Multinuclear NMR Spectroscopy Studies on NH&lt;sub&gt;4&lt;/sub&gt;Cl-Induced Metabolic Alterations and Detoxification Processes in Primary Astrocytes and Glioma Cells

Zwingmann, Claudia; Brand, Annette; Richter‐Landsberg, Christiane; Leibfritz, Dieter

doi:10.1159/000017339

Cited by 34 publications

(19 citation statements)

References 47 publications

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“…50%) after pretreatment with MSO. These results were described in detail in a previous study and are consistent with the observation that inhibition of GS by MSO largely prevents the NH 4 Clinduced decrease in myo-Ins and hypotaurine in primary astrocytes [22].…”

Section: Energy State Phosphate Metabolites and Organic Solutessupporting

confidence: 92%

“…The observed swelling of glioma cells already 3 h after ammonia treatment and the complementary rise in intracellular Gln with simultaneous release of organic osmolytes give further evidence for the role of Gln as an accumulated osmolyte in ammonia-induced brain edema, seen in acute HE [5][6][7][8][9][10]. The concept is supported by previous results from our laboratory, where both the increase in Gln and the decrease in the osmolyte content, induced by 3 h incubation with ammonia, were prevented in primary astrocytes and F98 glioma cells by administration of MSO, although cytosolic NH 4 + levels were elevated even more [22]. Although inhibition of GS did not abolish the ammonia-induced cell swelling completely, the normalization of intracellular Gln also diminished the extent of myo-Ins and taurine depletion in glial cells.…”

Section: Discussionsupporting

confidence: 77%

“…Whereas brain myo-Ins is decreased in chronic HE [19], it appears unchanged in acute liver failure [20]. In contrast, brain edema is seldom seen under chronic conditions [21], and increased Gln concentrations were already observed after short-term exposure to NH 4 Cl in brain cell cultures [22].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Ammonia Exposition on Glioma Cells: Changes in Cell Volume and Organic Osmolytes Studied by Diffusion-Weighted and High-Resolution NMR Spectroscopy

et al. 2000

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NH₄Cl (10 mM) caused a sustained increase in the cell volume in immobilized, perfused F98 glioma cells to approx. 125% of control after 3 h, as measured by diffusion-weighted ¹H NMR spectroscopy. Concomitantly, the glutamine (Gln) concentration increased by 130%, accompanied by a marked decrease in cytosolic osmolytes, i.e. myo-inositol and taurine, determined from ¹H NMR spectra of PCA extracts. Inhibition of Gln synthetase partially prevented the increase in water content. While losses of organic osmolytes are also observed under hypotonic conditions, the rapid cell swelling is followed by the regulatory cell volume decrease (RVD), and is accompanied by decreased cytosolic Gln. We suggest that the rise in intracellular osmolarity, which is attributed to NH₄Cl metabolism to Gln, but also to alanine (Ala), is not compensated by the release of other osmolytes, and causes cell swelling without RVD.

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Section: Energy State Phosphate Metabolites and Organic Solutessupporting

confidence: 92%

Section: Discussionsupporting

confidence: 77%

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Effects of Ammonia Exposition on Glioma Cells: Changes in Cell Volume and Organic Osmolytes Studied by Diffusion-Weighted and High-Resolution NMR Spectroscopy

et al. 2000

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“…These findings confirm and extend those of previous biochemical and spectroscopic studies in cerebrospinal fluid and brain tissue from experimental animal models of ALF because of hepatectomy, 1 hepatic devascularization, [2][3][4] or toxic liver injury 5 and in autopsied brain tissue from patients with ALF 6 as well as in astrocytes after exposure to ammonia. 20,21 Ammonia is detoxified in brain mainly by glutamine synthetase, an astrocytic enzyme. Increased brain glutamine has been demonstrated by in vivo 1 H NMR spectroscopy in animal models 22,23 and in patients with ALF.…”

Section: Discussionmentioning

confidence: 99%

Selective increase of brain lactate synthesis in experimental acute liver failure: Results of a [1H-13C] nuclear magnetic resonance study

2003

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Acute liver failure (ALF) results in alterations of energy metabolites and of glucose-derived amino acid neurotransmitters in brain. However, the dynamics of changes in glucose metabolism remain unclear. The present study was undertaken using 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of glucose into amino acids and lactate via cell-specific pathways in relation to the severity of encephalopathy and brain edema in rats with ALF because of hepatic devascularization. Early (precoma) stages of encephalopathy were accompanied by significant 2-to 4.5-fold (P < .001) increases of total brain glutamine and lactate concentrations. More severe (coma) stages of encephalopathy and brain edema led to a further significant increase in brain lactate but no such increase in glutamine. Furthermore, 13 C isotopomer analysis showed a selective increase of de novo synthesis of lactate from [1-13 C]glucose resulting in 2.5-fold increased fractional 13 C enrichments in lactate at coma stages. [2-13 C]glutamine, synthesized through the astrocytic enzyme pyruvate carboxylase, increased 10-fold at precoma stages but showed no further increase at coma stages of encephalopathy. 13 C-label incorporation into [4-13 C]glutamate, synthesized mainly through neuronal pyruvate dehydrogenase, was selectively reduced at coma stages, whereas brain GABA synthesis was unchanged at all time points. In conclusion, increased brain lactate synthesis and impaired glucose oxidative pathways rather than intracellular glutamine accumulation are the major cause of brain edema in ALF. Future NMR spectroscopic studies using stable isotopes and real-time measurements of metabolic rates could be valuable in the elucidation of the cerebral metabolic consequences of ALF in humans. (HEPATOLOGY 2003;37:420-428.) H epatic encephalopathy and brain edema are serious central nervous system complications of acute liver failure (ALF), which are accompanied by significant alterations of brain metabolites. For example, biochemical studies in brain tissue from animals with ALF resulting from hepatectomy, 1 hepatic devascularization, 2-4 or toxic liver injury 5 as well as autopsied brain tissue from patients with ALF 6 reveal significant increases in concentrations of glutamine and a concomitant reduction of glutamate. Several of these studies also show that brain lactate concentrations are elevated as a function of the deterioration of central nervous system function in ALF, a finding that has been attributed to decreased pyruvate oxidation because of ammonia exposure. 7 Although these biochemical studies provide important hints on metabolic derangements in ALF, they do not permit the elucidation of rates of synthesis/degradation of these metabolites, nor do they provide information on the cellular localization of the altered metabolism. The use of nuclear magnetic resonance (NMR) spectroscopy and stable isotope precursors provides an effective approach to the study of metabolic turnover in the brain. In particular, ...

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“…However, Leke et al [75,76] found a significant increase in GABA formation from labeled glucose during hyperammonemic conditions in both co-cultures of cerebral neurons and astrocytes and in rats with liver cirrhosis. Increased anaplerosis has also been observed in cultured astrocytes in the presence of ammonia by Lapidot and Gopher [77] and in additional studies using cultured cells or animal models of hyperammonemia [78][79][80]. Zwingmann [81] has pointed out that the activity of an enzyme measured in tissue homogenates does not necessarily reflect the actual metabolic flux through the enzyme and reviewed additional studies indicating that ammonia increases anaplerosis.…”

Section: Glutathione Malate-aspartate Shuttle Tricarboxylic Acid (Tmentioning

confidence: 97%

Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

et al. 2016

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Effects of ammonia on astrocytes play a major role in hepatic encephalopathy, acute liver failure and other diseases caused by increased arterial ammonia concentrations (e.g., inborn errors of metabolism, drug or mushroom poisoning). There is a direct correlation between arterial ammonia concentration, brain ammonia level and disease severity. However, the pathophysiology of hyperammonemic diseases is disputed. One long recognized factor is that increased brain ammonia triggers its own detoxification by glutamine formation from glutamate. This is an astrocytic process due to the selective expression of the glutamine synthetase in astrocytes. A possible deleterious effect of the resulting increase in glutamine concentration has repeatedly been discussed and is supported by improvement of some pathologic effects by GS inhibition. However, this procedure also inhibits a large part of astrocytic energy metabolism and may prevent astrocytes from responding to pathogenic factors. A decrease of the already low glutamate concentration in astrocytes due to increased synthesis of glutamine inhibits the malate-aspartate shuttle and energy metabolism. A more recently described pathogenic factor is the resemblance between NH and K in their effects on the Na,K-ATPase and the Na,K, 2 Cl and water transporter NKCC1. Stimulation of the Na,K-ATPase driven NKCC1 in both astrocytes and endothelial cells is essential for the development of brain edema. Na,K-ATPase stimulation also activates production of endogenous ouabains. This leads to oxidative and nitrosative damage and sensitizes NKCC1. Administration of ouabain antagonists may accordingly have therapeutic potential in hyperammonemic diseases.

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Multinuclear NMR Spectroscopy Studies on NH<sub>4</sub>Cl-Induced Metabolic Alterations and Detoxification Processes in Primary Astrocytes and Glioma Cells

Cited by 34 publications

References 47 publications

Effects of Ammonia Exposition on Glioma Cells: Changes in Cell Volume and Organic Osmolytes Studied by Diffusion-Weighted and High-Resolution NMR Spectroscopy

Effects of Ammonia Exposition on Glioma Cells: Changes in Cell Volume and Organic Osmolytes Studied by Diffusion-Weighted and High-Resolution NMR Spectroscopy

Selective increase of brain lactate synthesis in experimental acute liver failure: Results of a [1H-13C] nuclear magnetic resonance study

Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity

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