Redistribution of astrocytic glutamine synthetase in the hippocampus of chronic epileptic rats

Papageorgiou, Ismini; Gabriel, Siegrun; Fetani, Andriani F.; Kann, Oliver; Heinemann, Uwe

doi:10.1002/glia.21217

Cited by 45 publications

(37 citation statements)

References 89 publications

(97 reference statements)

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“…However, the GS protein is markedly deficient in the most distal astrocyte processes in the subiculum in MTLE when compared with the subiculum in non-epileptic subjects (Eid et al, 2004b). Similarly, in the rat pilocarpine model of MTLE, more GS is found in proximal than in distal astrocyte branches (Papageorgiou et al, 2011). The GS-expressing astrocyte cell bodies are located closer to brain microvessels, whereas the density and volume of GS-immunopositive astrocytes are not altered (Papageorgiou et al, 2011).…”

Section: Regulation Of Gs In Astrocytesmentioning

confidence: 98%

Regulation of astrocyte glutamine synthetase in epilepsy

Eid

Lee

et al. 2013

Neurochemistry International

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Astrocytes play a crucial role in regulating and maintaining the extracellular chemical milieu of the central nervous system under physiological conditions. Moreover, proliferation of phenotypically altered astrocytes (a.k.a. reactive astrogliosis) has been associated with many neurologic and psychiatric disorders, including mesial temporal lobe epilepsy (MTLE). Glutamine synthetase (GS), which is found in astrocytes, is the only enzyme known to date that is capable of converting glutamate and ammonia to glutamine in the mammalian brain. This reaction is important, because a continuous supply of glutamine is necessary for the synthesis of glutamate and GABA in neurons. The known stoichiometry of glutamate transport across the astrocyte plasma membrane also suggests that rapid metabolism of intracellular glutamate via GS is a prerequisite for efficient glutamate clearance from the extracellular space. Several studies have indicated that the activity of GS in astrocytes is diminished in several brain disorders, including MTLE. It has been hypothesized that the loss of GS activity in MTLE leads to increased extracellular glutamate concentrations and epileptic seizures. Understanding the mechanisms by which GS is regulated may lead to novel therapeutic approaches to MTLE, which is frequently refractory to antiepileptic drugs. This review discusses several known mechanisms by which GS expression and function are influenced, from transcriptional control to enzyme modification.

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Section: Regulation Of Gs In Astrocytesmentioning

confidence: 98%

Regulation of astrocyte glutamine synthetase in epilepsy

Eid

Lee

et al. 2013

Neurochemistry International

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“…8,9,22 Similarly, a recent study of pilocarpine-SE rats revealed no quantitative changes in the number and volume of astrocytes expressing GS but there was a redistribution of the enzyme from distal to proximal astrocyte processes within the hippocampus. 29 Analyzing metabolites using GC-MS revealed a decrease in 13 C enrichment of the TCA cycle intermediates citrate and malate in the HF suggesting decreased TCA cycle turnover in this region, which also can explain the reduction in total levels of succinate and glutamate. Furthermore, this study revealed a decrease in the 13 C enrichment of GABA and aspartate, which was not the case for glutamate and glutamine.…”

Section: Amino-acid and Neurotransmitter Metabolismmentioning

confidence: 99%

Brain Mitochondrial Metabolic Dysfunction and Glutamate Level Reduction in the Pilocarpine Model of Temporal Lobe Epilepsy in Mice

Smeland

Hadera

McDonald

et al. 2013

J Cereb Blood Flow Metab

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Although certain metabolic characteristics such as interictal glucose hypometabolism are well established for temporal lobe epilepsy (TLE), its pathogenesis still remains unclear. Here, we performed a comprehensive study of brain metabolism in a mouse model of TLE, induced by pilocarpine-status epilepticus (SE). To investigate glucose metabolism, we injected mice 3.5-4 weeks after SE with [1,2-13 C]glucose before microwave fixation of the head. Using 1 H and 13 C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry and high-pressure liquid chromatography, we quantified metabolites and 13 C labeling in extracts of cortex and hippocampal formation (HF). Hippocampal levels of glutamate, glutathione and alanine were decreased in pilocarpine-SE mice compared with controls. Moreover, the contents of N-acetyl aspartate, succinate and reduced nicotinamide adenine dinucleotide (phosphate) NAD(P)H were decreased in HF indicating impairment of mitochondrial function. In addition, the reduction in 13 C enrichment of hippocampal citrate and malate suggests decreased tricarboxylic acid (TCA) cycle turnover in this region. In cortex, we found reduced 13 C labeling of glutamate, glutamine and aspartate via the pyruvate carboxylation and pyruvate dehydrogenation pathways, suggesting slower turnover of these amino acids and/or the TCA cycle. In conclusion, mitochondrial metabolic dysfunction and altered amino-acid metabolism is found in both cortex and HF in this epilepsy model. Keywords: 13 C isotope; glutamate; mitochondria; neurometabolism; NMR spectroscopy; temporal lobe epilepsy Journal of Cerebral Blood INTRODUCTIONTemporal lobe epilepsy (TLE) is one of the most common forms of human epilepsy and is associated with a high level of drug resistance among patients. The mechanisms underlying the pathogenesis of TLE still remain unclear, although increasing evidence points to a disturbance in amino-acid neurotransmitter homeostasis and energy metabolism, as well as neuronal injury. Metabolic characteristics of human TLE include interictal glucose hypometabolism and a decrease in the levels of the neuronal marker N-acetyl aspartate (NAA) in the epileptogenic region. 1,2 Increased levels of extracellular glutamate in epileptogenic hippocampi have been reported before and during seizures 3 and interictally. 4 Moreover, it has been suggested that the uptake of glutamate from the extracellular space by astrocytes is slower in the epileptic brain as the expression of glutamine synthetase, the glial enzyme that converts glutamate to glutamine, was decreased in the epileptogenic hippocampi from patients with TLE. 5,6 Changes in brain metabolism in rat models of TLE resemble those reported in human TLE such as interictal glucose hypometabolism demonstrated in lithium-pilocarpine rats, 7 as well as alterations in NAA and glutamate reported in post-status epilepticus (SE) models induced by kainic acid and lithiumpilocarpine. [8][9][10] There are, however, few comprehensive studies on brain metabolism in mouse model...

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“…4A). In the brain, GS functions as an inhibitor of glutamate-dependent excitotoxicity [50]. Intracellular excessive glutamate is converted into GABA and/or α-ketoglutarate by GAD65/67 and GLUD1/2, respectively (Fig.…”

Section: Discussionmentioning

confidence: 99%

Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells

Kaneko

Pappas²,

Malapira

et al. 2017

Cell Physiol Biochem

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Background/Aims: Neuroinflammatory processes have been implicated in the pathophysiology of seizure/epilepsy. High mobility group box 1 (HMGB1), a non-histone DNA binding protein, behaves like an inflammatory cytokine in response to epileptogenic insults. Kainic acid (KA) is an excitotoxic reagent commonly used to induce epilepsy in rodents. However, the molecular mechanism by which KA-induced HMGB1 affords the initiation of epilepsy, especially the role of extracellular HMGB1 in neurotransmitter expression, remains to be elucidated. Methods: Experimental early stage of epilepsy-related hyperexcitability was induced in primary rat neural cells (PRNCs) by KA administration. We measured the localization of HMGB1, cell viability, mitochondrial activity, and expression level of glutamate metabolism-associated enzymes. Results: KA induced the translocation of HMGB1 from nucleus to cytosol, and its release from the neural cells. The translocation is associated with post-translational modifications. An increase in extracellular HMGB1 decreased PRNC cell viability and mitochondrial activity, downregulated expression of glutamate decarboxylase67 (GAD67) and glutamate dehydrogenase (GLUD1/2), and increased intracellular glutamate concentration and major histocompatibility complex II (MHC II) level. Conclusions: That a surge in extracellular HMGB1 approximated seizure initiation suggests a key pathophysiological contribution of HMGB1 to the onset of epilepsy-related hyperexcitability.

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Redistribution of astrocytic glutamine synthetase in the hippocampus of chronic epileptic rats

Cited by 45 publications

References 89 publications

Regulation of astrocyte glutamine synthetase in epilepsy

Regulation of astrocyte glutamine synthetase in epilepsy

Brain Mitochondrial Metabolic Dysfunction and Glutamate Level Reduction in the Pilocarpine Model of Temporal Lobe Epilepsy in Mice

Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells

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