scholarly journals Ceftriaxone Treatment Affects EAAT2 Expression and Glutamatergic Neurotransmission and Exerts a Weak Anticonvulsant Effect in Young Rats

2019 ◽  
Vol 20 (23) ◽  
pp. 5852 ◽  
Author(s):  
Zaitsev ◽  
Malkin ◽  
Postnikova ◽  
Smolensky ◽  
Zubareva ◽  
...  
Keyword(s):  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Temporal Cortex ◽  
Young Male ◽  
Anticonvulsant Effect ◽  
Maximal Electroshock ◽  
Glutamatergic Neurotransmission ◽  
Excitatory Amino Acid Transporter ◽  
Young Rats ◽  
Wide Range

Epilepsy is a common neurological disorder. Despite the availability of a wide range of antiepileptic drugs, these are unsuccessful in preventing seizures in 20–30% of patients. Therefore, new pharmacological strategies are urgently required to control seizures. Modulation of glutamate uptake may have potential in the treatment of pharmacoresistant forms of epilepsy. Previous research showed that the antibiotic ceftriaxone (CTX) increased the expression and functional activity of excitatory amino acid transporter 2 (EAAT2) and exerted considerable anticonvulsant effects. However, other studies did not confirm a significant anticonvulsant effect of CTX administration. We investigated the impacts of CTX treatment on EAAT expression and glutamatergic neurotransmission, as well its anticonvulsant action, in young male Wistar rats. As shown by a quantitative real-time polymerase chain reaction (qPCR) assay and a Western blot analysis, the mRNA but not the protein level of EAAT2 increased in the hippocampus following CTX treatment. Repetitive CTX administration had only a mild anticonvulsant effect on pentylenetetrazol (PTZ)-induced convulsions in a maximal electroshock threshold test (MEST). CTX treatment did not affect the glutamatergic neurotransmission, including synaptic efficacy, short-term facilitation, or the summation of excitatory postsynaptic potentials (EPSPs) in the hippocampus and temporal cortex. However, it decreased the field EPSP (fEPSP) amplitudes evoked by intense electrical stimulation. In conclusion, in young rats, CTX treatment did not induce overexpression of EAAT2, therefore exerting only a weak antiseizure effect. Our data provide new insight into the effects of modulation of EAAT2 expression on brain functioning.

scholarly journals MTEP, a Selective mGluR5 Antagonist, Had a Neuroprotective Effect but Did Not Prevent the Development of Spontaneous Recurrent Seizures and Behavioral Comorbidities in the Rat Lithium–Pilocarpine Model of Epilepsy

2022 ◽  
Vol 23 (1) ◽  
pp. 497
Author(s):  
Alexandra V. Dyomina ◽  
Anna A. Kovalenko ◽  
Maria V. Zakharova ◽  
Tatiana Yu. Postnikova ◽  
Alexandra V. Griflyuk ◽  
...  
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Excitatory Amino Acid ◽  
Neuroprotective Effect ◽  
Neuronal Loss ◽  
Brain Diseases ◽  
Excitatory Amino Acid Transporter ◽  
Wide Range ◽  
Pilocarpine Model ◽  
Mglur5 Antagonist ◽  
Behavioral Impairments

Metabotropic glutamate receptors (mGluRs) are expressed predominantly on neurons and glial cells and are involved in the modulation of a wide range of signal transduction cascades. Therefore, different subtypes of mGluRs are considered a promising target for the treatment of various brain diseases. Previous studies have demonstrated the seizure-induced upregulation of mGluR5; however, its functional significance is still unclear. In the present study, we aimed to clarify the effect of treatment with the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on epileptogenesis and behavioral impairments in rats using the lithium–pilocarpine model. We found that the administration of MTEP during the latent phase of the model did not improve survival, prevent the development of epilepsy, or attenuate its manifestations in rats. However, MTEP treatment completely prevented neuronal loss and partially attenuated astrogliosis in the hippocampus. An increase in excitatory amino acid transporter 2 expression, which has been detected in treated rats, may prevent excitotoxicity and be a potential mechanism of neuroprotection. We also found that MTEP administration did not prevent the behavioral comorbidities such as depressive-like behavior, motor hyperactivity, reduction of exploratory behavior, and cognitive impairments typical in the lithium–pilocarpine model. Thus, despite the distinct neuroprotective effect, the MTEP treatment was ineffective in preventing epilepsy.

Glutamate metabolism in HIV-infected macrophages: implications for the CNS

2006 ◽  
Vol 291 (4) ◽  
pp. C618-C626 ◽  
Author(s):  
Fabrice Porcheray ◽  
Cathie Léone ◽  
Boubekeur Samah ◽  
Anne-Cécile Rimaniol ◽  
Nathalie Dereuddre-Bosquet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glutamine Synthetase ◽  
Hiv Infection ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Glutamate Transport ◽  
Activated Macrophages ◽  
Glutamate Metabolism ◽  
Excitatory Amino Acid Transporter ◽  
Hiv Encephalitis

Central nervous system disorders are still a common complication of human immunodeficiency virus (HIV) infection and can lead to dementia and death. They are mostly the consequences of an inflammatory macrophagic activation and relate to glutamate-mediated excitotoxicity. However, recent studies also suggest neuroprotective aspects of macrophage activation through the expression of glutamate transporters and glutamine synthetase. We thus aimed to study whether HIV infection or activation of macrophages could modulate glutamate metabolism in these cells. We assessed the effect of HIV infection on glutamate transporter expression as well as on glutamate uptake by macrophages and showed that glutamate transport was partially decreased in the course of virus replication, whereas excitatory amino acid transporter-2 (EAAT-2) gene expression was dramatically increased. The consequences of HIV infection on glutamine synthetase were also measured and for the first time we show the functional expression of this key enzyme in macrophages. This expression was repressed during virus production. We then quantified EAAT-1 and EAAT-2 gene expression as well as glutamate uptake in differentially activated macrophages and show that the effects of HIV are not directly related to pro- or anti-inflammatory mediators. Finally, this study shows that glutamate transport by macrophages is less affected than what has been described in astrocytes. Macrophages may thus play a role in neuroprotection against glutamate in the infected brain, through their expression of both EAATs and glutamine synthetase. Because glutamate metabolism by activated macrophages is sensitive to both HIV infection and inflammation, it may thus be of potential interest as a therapeutic target in HIV encephalitis.

scholarly journals Chemical activation of a high-affinity glutamate transporter in human erythrocytes and its implications for malaria-parasite–induced glutamate uptake

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3604-3612 ◽  
Author(s):  
Markus Winterberg ◽  
Esther Rajendran ◽  
Stefan Baumeister ◽  
Sven Bietz ◽  
Kiaran Kirk ◽  
...  
Keyword(s):  
Malaria Parasite ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Chemical Activation ◽  
Glutamate Transporter ◽  
Human Erythrocytes ◽  
Excitatory Amino Acid Transporter ◽  
Western Blots ◽  
High Affinity ◽  
Parasite Plasmodium Falciparum

Human erythrocytes have a low basal permeability to L-glutamate and are not known to have a functional glutamate transporter. Here, treatment of human erythrocytes with arsenite was shown to induce the uptake of L-glutamate and D-aspartate, but not that of D-glutamate or L-alanine. The majority of the arsenite-induced L-glutamate influx was via a high-affinity, Na+-dependent system showing characteristics of members of the “excitatory amino acid transporter” (EAAT) family. Western blots and immunofluorescence assays revealed the presence of a member of this family, EAAT3, on the erythrocyte membrane. Erythrocytes infected with the malaria parasite Plasmodium falciparum take up glutamate from the extracellular environment. Although the majority of uptake is via a low-affinity Na+-independent pathway there is, in addition, a high-affinity uptake component, raising the possibility that the parasite activates the host cell glutamate transporter.

scholarly journals Cryo-EM structures of excitatory amino acid transporter 3 visualize coupled substrate, sodium, and proton binding and transport

2021 ◽  
Vol 7 (10) ◽  
pp. eabf5814
Author(s):  
Biao Qiu ◽  
Doreen Matthies ◽  
Eva Fortea ◽  
Zhiheng Yu ◽  
Olga Boudker
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Amino Acid Transporter ◽  
Sodium Ions ◽  
Excitatory Amino Acid Transporter ◽  
Proton Symport ◽  
Functional States ◽  
Rapid Transport ◽  
Acid Transporter

Human excitatory amino acid transporter 3 (hEAAT3) mediates glutamate uptake in neurons, intestine, and kidney. Here, we report cryo-EM structures of hEAAT3 in several functional states where the transporter is empty, bound to coupled sodium ions only, or fully loaded with three sodium ions, a proton, and the substrate aspartate. The structures suggest that hEAAT3 operates by an elevator mechanism involving three functionally independent subunits. When the substrate-binding site is near the cytoplasm, it has a remarkably low affinity for the substrate, perhaps facilitating its release and allowing the rapid transport turnover. The mechanism of the coupled uptake of the sodium ions and the substrate is conserved across evolutionarily distant families and is augmented by coupling to protons in EAATs. The structures further suggest a mechanism by which a conserved glutamate residue mediates proton symport.

scholarly journals PKN1 promotes synapse maturation by inhibiting mGluR-dependent silencing through neuronal glutamate transporter activation

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Hiroki Yasuda ◽  
Hikaru Yamamoto ◽  
Kenji Hanamura ◽  
Mona Mehruba ◽  
Toshio Kawamata ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Metabotropic Glutamate Receptor ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Critical Role ◽  
Glutamate Transporter ◽  
Wild Type ◽  
Excitatory Amino Acid Transporter ◽  
The Brain ◽  
Neuronal Glutamate Transporter

AbstractAbnormal metabotropic glutamate receptor (mGluR) activity could cause brain disorders; however, its regulation has not yet been fully understood. Here, we report that protein kinase N1 (PKN1), a protein kinase expressed predominantly in neurons in the brain, normalizes group 1 mGluR function by upregulating a neuronal glutamate transporter, excitatory amino acid transporter 3 (EAAT3), and supports silent synapse activation. Knocking out PKN1a, the dominant PKN1 subtype in the brain, unmasked abnormal input-nonspecific mGluR-dependent long-term depression (mGluR-LTD) and AMPA receptor (AMPAR) silencing in the developing hippocampus. mGluR-LTD was mimicked by inhibiting glutamate transporters in wild-type mice. Knocking out PKN1a decreased hippocampal EAAT3 expression and PKN1 inhibition reduced glutamate uptake through EAAT3. Also, synaptic transmission was immature; there were more silent synapses and fewer spines with shorter postsynaptic densities in PKN1a knockout mice than in wild-type mice. Thus, PKN1 plays a critical role in regulation of synaptic maturation by upregulating EAAT3 expression.

Elevated ammonium levels: differential acute effects on three glutamate transporter isoforms

2012 ◽  
Vol 302 (6) ◽  
pp. C880-C891 ◽  
Author(s):  
Rikke Søgaard ◽  
Ivana Novak ◽  
Nanna MacAulay
Keyword(s):  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Brain Slices ◽  
Glutamate Transporter ◽  
Surface Expression ◽  
Glutamate Transport ◽  
Excitatory Amino Acid Transporter ◽  
Ph Buffering ◽  
Specific Effects ◽  
Intracellular Alkalinization

Increased ammonium (NH4+/NH3) in the brain is a significant factor in the pathophysiology of hepatic encephalopathy, which involves altered glutamatergic neurotransmission. In glial cell cultures and brain slices, glutamate uptake either decreases or increases following acute ammonium exposure but the factors responsible for the opposing effects are unknown. Excitatory amino acid transporter isoforms EAAT1, EAAT2, and EAAT3 were expressed in Xenopus oocytes to study effects of ammonium exposure on their individual function. Ammonium increased EAAT1- and EAAT3-mediated [3H]glutamate uptake and glutamate transport currents but had no effect on EAAT2. The maximal EAAT3-mediated glutamate transport current was increased but the apparent affinities for glutamate and Na+ were unaltered. Ammonium did not affect EAAT3-mediated transient currents, indicating that EAAT3 surface expression was not enhanced. The ammonium-induced stimulation of EAAT3 increased with increasing extracellular pH, suggesting that the gaseous form NH3 mediates the effect. An ammonium-induced intracellular alkalinization was excluded as the cause of the enhanced EAAT3 activity because 1) ammonium acidified the oocyte cytoplasm, 2) intracellular pH buffering with MOPS did not reduce the stimulation, and 3) ammonium enhanced pH-independent cysteine transport. Our data suggest that the ammonium-elicited uptake stimulation is not caused by intracellular alkalinization or changes in the concentrations of cotransported ions but may be due to a direct effect on EAAT1/EAAT3. We predict that EAAT isoform-specific effects of ammonium combined with cell-specific differences in EAAT isoform expression may explain the conflicting reports on ammonium-induced changes in glial glutamate uptake.

scholarly journals NDRG2 Expression Correlates with Neurofibrillary Tangles and Microglial Pathology in the Ageing Brain

2020 ◽  
Vol 21 (1) ◽  
pp. 340
Author(s):  
Motaz M. Fadul ◽  
Claire J. Garwood ◽  
Rachel Waller ◽  
Navonna Garrett ◽  
Paul R. Heath ◽  
...  
Keyword(s):  
Neurofibrillary Tangles ◽  
Excitatory Amino Acid ◽  
Temporal Cortex ◽  
Excitatory Amino Acid Transporter ◽  
Damage Response ◽  
Ndrg2 Expression ◽  
Β Amyloid ◽  
The Relationship ◽  
Ageing Brain ◽  
Insight Into

Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer’s disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc downstream regulated gene 2 (NDRG2) in the ageing brain, investigate the relationship between NDRG2 and a panel of astrocyte markers, and relate NDRG2 expression to pathology. NDRG2 specifically immunolabelled the cell body and radiating processes of astrocytes in the temporal cortex of the Cognitive Function and Ageing Study (CFAS) neuropathology cohort. Expression of NDRG2 did not correlate with other astrocyte markers, including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter 2 (EAAT2) and glutamine synthetase (GS). NDRG2 showed a relationship to AT8+ neurofibrillary tangles (p = 0.001) and CD68+ microglia (p = 0.047), but not β-amyloid plaques or astrocyte nuclear γH2AX immunoreactivity, a marker of DNA damage response. These findings provide new insight into the astrocyte response to pathology in the ageing brain, and suggest NDRG2 may be a potential target to modulate this response.

scholarly journals Coping with dehydration: sympathetic activation and regulation of glutamatergic transmission in the hypothalamic PVN

2014 ◽  
Vol 306 (11) ◽  
pp. R804-R813 ◽  
Author(s):  
Megan E. Bardgett ◽  
Qing-Hui Chen ◽  
Qing Guo ◽  
Alfredo S. Calderon ◽  
Mary Ann Andrade ◽  
...  
Keyword(s):  
Heart Failure ◽  
Nmda Receptor ◽  
Ampa Receptors ◽  
Neuronal Excitability ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Chronic Hypertension ◽  
Excitatory Amino Acid Transporter ◽  
Pressor Responses

Autonomic and endocrine profiles of chronic hypertension and heart failure resemble those of acute dehydration. Importantly, all of these conditions are associated with exaggerated sympathetic nerve activity (SNA) driven by glutamatergic activation of the hypothalamic paraventricular nucleus (PVN). Here, studies sought to gain insight into mechanisms of disease by determining the role of PVN ionotropic glutamate receptors in supporting SNA and mean arterial pressure (MAP) during dehydration and by elucidating mechanisms regulating receptor activity. Blockade of PVN N-methyl-d-aspartate (NMDA) receptors reduced ( P < 0.01) renal SNA and MAP in urethane-chloralose-anesthetized dehydrated (DH) (48 h water deprivation) rats, but had no effect in euhydrated (EH) controls. Blockade of PVN α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors had no effect in either group. NMDA in PVN caused dose-dependent increases of renal SNA and MAP in both groups, but the maximum agonist evoked response ( Emax) of the renal SNA response was greater ( P < 0.05) in DH rats. The latter was not explained by increased PVN expression of NMDA receptor NR1 subunit protein, increased PVN neuronal excitability, or decreased brain water content. Interestingly, PVN injection of the pan-specific excitatory amino acid transporter (EAAT) inhibitor dl-threo-β-benzyloxyaspartic acid produced smaller sympathoexcitatory and pressor responses in DH rats, which was associated with reduced glial expression of EAAT2 in PVN. Like chronic hypertension and heart failure, dehydration increases excitatory NMDA receptor tone in PVN. Reduced glial-mediated glutamate uptake was identified as a key contributing factor. Defective glutamate uptake in PVN could therefore be an important, but as yet unexplored, mechanism driving sympathetic hyperactivity in chronic cardiovascular diseases.

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