Roles of AEG‐1 in CNS neurons and astrocytes during noncancerous processes
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Since its initial identification, Astrocyte Elevated Gene‐1 ( AEG‐1 ) has been recognized as a “star” gene detected in most of the analyzed cancers; AEG‐1 can interact with signaling transduction molecules, such as PI3K/Akt and MAPK, to affect the function and viability of cells. Furthermore, its multiple other functions are also gradually being recognized. AEG‐1 participates in several biological processes, including embryonic development, glutamate excitotoxicity, inflammation, and endoplasmic reticulum stress. Most of the noncancerous roles of the AEG‐1 were identified in studies of the neurological disorders of the CNS. As an oncogene that promotes aberrant cellular processes within the CNS, AEG‐1 may also represent an important therapeutic target for the treatment of neurological disease. However, the exact role of the AEG‐1 in CNS under normal conditions is still unknown. This review will focus on the literature describing the role of this molecule in CNS neurons and astrocytes during noncancerous processes. © 2017 Wiley Periodicals, Inc.Keywords:
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Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders, including stroke, trauma and neurodegenerative diseases. Astrocytes are the main cells for the removal of glutamate in the synaptic cleft and may affect the tolerance of neurons to the glutamate excitotoxicity. Therefore, the present study aimed to investigate the tolerance of rat cortical neurons to glutamate excitotoxicity in the presence and absence of astrocytes. Rat cortical neurons in the presence or absence of astrocytes were exposed to different concentrations of glutamate (10‑2,000 µM) and 10 µM glycine for different incubation periods. After 24 h, the Cell Counting kit‑8 (CCK‑8) assay was used to measure the cytotoxicity to neurons in the presence or absence of astrocytes. According to the results, in the absence of astrocytes, glutamate induced a concentration‑dependent decrease of neuronal survival rate compared with the control rat cortical neurons, and the neurotoxic half‑maximal inhibitory concentration (IC50) at 15, 30 and 60 min was 364.5, 258.5 and 138.3 µM, respectively. Furthermore, in the presence of astrocytes, glutamate induced a concentration‑dependent decrease of neuronal survival rate compared with the control rat cortical neurons, and the neurotoxic IC50 at 15, 30 and 60 min was 1,935, 932.8 and 789.3 µM, respectively. However, astrocytic toxicity was not observed when the rat cortical astrocytes alone were exposed to different concentrations of glutamate (500, 1,000 and 2,000 µM) for 6, 12 and 24 h. In conclusion, the glutamate‑induced neurotoxic IC50 values at 15, 30 and 60 min were respectively higher in the presence of astrocytes as compared with those in the absence of astrocytes, suggesting that astrocytes can protect against rat cortical neuronal acute damage induced by glutamate.
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Glutamate-induced excitotoxicity is a major contributor to motor neuron degeneration in the pathogenesis of amyotrophic lateral sclerosis (ALS). The spinal cord × Neuroblastoma hybrid cell line (NSC-34) is often used as a bona fide cellular model to investigate the physiopathological mechanisms of ALS. However, the physiological response of NSC-34 to glutamate remains insufficiently described. In this study, we evaluated the relevance of differentiated NSC-34 (NSC-34D) as an in vitro model for glutamate excitotoxicity studies. NSC-34D showed morphological and physiological properties of motor neuron-like cells and expressed glutamate receptor subunits GluA1-4, GluN1 and GluN2A/D. Despite these diverse characteristics, no specific effect of glutamate was observed on cultured NSC-34D survival and morphology, in contrast to what has been described in primary culture of motor neurons (MN). Moreover, a small non sustained increase in the concentration of intracellular calcium was observed in NSC-34D after exposure to glutamate compared to primary MN. Our findings, together with the inability to obtain cultures containing only differentiated cells, suggest that the motor neuron-like NSC-34 cell line is not a suitable in vitro model to study glutamate-induced excitotoxicity. We suggest that the use of primary cultures of MN is more suitable than NSC-34 cell line to explore the pathogenesis of glutamate-mediated excitotoxicity at the cellular level in ALS and other motor neuron diseases.
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This hypothesis proposes that increased extracellular glutamate in Amyotrophic Lateral Sclerosis (ALS) and cerebral ischemia, currently viewed as a trigger for excitotoxicity, is actually beneficial as it stimulates the utilization of glutamate as metabolic fuel. Renewed appreciation of glutamate oxidation by ischemic neurons has raised questions regarding the role of extracellular glutamate in ischemia. Is it detrimental, as suggested by excitotoxicity in early in vitro studies, or beneficial, as suggested by its oxidation in later in vivo studies? The answer may depend on the activity of N-methyl-D-aspartate (NMDA) glutamate receptors. Early in vitro procedures co-activated NMDA receptors (NMDARs) containing 2A (GluN2A) and 2B (GluN2B) subunits, an event now believed to trigger excitotoxicity; however, during in vivo ischemia D-serine and zinc molecules are released and these ensure only GluN2B receptors are stimulated. This not only prevents excitotoxicity but also initiates signaling cascades that allow ischemic neurons to import and oxidize glutamate.
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ABSTRACT: In models of neurological disorders, increased extracellular glutamate and beneficial effects produced by glutamate‐receptor antagonists are consistently taken as supporting evidence of excitotoxicity. This systematic interpretation is over‐simplified and potentially misleading. High extracellular glutamate is not a reliable indicator of endogenous excitotoxixity, i.e., the intrinsic, potential neurotoxicity of endogenous glutamate whenever it accumulates extracellularly. Firstly, because the extracellular levels of glutamate necessary to produce depolarization and death in vivo , are far above those measured in models of neurological disorders. Secondly, because changes in the concentration of glutamate in the synaptic cleft (i.e., the relevant compartment for endogenous excitotoxicity) are not reflected extracellularly. Protection by glutamate‐receptor antagonists does not necessarily imply inhibition of excitotoxic abnormalities. Indeed, neuronal death initiated by insults such as ischemia results from multifactorial processes that may be interrelated. Therefore, beneficial effects resulting from an interaction with glutamate‐mediated transmission may actually render the cell more resistant to other deleterious mechanisms (e.g., mitochondrial injury, oxidative stress).
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Inhibition of Mg2+ Extrusion Attenuates Glutamate Excitotoxicity in Cultured Rat Hippocampal Neurons
Magnesium plays important roles in the nervous system. An increase in the Mg2+ concentration in cerebrospinal fluid enhances neural functions, while Mg2+ deficiency is implicated in neuronal diseases in the central nervous system. We have previously demonstrated that high concentrations of glutamate induce excitotoxicity and elicit a transient increase in the intracellular concentration of Mg2+ due to the release of Mg2+ from mitochondria, followed by a decrease to below steady-state levels. Since Mg2+ deficiency is involved in neuronal diseases, this decrease presumably affects neuronal survival under excitotoxic conditions. However, the mechanism of the Mg2+ decrease and its effect on the excitotoxicity process have not been elucidated. In this study, we demonstrated that inhibitors of Mg2+ extrusion, quinidine and amiloride, attenuated glutamate excitotoxicity in cultured rat hippocampal neurons. A toxic concentration of glutamate induced both Mg2+ release from mitochondria and Mg2+ extrusion from cytosol, and both quinidine and amiloride suppressed only the extrusion. This resulted in the maintenance of a higher Mg2+ concentration in the cytosol than under steady-state conditions during the ten-minute exposure to glutamate. These inhibitors also attenuated the glutamate-induced depression of cellular energy metabolism. Our data indicate the importance of Mg2+ regulation in neuronal survival under excitotoxicity.
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Glutamate neurotoxicity has been implicated in acute neurological disorders such as ischemia, and in chronic neurodegenerative diseases such as Huntington's disease (HD). Recently, a link between excitotoxicity and impairment of energy metabolism has been proposed. Important evidence suggests that metabolic inhibition exacerbates the toxic effect of glutamate. During hypoxic/ischemia metabolic disturbances are obvious, and several metabolic defects have been found in HD patients. Disruption of the ionic gradients during inhibition of metabolism can lead to glutamate release, impairment of glutamate transport, and activation of NMDA receptors. Glutamate receptor activation results in calcium influx which is a determinant step leading to cell death. Additionally mitochondrial failure results in an inadequate buffering of the calcium load induced by glutamate contributing to cell death.
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