patients with complex partial seizures. Brain GABA content increased following the start of vigabatrin treatment up to a daily dose of 60 mg/kg. Additional increases in dose failed to increase brain GABA content further. GABA synthesis may decrease with sustained elevations of human brain GABA levels. Starting vigabatrin treatment reduced seizure frequency by 〉50%, from six to seven per month to three. Improved seizure control was not associated with further increases of vigabatrin dose. Increased brain GABA concentration was associated with improved seizure control. Starting vigabatrin treatment improved seizure control twofold when GABA levels increased above 1.8 mmol/kg. Further increases in brain GABA content above 2.5 mmol/kg provided less protection. Measuring occipital lobe GABA concentrations may predict improved seizure control when using antiepileptic drugs designed to increase brain GABA levels.
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  • 2
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: The effects of an acute intravenous infusion of ammonium acetate on rat cerebral glutamate and glutamine concentrations, energy metabolism, and intracellular pH were measured in vivo with 1H and 31P nuclear magnetic resonance (NMR). The level of blood ammonia maintained by the infusion protocol used in this study (∼ 500 μM, arterial blood) did not cause significant changes in arterial Pco2, Po2, or pH. Cerebral glutamate levels fell to at least 80% of the preinfusion value, whereas glutamine concentrations increased 170% relative to the preinfusion controls. The fall in brain glutamate concentrations followed a time course similar to that of the rise of brain glutamine. There were no detectable changes in the content of phosphocreatine (PCr) or nucleoside triphosphates (NTP), within the brain regions contributing to the sensitive volume of the surface coil, during the ammonia infusion. Intracellular pH, estimated from the chemical shift of the inorganic phosphate resonance relative to the resonance of PCr in the 31P spectrum, was also unchanged during the period of hyperammonemia. 1H spectra, specifically edited to allow quantitation of the brain lactate content, indicated that lactate rose steadily during the ammonia infusion. Detectable increases in brain lactate levels were observed ∼ 10 min after the start of the ammonia infusion and by 50 min of infusion had more than doubled. Spectra acquired from rats that received a control infusion of sodium acetate were not different from the spectra acquired prior to the infusion of either ammonium or sodium acetate. The results reported here support earlier findings that an increased blood ammonia concentration has a pronounced effect on the brain concentrations of two important amino acids, glutamate and glutamine. They also provide in vivo evidence for the absence of a sustained alteration in either brain intracellular pH or in the concentration of high-energy phosphate compounds during a period of acute hyperammonemia. The technique of in vivo NMR spectroscopy permits multiple, simultaneous measurements of important intermediary and energy metabolites in a single animal, in real time, prior to and during the systemic perturbation.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The aims of this study were twofold: (i) to determine quantitatively the contribution of glutamate/glutamine cycling to total astrocyte/neuron substrate trafficking for the replenishment of neurotransmitter glutamate; and (ii) to determine the relative contributions of anaplerotic flux and glutamate/glutamine cycling to total glutamine synthesis. In this work in vivo and in vitro13C NMR spectroscopy were used, with a [2-13C]glucose or [5-13C]glucose infusion, to determine the rates of glutamate/glutamine cycling, de novo glutamine synthesis via anaplerosis, and the neuronal and astrocytic tricarboxylic acid cycles in the rat cerebral cortex. The rate of glutamate/glutamine cycling measured in this study is compared with that determined from re-analysis of 13C NMR data acquired during a [1-13C]glucose infusion. The excellent agreement between these rates supports the hypothesis that glutamate/glutamine cycling is a major metabolic flux (∼0.20 µmol/min/g) in the cerebral cortex of anesthetized rats and the predominant pathway of astrocyte/neuron trafficking of neurotransmitter glutamate precursors. Under normoammonemic conditions anaplerosis was found to comprise 19–26% of the total glutamine synthesis, whilst this fraction increased significantly during hyperammonemia (∼32%). These findings indicate that anaplerotic glutamine synthesis is coupled to nitrogen removal from the brain (ammonia detoxification) under hyperammonemic conditions.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 65 (2003), S. 401-427 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Notes: Abstract Until very recently, non-invasive measurement of the glutamate-glutamine cycle in the intact mammalian brain had not been possible. In this review, we describe some studies that have led to quantitative assessment of the glutamate-glutamine cycle (Vcyc), as well as other important metabolic fluxes (e.g., glucose oxidation, CMRglc(ox)), with 13C magnetic resonance spectroscopy (MRS) in vivo. These 13C MRS studies clearly demonstrate that glutamate released from presynaptic neurons is taken up by the astrocyte for subsequent glutamine synthesis. Contrary to the earlier concept of a small, metabolically inactive neurotransmitter pool, in vivo 13C MRS studies demonstrate that glutamate release and recycling is a major metabolic pathway that cannot be distinguished from its actions of neurotransmission. Furthermore, the in vivo 13C MRS studies demonstrate in the rat cerebral cortex that increases in Vcyc and neuronal CMRglc(ox) are linearly related with a close to 1:1 slope. Measurements in human cerebral cortex are in agreement with this result. This relationship is consistent with more than two thirds of the energy yielded by glucose oxidation being used to support events associated with glutamate neurotransmission, and it supports a molecular model of a stoichiometric coupling between glutamate neurotransmission and functional glucose oxidation. 13C MRS measurements of resting human cerebral cortex have found a high level of glutamate-glutamine cycling. This high resting neuronal activity, which is subtracted away in brain mapping studies by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), has significant implications for the interpretations of functional imaging data. Here we review and discuss the importance of neurotransmission and neuroenergetics as measured by 13C MRS for understanding brain function and interpreting fMRI.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Metabolic brain disease 11 (1996), S. 283-313 
    ISSN: 1573-7365
    Keywords: Nuclear Magnetic Resonance ; Carbon-13 ; Brain metabolismin vivo
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract As studies of brain metabolism grow in complexity, investigators turn increasingly to nuclear magnetic resonance spectroscopy combined with13C isotopic labeling. The unique ability to detect labeling non-destructively in specific carbon positions of individual compounds has opened the way to investigate brain metabolism in systems ranging from cellular preparations to the human brainin vivo. This review is written for investigators whose backgrounds do not include detailed knowledge of principles of nuclear magnetic resonance. Its purpose is to show the wide array of NMR techniques for13C detection that are available for application in different systems to study aspects of brain metabolism, such as metabolic compartmentation and measurements of the tricarboxylic acid cycle ratein vivo. Basic NMR concepts are explained, and, because each detection method possesses specific advantages to address the requirements of different experimental goals, basic explanations and examples are given for each technique. The review should provide readers with a basic understanding of the methods of13C detection by NMR and assess which of the methods are most applicable to the particular issues they may face in their own research.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Metabolic brain disease 14 (1999), S. 125-133 
    ISSN: 1573-7365
    Keywords: Brain hexokinase and its regulation ; astrocytes ; glucose metabolism ; kinetic properties of astroglial hexokinase ; glucose-1,6-bisphosphate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Hexokinase (HK, EC 2.7.1.1) is a key enzyme in the control of brain glucose metabolism. The regulatory role of HK in different neural cell types has not been elucidated. In this study we determined some kinetic and regulatory properties of HK in mouse cerebrocortical astrocytes in primary culture. Astroglial HK showed an absolute requirement for Mg-ATP and D-glucose. The pH optimum of HK was between 7.4 and 8.0. For astroglial HK, the Km for Mg-ATP was ~ 208 μM and Vmax ~ 35.4 mU/mg protein. At levels higher than 0.2 mM, D-glucose-1,6-bisphosphate, a known regulator of glycolysis, inhibited astroglial HK in a concentration-dependent manner, with an IC50 of ~ 0.4 mM; at 1.2 mM, it almost completely inhibited HK activity. The results obtained for astroglial HK are compatible with those reported for the highly purified preparations of brain HK. These data are of direct relevance to the assessment of glycolytic flux and its regulation in astrocytes.
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