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  • br Dysregulation of glutamate transporter expression and fun


    Dysregulation of glutamate transporter expression and function Aberrant glutamate transporter function and expression are associated with various neurological disorders. Therefore, understanding the underlying mechanisms of EAAT1/2 expression may provide therapeutic targets for treating neurological disorders associated with impaired glutamate transporters (Fig. 2).
    Impairment of glutamate transporters in neurological disorders
    Pharmacological interventions targeting astrocytic glutamate transporters Several pharmacological agents have been shown to modulate GLAST/GLT-1 expression at the transcriptional and translational levels (Kim et al., 2003b, Kong et al., 2014, Pawlak et al., 2005). Despite the significant efficacy of these compounds, the molecular mechanisms involved in the upregulation of these transporters remain to be elucidated. For example, estrogen (primarily 17β-estradiol) increased both GLAST and GLT-1 at the transcriptional level and reversed manganese (Mn)-induced reduction of those transporters (Lee et al., 2009, Pajarillo et al., 2018). Various pharmacological agents regulating GLAST/GLT-1 expression and function are compared by their mode of action (Table 1).
    Conclusion Dysregulation of EAAT1/GLAST and EAAT2/GLT-1 have been strongly linked to the pathogenesis of various neurological disorders such as ALS, AD, PD, manganism, ischemia, schizophrenia, epilepsy, and autism. While epigenetic modifications, transcriptional regulation, RNA splicing and PTMs support the Bezafibrate sale and pleiotropic functions of astrocytic glutamate transporters, aberrancy of these processes contributes to the onset and progression of glutamate excitotoxicity. Accordingly, delineating the molecular mechanisms involved in the genetic, epigenetic, transcriptional and translational regulation of GLAST/GLT-1 expression and function is critical to further our understanding of glutamate excitotoxicity and neuropathogenesis. Likewise, drug targeting of glutamate transporters constitutes an exciting direction for exploration, which would extend our collective comprehension of neurological disorders and aid in the identification of potential therapeutic targets. Pharmacological agents such as β-lactam antibiotics, estrogen and SERMs, growth factors, HDACi, and translational activators show promising efficacy in increasing GLAST/GLT-1 expression and glutamate uptake in astrocytes, thus preventing Bezafibrate sale excitotoxic neuronal injury (Fig. 3).
    Introduction Ischemic stroke, resulting from the interruption of blood supply to the brain, is one of the most frequent causes of morbidity and mortality worldwide [1]. During the acute phase of stroke, glutamate homeostasis is disrupted, and glutamate levels rise above physiological concentrations in the extracellular fluid. This pathological situation leads to an overstimulation of glutamate receptors, followed by the excitotoxic death of neurons [2,3]. Under physiological conditions, once glutamate is released from excitatory neurons upon an action potential, the concentration of extracellular glutamate is tightly regulated by integral membrane electrogenic transporters, known as excitatory amino acid transporters (EAATs) [3]. Five subtypes of EAATs have been identified and characterized thus far [4]. Among these, the EAAT2 protein, which is mainly expressed in astroglial cells, is responsible for 90% of total glutamate uptake, thereby preventing neuronal excitotoxicity. Inside the astrocytes, glutamate is metabolized to glutamine or used for energy production. Glutamine is subsequently transferred to neurons for the replenishment of the glutamate pool via the glutamate–glutamine cycle [2,5,6]. The expression of EAAT2 has also been described on the antiluminal surface, i.e., the parenchymal side, of brain capillary endothelial cells. Here, the transporter assists in maintaining low glutamate concentrations in the cerebral extracellular fluid, thereby establishing a brain-to-blood glutamate efflux mechanism [7,8]. When the concentration of glutamate in the extracellular fluid is elevated, glutamate is actively transported unidirectionally via the endothelial EAAT2 into the endothelial cells, where it is accumulated until it overrides the blood concentration. Finally, glutamate is transported across the luminal membrane into the blood by facilitated diffusion [7,9,10]. Therefore, while blood glutamate may enter into endothelial cells, it can no go further, as no transport of glutamate is possible from endothelial cells into the brain [11].