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  • 1
    Electronic Resource
    Electronic Resource
    Dynamic Measurements of Cerebral Pentose Phosphate Pathway Activity In Vivo Using [1,6-13C2,6,6-2H2] Glucose and Microdialysis (1995)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 64 (1995), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Cerebral pentose phosphate pathway (PPP) activity has been linked to NADPH-dependent anabolic pathways, turnover of neurotransmitters, and protection from oxidative stress. Research on this potentially important pathway has been hampered, however, because measurement of regional cerebral PPP activity in vivo has not been possible. Our efforts to address this need focused on the use of a novel isotopically substituted glucose molecule, [1,6-13C2,6,6-2H2]glucose, in conjunction with microdialysis techniques, to measure cerebral PPP activity in vivo, in freely moving rats. Metabolism of [1,6-13C2,6,6-2H2]glucose through glycolysis produces [3-13C]lactate and [3-13C,3,3-2H2]lactate, whereas metabolism through the PPP produces [3-13C,3,3-2H2]lactate and unlabeled lactate. The ratios of these lactate isotopomers can be quantified using gas chromatography/mass spectrometry (GC/MS) for calculation of PPP activity, which is reported as the percentage of glucose metabolized to lactate that passed through the PPP. Following addition of [1,6-13C2,6,6-2H2]glucose to the perfusate, labeled lactate was easily detectable in dialysate using GC/MS. Basal forebrain and intracerebral 9L glioma PPP values (mean ± SD) were 3.5 ± 0.4 (n = 4) and 6.2 ± 0.9% (n = 4), respectively. Furthermore, PPP activity could be stimulated in vivo by addition of phenazine methosulfate, an artificial electron acceptor for NADPH, to the perfusion stream. These results show that the activity of the PPP can now be measured dynamically and regionally in the brains of conscious animals in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1995.64031336.x
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  • 2
    Electronic Resource
    Electronic Resource
    Assessment of the Role of the Glutathione and Pentose Phosphate Pathways in the Protection of Primary Cerebrocortical Cultures from Oxidative Stress (1996)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 66 (1996), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: Reactive oxygen species have been implicated in neuronal injury associated with various neuropathological disorders. However, little is known regarding the relationship between antioxidant enzyme capacity and resultant toxicity. The antioxidant pathways of primary cerebrocortical cultures were directly examined using a novel technique that measures pentose phosphate pathway (PPP) activity, which is enzymatically coupled to glutathione peroxidase (GPx) detoxification of hydrogen peroxide (H2O2). PPP activity was quantified from data obtained by gas chromatography/mass spectrometry analysis of released labeled lactate following metabolic degradation of [1,6-13C2,6,6-2H2]glucose by cerebrocortical cultures. The antioxidant capacity of these cultures was systematically evaluated using H2O2, and the resultant toxicity was quantified by lactate dehydrogenase release. Exposure of primary mixed and purified astrocytic cultures to H2O2 caused stimulation of PPP activity in a concentration-dependent fashion from 0.25 to 22.2% and from 6.9 to 66.7% of glucose metabolized to lactate through the PPP, respectively. In the mixed cultures, chelation of iron before H2O2 exposure was protective and resulted in a correlation between PPP saturation and toxicity. Conversely, addition of iron, inhibition of GPx, or depletion of glutathione decreased H2O2-induced PPP stimulation and increased toxicity. These results implicate the Fenton reaction, reflect the pivotal role of GPx in H2O2 detoxification, and contribute to our understanding of the etiological role of free radicals in neuropathological conditions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1996.66062329.x
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  • 3
    Electronic Resource
    Electronic Resource
    Use of 1,2-Bis(2-Amino-5-Fluorophenoxy)ethane-N,N,N′,N′-Tetraacetic Acid (5FBAPTA) in the Measurement of Free Intracellular Calcium in the Brain by 19F-Nuclear Magnetic Resonance Spectroscopy (1990)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 55 (1990), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We have applied the 19F-nuclear magnetic resonance (NMR) calcium indicator 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N′,N′-tetraacetic acid (5FBAPTA) to the measurement of the free intracellular calcium concentration ([Ca2+] i) in superfused brain slices. A mean ± SD control value of 380 ± 71 nM(n = 18) was obtained at 37°C using 2.4 mM extracellular Ca2+. Subcellular fractionation studies using [3 H] 5FBAPTA showed that after loading of its tetraac-etoxymethyl ester, ∼55% was de-esterified, with the other 45% remaining as the tetraester bound to membranes. Of the de-esterified 5FBAPTA, 〉90% was in the cytosolic fractions, with 〉1% in the mitochondria or microsomes. The NMR-visible de-esterified 5FBAPTA slowly disappeared from the tissue with a t1/2 of 4 h. A time course after loading confirmed that the calculated [Ca2+], was constant over a 5-h period, although the scatter of individual results was ±20%. The [Ca2+]; was increased by a high extracellular K+ concentration ([K+]e), by a low extracellular concentration of Na+, and by the calcium ionophore A23187. On recovery from high [K+]e. the [Ca2+]i“overshot” to values lower than the original control value. The [Ca2+]i was surprisingly resistant to changes in extracellular Ca2+ concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1990.tb04573.x
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  • 4
    Electronic Resource
    Electronic Resource
    Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification (1998)
    Springer
    Journal of neuro-oncology 36 (1998), S. 149-157 
    Details
    ISSN: 1573-7373
    Keywords: lonidamine ; 9L brain tumor ; 31P magnetic resonance spectroscopy ; radiation and hyperthermia sensitizer ; acidosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Malignant gliomas have been associated with a high rate of glycolytic activity which is believed necessary to sustain cellular function and integrity. Since lonidamine (LND) is believed to reduce tumor glucose utilization by inhibition of the mitochondrially-bound glycolytic enzyme hexokinase (HK), 31P magnetic resonance spectroscopy (MRS) was used to noninvasively follow the effects of LND on both tumor pH and the high-energy phosphate metabolites; ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) in subcutaneous rat 9L gliosarcomas. 31P tumor spectra acquired in 5 min intervals pre- and post LND administration of 50 and 100 mg/kg, i.p. revealed an acidotic pH shift of − 0.25 and − 0.45 pH units, respectively within 30 min post administration. The ATP/Pi ratio of 9L tumors decreased to 40% of control and Pi levels increased to 280% of control over a 3 hr period. LND exerted no effect on tumor blood flow and mean arterial blood pressure. Brain and muscle metabolite levels and pH were also unaffected by LND. In vitro measurements of cultured 9L tumor cell intra- and extracellular lactate, pentose phosphate pathway (PPP) and hexokinase (HK) activities suggest that the mode of action of LND involves inhibition of lactate efflux and intracellular acidification. The selective reduction of tumor energy metabolites and pH by LND may be exploitable for sensitizing gliomas to radiation, chemotherapy or hyperthermia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005819604858
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  • 5
    Electronic Resource
    Electronic Resource
    13C-MRS studies on cerebral metabolism (1994)
    Springer
    Magnetic resonance materials in physics, biology and medicine 2 (1994), S. 285-289 
    Details
    ISSN: 1352-8661
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Physics
    Notes: Abstract 13C from labeled glucose is normally incorporated rapidly into cerebral glutamate with little detectable glutamine or citrate. In contrast, glutamine and citrate only show significant labeling from13C acetate, which reflects metabolism in glial cells. When brain slices are depolarized with 40 mM KC1 (which mirrors some of the conditions of epilepsy) the13C enrichment of glutamine and citrate from glucose is accelerated in contrast to that of glutamate, which is not. This clearly indicates that depolarizing conditions stimulate glial rather than neuronal consumption of glucose. In tissues subjected to hypoxia, there is greatly increased labeling of glycerol 3-phosphate, which was confirmed by its increased presence in31P-MR (magnetic resonance) spectra. Analysis of the labeling of lactate, alanine, and glycerol 3-phosphate demonstrated that the ability of the brain to maintain normal function in hypoxia is limited by the capacity of the key enzyme, lactate dehydrogenase. This has implications in the clinical assessment and management of stroke. These results also have implications in the interpretation of activation studies, where increased lactate could be due either to depolarization or hypoxia, or both. The spectra observed in studies on metabolism of U-[13C] glutamate in cerebral preparations revealed clear signals from glutamine and lactate released to the media. The isotopomer patterns of the lactate showed that it must have arisen from the exogenous glutamate, because if it were due to naturally abundant13C in the lactate, only singlets would have appeared. Comparison of the isotopomer patterns and the percentage13C enrichments of the glutamine and lactate showed that there is higher incorporation of13C from exogenous glutamate into lactate than into glutamine. The enrichment of the lactate indicated that very little was derived from glucose and suggests that the glutamate is converted to lactate in the glia for use by the neurones.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01705254
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