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Journal ArticleDOI

Role of Excitatory Amino Acid Transporter‐2 (EAAT2) and glutamate in neurodegeneration: Opportunities for developing novel therapeutics

TL;DR: The potential utility of the EAAT2 promoter is emphasized for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration.
Abstract: Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft. Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Analysis of the 2.5 kb human EAAT2 promoter showed that NF-κB is an important regulator of EAAT2 expression in astrocytes. Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many β-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels. Treatment of animals with ceftriaxone (CEF), a β-lactam antibiotic, led to an increase of EAAT2 expression and glutamate transport activity in the brain. CEF has neuroprotective effects in both in vitro and in vivo models based on its ability to inhibit neuronal cell death by preventing glutamate excitotoxicity. CEF increases EAAT2 transcription in primary human fetal astrocytes through the NF-κB signaling pathway. The NF-κB binding site at −272 position was critical in CEF-mediated EAAT2 protein induction. These studies emphasize the importance of transcriptional regulation in controlling glutamate levels in the brain. They also emphasize the potential utility of the EAAT2 promoter for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration. J. Cell. Physiol. 226: 2484–2493, 2011. © 2010 Wiley-Liss, Inc.
Citations
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Journal ArticleDOI
TL;DR: Understanding of the mechanisms by which stress and glucocorticoids affect glutamate transmission provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.
Abstract: Mounting evidence suggests that acute and chronic stress, especially the stress-induced release of glucocorticoids, induces changes in glutamate neurotransmission in the prefrontal cortex and the hippocampus, thereby influencing some aspects of cognitive processing. In addition, dysfunction of glutamatergic neurotransmission is increasingly considered to be a core feature of stress-related mental illnesses. Recent studies have shed light on the mechanisms by which stress and glucocorticoids affect glutamate transmission, including effects on glutamate release, glutamate receptors and glutamate clearance and metabolism. This new understanding provides insights into normal brain functioning, as well as the pathophysiology and potential new treatments of stress-related neuropsychiatric disorders.

1,121 citations

Journal ArticleDOI
TL;DR: An overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration is provided.
Abstract: Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.

519 citations


Cites background from "Role of Excitatory Amino Acid Trans..."

  • ...…L-glu and L-asp clearance should dampen the excitotoxic component of these diseases, many researchers have set out to identify compounds that induce EAAT2, which is the principal EAAT in the brain and most frequently found to be downregulated (Sheldon and Robinson, 2007; Kim et al., 2011)....

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Journal ArticleDOI
TL;DR: An overview of the involvement of neuronal apoptosis and oxidative stress in the most important neurodegenerative diseases is presented, mainly focusing the attention on several genetic disorders, discussing the interaction between primary genetic abnormalities and the apoptotic pathways.
Abstract: Neurodegenerative disorders affect almost 30 million individuals leading to disability and death. These disorders are characterized by pathological changes in disease-specific areas of the brain and degeneration of distinct neuron subsets. Despite the differences in clinical manifestations and neuronal vulnerability, the pathological processes appear similar, suggesting common neurodegenerative pathways. Apoptosis seems to play a key role in the progression of several neurologic disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis as demonstrated by studies on animal models and cell lines. On the other hand, research on human brains reported contradictory results. However, many dying neurons have been detected in brains of patients with neurodegenerative diseases, and these conditions are often associated with significant cell loss accompanied by typical morphological features of apoptosis such as chromatin condensation, DNA fragmentation, and activation of cysteine-proteases, caspases. Cell death and neurodegenerative conditions have been linked to oxidative stress and imbalance between generation of free radicals and antioxidant defenses. Multiple sclerosis, stroke, and neurodegenerative diseases have been associated with reactive oxygen species and nitric oxide. Here we present an overview of the involvement of neuronal apoptosis and oxidative stress in the most important neurodegenerative diseases, mainly focusing the attention on several genetic disorders, discussing the interaction between primary genetic abnormalities and the apoptotic pathways.

442 citations

Journal ArticleDOI
TL;DR: In this paper, the authors review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease, Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research.
Abstract: Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.

300 citations

Journal ArticleDOI
TL;DR: The SLC1 family encompasses two transporters of neutral amino acids, ASCT1 (S LC1A4) and ASCT2 (SLC1A5), which facilitate electroneutral exchange of amino acids in neurons and/or cells of the peripheral tissues and Activators of SLC2 family members have also been discovered.

244 citations

References
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Journal ArticleDOI
TL;DR: The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases.
Abstract: ▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...

5,833 citations


Additional excerpts

  • ...NF-kB is primarily a transcriptional activator (Baldwin, 1996)....

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Journal ArticleDOI
01 Mar 1996-Neuron
TL;DR: It is suggested that glial glutamate transporters provide the majority of functional glutamate transport and are essential for maintaining low extracellular glutamate and for preventing chronic glutamate neurotoxicity.

2,482 citations


"Role of Excitatory Amino Acid Trans..." refers background in this paper

  • ...The human EAAT2 promoter was significantly activated by CEF, amoxicillin and dibutyryl cyclic AMP while controls such as glutamate and glycine had no effect (Rothstein et al., 2005)....

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  • ...We have identified b-lactam antibiotics, such as CEF, as transcriptional activators of EAAT2 that are capable of providing neuronal protection through facilitating glutamate uptake by astroglial cells (Rothstein et al., 2005)....

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  • ...CEF also altered cellular neurodegeneration in vivo and G93A mice receiving CEF at 70 days of age showed a significant prevention of motor neuron loss and reduction JOURNAL OF CELLULAR PHYSIOLOGY of hypercellular gliosis compared to control mice (Rothstein et al., 2005)....

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  • ...…A N D G L U T A M A T E I N N E U R O D E G E N E R A T I O N 2489 Biochemically, glutamate transport activity was enhanced by treatment with cephalosporin, one of the derivatives of CEF, as evidenced by increased glutamate uptake into the cortical membrane or spinal cord (Rothstein et al., 2005)....

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  • ...…of compounds identifies b-lactam antibiotics as inducers of EAAT2 Administration of 1,040 FDA-approved drugs and nutritionals to spinal cord slice cultures derived from 9-day-old rats identified compounds that increased activity of EAAT2 and the levels of EAAT2 protein (Rothstein et al., 2005)....

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Journal ArticleDOI
12 Aug 1993-Nature
TL;DR: It is reported that NO.-mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O.-2), apparently leading to formation of peroxynitrite (ONOO−), and not by NO.
Abstract: Congeners of nitrogen monoxide (NO) are neuroprotective and neurodestructive. To address this apparent paradox, we considered the effects on neurons of compounds characterized by alternative redox states of NO: nitric oxide (NO.) and nitrosonium ion (NO+). Nitric oxide, generated from NO. donors or synthesized endogenously after NMDA (N-methyl-D-aspartate) receptor activation, can lead to neurotoxicity. Here, we report that NO.- mediated neurotoxicity is engendered, at least in part, by reaction with superoxide anion (O2.-), apparently leading to formation of peroxynitrite (ONOO-), and not by NO. alone. In contrast, the neuroprotective effects of NO result from downregulation of NMDA-receptor activity by reaction with thiol group(s) of the receptor's redox modulatory site. This reaction is not mediated by NO. itself, but occurs under conditions supporting S-nitrosylation of NMDA receptor thiol (reaction or transfer of NO+). Moreover, the redox versatility of NO allows for its interconversion from neuroprotective to neurotoxic species by a change in the ambient redox milieu. The details of this complex redox chemistry of NO may provide a mechanism for harnessing neuroprotective effects and avoiding neurotoxicity in the central nervous system.

2,478 citations


"Role of Excitatory Amino Acid Trans..." refers background in this paper

  • ...Additionally, NO reacts with O 2 , producing peroxynitrite (OONO ) leading to neuron damage (Lipton et al., 1993; Yamauchi et al., 1998)....

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Journal ArticleDOI
14 Nov 1997-Cell
TL;DR: It is heartening to see that the caspase 1 knockout mouse has a complete absence of IL-1 and IL-18 activity, which bodes well for targeting by synthetic protease inhibitors without interfering with essential apoptotic functions, at least in the short term.

2,095 citations


"Role of Excitatory Amino Acid Trans..." refers background in this paper

  • ...Rats that received optimal doses of CEF displayed attenuation of cue-induced relapse to cocaineseeking behavior due to an increase in GLT1 expression in both prefrontal cortex and nucleus accumbens (Sari et al., 2009)....

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Journal ArticleDOI
13 Jun 1997-Science
TL;DR: Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury, which can be attributed to elevated levels of residual glutamate in the brains of these mice.
Abstract: Extracellular levels of the excitatory neurotransmitter glutamate in the nervous system are maintained by transporters that actively remove glutamate from the extracellular space. Homozygous mice deficient in GLT-1, a widely distributed astrocytic glutamate transporter, show lethal spontaneous seizures and increased susceptibility to acute cortical injury. These effects can be attributed to elevated levels of residual glutamate in the brains of these mice.

1,700 citations


"Role of Excitatory Amino Acid Trans..." refers background in this paper

  • ...A number of neurodegenerative diseases demonstrate a level of misfolded protein accumulation including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis (ALS; Kopito and Ron, 2000; Taylor et al., 2002)....

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