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  • We observed the reduced expression of the GluN a


    We observed the reduced expression of the GluN2a subunit in the temporal and entorhinal cortexes and ventral hippocampus, which may result in the predominance of GluN2b-containing NMDA receptors during the latent period. Previously, using the same model, we revealed the reduction of the GluN2a/GluN2b mRNA expression ratio in the dorsal hippocampus one day after seizures. However, no changes were found in the ventral hippocampus or temporal cortex [38]. Di Maio et al., using Western blot analysis, revealed increased immunoreactivity for the GluN2b subunit in the hippocampus 24 h after pilocarpine injection [37]. The early up-regulation of GluN2b subunit production was shown in the hippocampus after pentylenetetrazole-induced convulsions [14] and in the pentylenetetrazole-kindling model [39]. However, a reduction in GluN2b and an increase in the expression of the GluN2a subunits were revealed in the hippocampus after seizures induced by the repeated administration of the convulsant drug 3-mercaptopropionic dpni [10,40]. An increase in GluN2a, but not of GluN2b, production was found upon immunohistochemical analysis after repeated epileptic seizures induced by the 12-day administration of 4-aminopyridine [41]. The difference between the models suggests that seizures may activate independent pathways that are critical in aberrant NMDA receptor subunit expression. Changes in the subunit composition of NMDA receptors are accompanied by alterations in the properties of excitatory synaptic transmission [38]. GluN2b-containing receptors provide a greater influx of Ca2+ through NMDA channels as compared to GluN2a-containing receptors. GluN2b-containing receptors likely play a crucial role in triggering neuronal hyperexcitability [11] and excitotoxicity [42].
    Conflicts of interest
    Acknowledgment This work was supported bythe Russian Science Foundation (grant number 16-15-10202).
    Introduction Many important biological processes involve redox reactions, and as a result, produce potentially dangerous byproducts. Oxidative phosphorylation, or oxidative metabolism, provides brain cells with most of their energy requirements. In fact, human brain cells use approximately 20% of the total oxygen consumed by the body, although the brain only makes up 2% of body weight (Clarke and Sokoloff, 1999). Reactive oxygen species (ROS) are continuously generated as a result of this large usage of oxygen, and therefore mechanisms are required to regulate the redox state of the brain. An unbalanced redox state and buildup of reactive oxygen species results in cell death and detrimental consequences for the brain. Oxidative stress occurs if an imbalance exists between oxidant production and neutralization. ROS, as free radical species, are highly reactive compounds. If they are not neutralized by cellular antioxidants, they create DNA damage and protein/enzyme oxidation, which leads to cellular dysfunction and death (Brooker, 2011). A number of characteristics of the brain make it more vulnerable to oxidative stress. In addition to the amount of ROS produced by its high oxygen consumption (Clarke and Sokoloff, 1999), some areas of the brain contain a high content of iron (Gerlach et al., 1994), which catalyzes ROS generation (Dringen, 2000), and the large amount of unsaturated fatty acid lipids found in the brain are targets for lipid peroxidation (Porter, 1984, Halliwell, 1992). Surprisingly, the levels of activity of common enzymes that catalyze the neutralization of free radicals, specifically superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), are lower in the brain than in other organs such as the liver and kidney (Ho et al., 1997). Common pathologies including neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS) involve ROS-mediated oxidative stress as part of their etiology (Dringen, 2000, Surmeier et al., 2011, Dalle-Donne et al., 2008, Dringen and Hirrlinger, 2003, Uttara et al., 2009, Zundorf and Reiser, 2011). Even normal aging may be, at least in part, due to ROS. The “free radical theory of aging” hypothesizes that free radical induced cellular damage builds up over time, ultimately resulting in aging and death [see Richman and Meister, 1975 for more on this topic]. Many mechanisms exist to regulate redox homeostasis. Here, we focus on the main mechanisms of redox control in the brain. We review the role of glutamate transporters in the production of the intracellular antioxidant glutathione (GSH) and its importance in redox homeostasis. We also discuss the role of glutamate transporter mediated redox imbalance in disease, and present new evidence suggesting their involvement in the radiation resistance of gliomas.