Regulatory drugs of glutamate transporter 1 (EAAT2/GLT-1) expression and activity: role in quenching oxidative damage

in Redox Experimental Medicine
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Davinia Domínguez-González Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia- INCLIVA, Valencia, Spain

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Blanca Romero-Llopis Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia- INCLIVA, Valencia, Spain

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Marta Roldán-Lázaro Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia- INCLIVA, Valencia, Spain
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain

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Lorena Baquero Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia- INCLIVA, Valencia, Spain
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Rita Noverques Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia- INCLIVA, Valencia, Spain

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Federico V Pallardó Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia- INCLIVA, Valencia, Spain
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Juan Antonio Navarro Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
Department of Genetics, Universitat de València, Valencia, Spain
INCLIVA Biomedical Research Institute, Unversitat de València, Valencia, Spain

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Pilar Gonzalez-Cabo Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia- INCLIVA, Valencia, Spain
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Correspondence should be addressed to J A Navarro: juan.a.navarro@uv.es or P González: pilar.gonzalez-cabo@uv.es
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l-glutamate is one of the major neurotransmitters in the central nervous system, directly and indirectly involved in numerous brain functions. In several neurodegenerative diseases, it has been observed that an excess of extracellular glutamate overstimulates glutamate receptors, leading to exacerbated neuronal excitation in a process of excitotoxicity and oxidative damage that promotes neuronal death. A number of l-glutamate transporters have been identified in the membrane of neurons and astrocytes. They are responsible for the reuptake of glutamate released into the synaptic cleft after excitatory neurotransmission concomitantly regulating the extracellular concentration of glutamate, protecting neurons from its excitotoxic action. Among all of them, literature highlights glutamate transporter 1, known as excitatory amino acid transporter type 2 in humans and glutamate transporter type 1 in rodents, also known as solute carrier family 1 member 2. It is the predominant glutamate transporter in the brain and ensures the majority of l-glutamate reuptake. Decreased expression of this transporter along with increased levels of oxidative stress have been observed in several chronic and acute neurodegenerative disorders. For this reason, the use of drugs capable of both increasing the expression of glutamate transporter 1 and mitigating oxidative damage has been proposed as an effective therapeutic strategy for these pathologies. We present in this work an overview of the main drugs displaying such a double effect.

Abstract

l-glutamate is one of the major neurotransmitters in the central nervous system, directly and indirectly involved in numerous brain functions. In several neurodegenerative diseases, it has been observed that an excess of extracellular glutamate overstimulates glutamate receptors, leading to exacerbated neuronal excitation in a process of excitotoxicity and oxidative damage that promotes neuronal death. A number of l-glutamate transporters have been identified in the membrane of neurons and astrocytes. They are responsible for the reuptake of glutamate released into the synaptic cleft after excitatory neurotransmission concomitantly regulating the extracellular concentration of glutamate, protecting neurons from its excitotoxic action. Among all of them, literature highlights glutamate transporter 1, known as excitatory amino acid transporter type 2 in humans and glutamate transporter type 1 in rodents, also known as solute carrier family 1 member 2. It is the predominant glutamate transporter in the brain and ensures the majority of l-glutamate reuptake. Decreased expression of this transporter along with increased levels of oxidative stress have been observed in several chronic and acute neurodegenerative disorders. For this reason, the use of drugs capable of both increasing the expression of glutamate transporter 1 and mitigating oxidative damage has been proposed as an effective therapeutic strategy for these pathologies. We present in this work an overview of the main drugs displaying such a double effect.

Introduction

To ensure optimal signaling between neurons and proper function of the central nervous system (CNS), it is essential to maintain the balance between the release and reuptake/degradation of neurotransmitters. These act as mediators during the transmission of nerve impulses, so any imbalance in their transmembrane transport could lead to altered neuronal signaling and, consequently, result in CNS disorders (Duncan 2002).

L-glutamate is one of the major neurotransmitters in the CNS, directly and indirectly involved in numerous brain functions (Engelsen 2009, Shan et al. 2012, Vandenberg & Ryan 2013). At the glutamatergic synapse, l-glutamate is stored within vesicles in the presynaptic neuron and subsequently released into the synaptic cleft to act on glutamate receptors located on the surface of the postsynaptic neuron (Fig. 1) (Niciu et al. 2012, Soni et al. 2014). In several neurodegenerative diseases, it has been observed that an excess of extracellular glutamate overstimulates these receptors, leading to exacerbated neuronal excitation. This results in a process called excitotoxicity and oxidative damage that promotes neuronal death (Obrenovitch et al. 2000, Hynd et al. 2004, Zhou & Danbolt 2014).

Figure 1
Figure 1

Representation of excitatory glutamatergic synapse. l-glutamate is released from the presynaptic neuron and subsequently binds in the postsynaptic neuron to AMPA receptors, which mediate fast excitatory potentials, and NMDA receptors, which possess a Ca2+-permeable cation channel. At the same time, l-glutamate is captured by the EAAT2 receptor on the surface of astrocytes, where it is converted to glutamine by glutamine synthetase. This glutamine is then released and used by neurons as a glutamate precursor (Figure created with BioRender.com).

Citation: Redox Experimental Medicine 2024, 1; 10.1530/REM-24-0004

A number of l-glutamate transporters have been identified in the membranes of neurons and astrocytes, including the excitatory amino acid transporters (EAATs), the vesicular glutamate transporters (VGLUTs), and the cystine/glutamate antiporter system xc (Mestikawy et al. 2011, Brumovsky 2013, Hung et al. 2021). These transporters are responsible for sequestering glutamate released into the synaptic cleft after excitatory neurotransmission, thereby regulating the extracellular concentration of glutamate and protecting neurons from its excitotoxic action (Shigeri et al. 2004, Vandenberg & Ryan 2013, Rimmele et al. 2021).

Most of this l-glutamate transport in the CNS is carried out by the family of EAATs, which couple glutamate uptake to the transport of inorganic ions (Grewer et al. 2014, Magi et al. 2019, Kovermann et al. 2022). Within this family of transporters, five subtypes can be distinguished: EAAT1, EAAT2, EAAT3, EAAT4, and EAAT5 (Bridges & Esslinger 2005, Zaitsev et al. 2020). EAAT1 is mainly expressed in the cerebellum and at lower levels in the forebrain and hippocampus. EAAT2 is predominantly expressed in the forebrain, EAAT3 in several brain regions but at low levels, EAAT4 in the cerebellum, and lastly, EAAT5 in the retina (Bridges & Esslinger 2005, Castañeda-Cabral et al. 2020).

This review focuses on glutamate transporter 1 (known as EAAT2 in humans and GLT-1 in rodents), which is the predominant l-glutamate transporter in the brain and ensures the majority of l-glutamate reuptake (Gegelashvili & Bjerrum 2019, Castañeda-Cabral et al. 2020). The structure of EAAT2 consists of a homotrimer (Zhang et al. 2022), where each protomer is constituted by eight transmembrane helices (TM1–TM8) and two helical hairpins (HP1 and HP2), which in turn can be divided into transport and scaffold domains (Fig. 2) (Kato et al. 2022).

Figure 2
Figure 2

Representation of EAAT2 transporter structure in complex with glutamate. (A) Front view of the homotrimer. (B) Top view of the homotrimer. Each protomer of the homotrimer is composed, in turn, of transport and scaffold domains. The transport domain consists of two helical hairpins: HP1 and HP2 (light orange), and four transmembrane helices: TM3, TM6, TM7, and TM8 (dark orange). The scaffold domain consists of four transmembrane helices: TM1, TM2, TM4, and TM5 (blue) (Figure created with UCSF Chimera).

Citation: Redox Experimental Medicine 2024, 1; 10.1530/REM-24-0004

EAAT2 was initially described to be exclusively expressed in astrocytes, oligodendrocytes, and activated microglia albeit at lower levels. However, it has also been detected in nerve endings and axons of some hippocampal neurons (Robinson 1998, Rimmele & Rosenberg 2016, Gegelashvili & Bjerrum 2019), and in other non-nerve cells of connective, glandular, and liver tissues (Zoia et al. 2005, Berger & Hediger 2006), although the role of EAAT2 in them is not entirely known.

The gene that codifies the human EAAT2 transporter, SLC1A2, is about 168 kb in length, while the gene that codifies the rodent GLT-1 transporter, Slc1a2, is approximately 132 kb. SLC1A2 is constituted by 11 exons and has numerous splice variants that give rise to three different isoforms (Fig. 3). EAAT2a is the full-length variant and is mainly detected in the human brain, whereas EAAT2b and EAAT2c present distinctive C-terminal domains whose functions are still unknown (Alijanpour et al. 2023). Several transcription factor-binding sequences have been identified in the promoter of EAAT2, including NF-κB, N-myc, CREB, NFAT, Sp1, and EGR. Among all of them, NF-κB has been shown to be crucial in EAAT2 regulation, acting as an intrinsic activator. In several studies, it has been observed that for both the activation and transcriptional repression of EAAT2, activation of NF-κB is required (Takahashi et al. 2015).

Figure 3
Figure 3

Schematic structure of the SLC1A2 gene variants. SLC1A2 has around 50 different splice variants, which give rise to three distinct isoforms. (A) Transcript encoding EAAT2a represents the canonical sequence. (B) Transcript encoding EAAT2b has a deletion in the 5′ coding region (1–9). (C) Transcript encoding EAAT2c differs from the canonical one in the 3′ coding region (553–574) (Figure created with BioRender.com, based on information from Ensembl.org, release 111 – January 2024 (Martin et al. 2023)).

Citation: Redox Experimental Medicine 2024, 1; 10.1530/REM-24-0004

A decreased expression of this transporter has been observed in several chronic and acute neurodegenerative disorders, including Huntington’s, epilepsy, stroke, and several spinocerebellar ataxias, among many other CNS-related diseases (Miller et al. 2008, Bacigaluppi et al. 2016, Suto et al. 2016, Ramandi et al. 2021, Cvetanovic & Gray 2023). Although the underlying mechanism has not been fully elucidated, several reports have suggested that ROS reduce glutamate reuptake by either impairing the correct expression of transporters (Hayashi et al. 2002, Sivasubramanian et al. 2020) or by their oxidative inactivation (Miralles et al. 2001, Yun et al. 2007). Furthermore, high levels of extracellular glutamate inhibit the import of cystine, resulting in the depletion of glutathione inducing a form of cell injury called oxidative glutamate toxicity (Murphy et al. 1989). Interestingly, EAAT2 molecules are prone to be localized at lipid rafts in which cholesterol levels are critical for glutamate transport (Schubert & Piasecki 2001). In this line, in a study of EAAT2 inhibition using Cryo-EM, it has been recently suggested that increased levels of lipid peroxides might affect the structure, conformation, and stability of specific membrane domains further affecting glutamate transport (Kato et al. 2022). As a consequence, l-glutamate accumulates in the extracellular space and triggers multiple pathogenic cascades that ultimately lead to significant oxidative damage and cell death. For this reason, pharmacological upregulation of EAAT2 expression has been suggested as an effective therapeutic strategy in these pathologies (Soni et al. 2014, Peterson et al. 2021). Importantly, it has been proposed that this upregulation must be accompanied by mitigation of oxidative stress to achieve the increased glutamate uptake, suggesting that neuroprotection could only be provided by targeting both aspects as a single unit (Wilkie et al. 2021).

In light of their great importance, an overview of the main drugs that have been shown to regulate EAAT2/GLT-1 will be presented.

β-lactam antibiotics

β-lactams are a family of antibiotics with bactericidal activity. They have low direct toxicity due to the fact that they inhibit the synthesis of the bacterial cell wall, which is absent in the eukaryotic animal cell (Suárez & Gudiol 2009). That is why, given their safety, these antibiotics have been widely used since their discovery for the treatment of numerous infectious diseases.

Several findings in recent years have shown that β-lactam antibiotics have great therapeutic potential in the CNS, and for this reason, many members of this family have been extensively studied for the treatment of numerous degenerative pathologies (Rothstein et al. 2005, Althobaiti et al. 2019).

Ceftriaxone

Ceftriaxone (CFX) is a semisynthetic cephalosporin, belonging to the group of β-lactam antibiotics. It has a broad spectrum of activity against gram-positive and gram-negative bacteria, as well as some anaerobic bacteria, and can be administered both intravenously and intramuscularly (Richards et al. 1984). This β-lactam has shown a neuroprotective role in some in vitro models of ischemic injury and motor neuron degeneration (Rothstein et al. 2005), as well as being able to delay neuronal loss and improve cognitive function in animal models of amyotrophic lateral sclerosis (ALS), Parkinson’s disease, and Alzheimer’s disease (Miller et al. 2008, Bisht et al. 2014, Fan et al. 2018).

It has been described that CFX is able to enhance the expression of the glutamate transporter EAAT2 through activation of its gene promoter, although the mechanism by which this promoter is activated remains unknown (Konaklieva et al. 2009, Chang et al. 2013, Hurkacz et al. 2021, Kumari & Deshmukh 2021). At the same time, CFX is also capable of increasing the levels of endogenous antioxidant defense systems, thus neutralizing the action of free radicals. It increased the expression of glutathione peroxidase (GPx) and superoxide dismutase (SOD) in a rat model of short-term global cerebral ischemia and reperfusion (Altaş et al. 2013), and inhibited the expression of pro-apoptotic proteins of the Bcl-2 family in an OXYS rat model (Tikhonova et al. 2018). It has also been reported that CFX is able to increase the activity of the cystine/glutamate antiporter system xc , which provides cystine for the synthesis of glutathione. As low intracellular levels of cystine can cause glutathione deficiencies, CFX could provide neuroprotection precisely by increasing its intracellular levels through this antiporter system, thereby increasing antioxidant defense (Wilkie et al. 2021). In this regard, CFX treatment has been shown to ameliorate synapse loss and dendritic degeneration in a GLT-1-dependent manner by inhibiting the activation of macrophages and subsequent phagocytosis, in a rodent model of Alzheimer’s disease (Liu et al. 2023). CFX was also able to rescue GLT-1 expression and decrease glutamate levels, as well as prevent lipopolysaccharide (LPS)-induced neuroinflammation in LPS-treated mice (Gao et al. 2024).

Unfortunately, the therapeutic usefulness of cephalosporins, such as CFX in CNS diseases is low due to their unfavorable pharmacokinetic and pharmacodynamic properties. Their main limitations are their poor brain penetration ability and the need for intravenous administration (Kim et al. 2016). Current studies are precisely focusing on addressing these limitations by, for instance, developing carriers that improve the brain penetration of this drug (Padhi et al. 2023, Dawood et al. 2024).

Clavulanic acid

Another member of the β-lactam family whose therapeutic potential in the CNS is being strongly explored is clavulanic acid (CA). It exhibits weak antibacterial activity; however, when administered in combination with other β-lactams, it is capable of broadening the spectrum and potentiating their activity. This is because CA acts as an irreversible competitive inhibitor of bacterial β-lactamases, which are enzymes that hydrolyze and inactivate the β-lactam ring of these drugs (Cole 1982, Kim et al. 2009, Ghanbarabadi et al. 2019). CA itself is active and is adequately absorbed after oral administration, having a bioavailability of about 64% (Bolton et al. 1986). Moreover, it has been described as being able to cross the blood–brain barrier and penetrate the brain more easily than other β-lactams (Nakagawa et al. 1994, Kost et al. 2011).

It has already been shown that this compound enhances GLT-1 expression and decreases oxidative stress conditions, thus improving brain functions in many animal models of neurodegenerative diseases, although its exact mechanism of CNS modulation has not yet been elucidated (Kim et al. 2016, Althobaiti et al. 2019, Ghanbarabadi et al. 2019).

Some previous studies have suggested that CA could inhibit the production of reactive oxygen species (ROS) and reduce mitochondrial stress in neurodegenerative diseases, thus contributing to the survival of neurons. In this sense, CA has been shown to be able to disrupt the cell death cascade by attenuating the expression of proapoptotic Bax protein and caspase-3 protein, and also to inhibit neurotoxin-induced release of ROS in an in vitro study with P12 cells (Silakhori et al. 2019). In addition, CA increased GLT-1 expression and reduced the expression of genes of oxidative damage such as inducible nitric oxide synthase (iNOS) and genes involved in apoptosis, including bcl2 and bax, alleviating neuropathic pain in a rat model of diabetes mellitus (Kolahdouz et al. 2021). Similarly, in a mouse model exposed to cathinone, which is known to downregulate GLT-1 expression, CA succeeded in increasing GLT-1 levels and also improved neurobehavioral dysfunctions, such as memory impairment and anxiety-like behaviors (Arab et al. 2023).

Nevertheless, therapeutic doses of amoxicillin/clavulanate have been shown to cause idiosyncratic drug-induced liver injury with a cholestatic pattern of injury in a relevant number of patients (Beraldo 2013, Weersink et al. 2021). Mechanisms of cholestasis induced by these drugs have been studied in human in vitro hepatic models. Results suggest that CA, and not amoxicillin, could downregulate several key biliary transporters, thus promoting intrahepatic cholestasis (Petrov et al. 2021). Therefore, further research is urgently needed to determine its safety.

Ampicillin

Ampicillin (AMP) is another β-lactam antibiotic. It is a semi-synthetic penicillin that is also being studied as a potential enhancer of GLT-1 expression. Its main advantages are its lack of toxicity and its easy absorption after oral administration, although it presents a strong limitation since it penetrates the blood–brain barrier with difficulty (Acred et al. 1962).

Despite this, several studies have been conducted to study its neuroprotective role. This compound normalized GLT-1 and cystine/glutamate antiporter system levels in rats exposed to cocaine, which is known to reduce their expression (Hammad et al. 2017). In a mouse model of transient global forebrain ischemia, administration of AMP not only increased GLT-1 expression in the hippocampus but also reduced the activity of matrix metalloproteinases (MMPs), which are involved in extracellular matrix degradation. By regulating these aspects together, this drug attenuated forebrain ischemia in the treated animals (Lee et al. 2016).

Interestingly, some studies with alcohol-preferring rats chronically exposed to ethanol have shown that AMP treatment decreases ethanol intake, and this is partially associated with the upregulation of GLT-1. This was also observed with other β-lactam antibiotics (cefazolin and cefoperazone), and the results were similar (Alasmari et al. 2015, Rao et al. 2015). In relation to this, it has been observed that chronic ethanol consumption increases extracellular glutamate concentrations in some regions of the brain and overstimulates NMDA receptors, which has been associated with the activation of neuroinflammatory parameters, such as HMGB1, RAGE, and TNF-α. Based on this, it has been proposed that AMP treatment could not only attenuate ethanol drinking but also the neuroinflammatory process associated with it (Alasmari et al. 2020).

Benzothiazoles

Benzothiazole belongs to the family of bicyclic heterocyclic compounds, characterized by a benzene nucleus fused to a five-membered ring comprising nitrogen and sulfur atoms (Gill et al. 2015). Benzothiazoles have therapeutic utilities in many fields as they possess a number of favorable properties, such as anticonvulsant, neuroprotective, antimicrobial, anti-inflammatory, and anticancer activity, among many others (Kamal et al. 2015). In this regard, one member of this class called riluzole has been widely studied.

Riluzole

Riluzole (RZL) is the only drug currently approved by the FDA for ALS treatment (Fumagalli et al. 2008, Dharmadasa & Kiernan 2018). It is a neuroprotective agent with interesting anticonvulsant and glutamatergic modulatory properties, so it has been proposed and extensively studied for the treatment of other psychiatric and neurological disorders (Zarate & Manji 2008).

It has been described that RZL is able to improve glutamate uptake mediated by EAAT2, as it increases the affinity for glutamate (Fumagalli et al. 2008). In several in vitro models of rodent neurons and astrocytes, RZL has increased GLT-1 levels and activity in a dose-dependent manner (dos Santos Frizzo et al. 2004, Carbone et al. 2012, Naskar et al. 2022). Related to this, the canonical WNT/β-catenin pathway has been proposed as a promising target for RZL in the treatment of neurodegenerative diseases. The WNT/β-catenin pathway is downregulated in Alzheimer’s disease, resulting in increased oxidative stress and neuroinflammation, as well as decreased EAAT2 activity that leads to neuronal death (Vallée et al. 2020). In previous in vitro studies, it has been observed that RZL is able to potentiate the WNT/β-catenin pathway, which has been associated with its beneficial action on Alzheimer’s disease (Biechele et al. 2010).

This ability to enhance glutamate uptake has also been observed in vivo. Both GLT-1 expression and glutamate uptake were significantly increased in spinal cord synaptosomes from rats treated with RZL (Azbill et al. 2000). This effect was also noticed in another study, in which RZL treatment decreased methylmercury-induced oxidative damage in rat cerebral cortex by activating glutamate transporters and increasing the synthesis of glutathione (Deng et al. 2012).

The efficacy of riluzole treatment is currently being tested in pilot clinical trials. In a pilot phase 2 (NCT01703117) conducted in patients with Alzheimer’s disease, RZL significantly decreased cerebral glucose metabolism, which is a disease biomarker and predictor of disease progression; this correlated positively with cognitive measures, suggesting that there is regulation of the glutamatergic system by RZL (Matthews et al. 2021).

It is worth mentioning that RZL has some pharmacokinetic issues: a high first-pass liver metabolism that also depends on the heterogeneous expression of the cytochrome P450 isoform CYP1A2, resulting in high interindividual variability, and a poor oral bioavailability (60%) that can worsen when the drug is administered with food (van Kan et al. 2005, https://cima.aemps.es/cima/dochtml/ft/75160/FT_75160.html#4.2). In order to solve these problems, several prodrugs are currently under investigation.

Troriluzole

One relevant RLZ prodrug is troriluzole (TRZL). TRZL consists of a tripeptide carrier and RZL. As TRZL reaches the blood circulation, it is cleaved by peptidases allowing the release of the active form of RZL (Al-Horani 2023). TRZL, like RZL, is able to decrease glutamate concentration levels in the synaptic space by increasing the expression of glutamate transporters (i.e. EAAT2) (Grassi et al. 2020).

With TRZL, the oral bioavailability is increased and the impact of food is avoided. TRZL could potentially be taken once a day (Al-Horani 2023), instead of the twice-a-day dose regimen of RZL, making it more comfortable for patients and potentially improving adherence to treatment.

TRZL consists of a tripeptide carrier and RZL. As TRZL reaches the blood circulation, it is cleaved by peptidases, allowing the release of the active form of RZL (Al-Horani 2023). TRZL, like RZL, is able to decrease glutamate concentration levels in the synaptic space by increasing the expression of glutamate transporters (i.e. EAAT2) (Grassi et al. 2020).

Several phase II–III clinical trials are investigating TRZL as treatment for neurologic disorders like Alzheimer’s disease (https://clinicaltrials.gov/study/NCT03605667) or spinocerebellar ataxia (https://clinicaltrials.gov/study/NCT03701399), and also for other diseases such as generalized anxiety disorder (https://clinicaltrials.gov/study/NCT03829241), obsessive-compulsive disorder (https://clinicaltrials.gov/study/NCT04708834, https://clinicaltrials.gov/study/NCT03299166), and cancer (https://clinicaltrials.gov/study/NCT03970447).

Glucocorticoids

Glucocorticoids are anti-inflammatory, anti-allergic, and immunosuppressive drugs derived from cortisol, a hormone produced by the adrenal cortex, which plays an important role as a marker of stress since its levels increase in response to stressful situations (Barnes 2014, Adcock & Mumby 2016).

It has been observed both in vitro and in vivo that glucocorticoids regulate the expression of GLT-1 during pathophysiological processes, including stress (Zschocke et al. 2005, Autry et al. 2006). Although some of them are able to increase their expression and the glutamate uptake, others such as corticosterone seem to decrease it (Jacobsson et al. 2006). Therefore, there is controversy about the beneficial and detrimental effects of these compounds in the treatment of neurological disorders with EAAT2 as a target.

Despite this, dexamethasone, a glucocorticoid, has attracted particular attention in this field. Hence, research is focusing on studying the GLT-1-activating role of this compound.

Dexamethasone

Dexamethasone (DEX) is a synthetic glucocorticoid with a wide variety of medical applications that can be administered by oral tablets, oral solutions, or intravenously (Cohen 1973). In recent years, this compound has been investigated for the treatment of neurodegenerative disorders. Nevertheless, its main limitation is that it has poor brain penetration since the efflux transporter P-glycoprotein (Pgp), expressed in the blood–brain barrier, appears to hinder DEX uptake in the brain (Ronald De Koloet 1997, Karssen et al. 2005).

A few studies related to the role of DEX in oxidative stress and the regulation of EAAT2 transporter expression by this glucocorticoid have been performed. On the one hand, DEX has proven to be able to enhance GLT-1 receptor-mediated glutamate uptake during pathophysiological processes, including stress, in rodent primary astrocytes (Zschocke et al. 2005, Carbone et al. 2012). Additionally, DEX treatment produced upregulation of this receptor in a model of morphine-tolerant rats after the morphine challenge (Wen et al. 2005). On the other hand, in some other studies, DEX had precisely the opposite effect. It decreased GLT-1 expression in a model of hypoxia–ischemia-induced brain injury in neonatal rat pups, suggesting that it may aggravate brain injuries rather than reduce them (Chang et al. 2013). Related to this, it was proposed that ceftriaxone administration may ameliorate the adverse effects of DEX treatment precisely by increasing GLT-1 expression, but it does not appear that DEX by itself enhances it (Yeh et al. 2017).

Histone deacetylase inhibitors

It is well known that neurodegenerative diseases are not only regulated by genetic factors but also by epigenetic factors. Over the years, many epigenetic modifications strongly related to neurodegeneration have been identified, which influence gene and protein expression without changing the DNA sequence (Ghosh & Saadat 2023).

There is increasing evidence for epigenetic modifications such as DNA methylation, sumoylation, non-coding RNAs, and histone modifications of EAAT2/GLT-1 in numerous neurological disorders (Alam & Datta 2019, Pajarillo et al. 2019). For this reason, researchers are focusing on finding different ways to reverse the dysregulation of the levels of this transporter and thus preventing oxidative damage and neurodegeneration.

One of the main approaches is the use of histone deacetylase inhibitors (HDACis). Histone deacetylases (HDACs) are enzymes that play a crucial role in chromatin remodeling and thus gene expression regulation (Fig. 4), so alterations of their expression could induce neurodegenerative diseases. This is the reason why their selective inhibition has become one of the main therapeutic strategies used in recent years (Daśko et al. 2022). Several HDACis have been proposed as potential EAAT2 regulators, among which valproic acid and trichostatin A should be highlighted.

Figure 4
Figure 4

Mechanism of action of histone deacetylases (HDACs). HDACs remove the acetyl groups from histone lysines, increasing the positive charge and affinity of histones for DNA. As a consequence, the DNA structure is condensed, and transcription is prevented. Histone acetyltransferases (HATs) do just the opposite: they transfer acetyl groups to histone lysines and promote transcription. When histone deacetylase inhibitors (HDACis) selectively inhibit HDACs, chromatin remains in a relaxed state, and gene transcription is allowed (Figure created with BioRender.com.).

Citation: Redox Experimental Medicine 2024, 1; 10.1530/REM-24-0004

Valproic acid

Valproic acid (VPA) is a branched short-chain fatty acid derived from valeric acid, mainly used for the treatment of epilepsy and seizures due to its antiepileptic properties, although it can also be used to treat some other psychiatric disorders (Singh et al. 2021). These properties have been attributed to the ability of VPA to inhibit the degradation of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the CNS, which is responsible for reducing neuronal activity and whose alteration can lead to seizures (Ghodke-Puranik et al. 2013). Moreover, VPA is also able to enhance the expression of the NMDA receptor subunits and thus increase synaptic transmission mediated by this receptor (Rinaldi et al. 2007).

VPA has recently been demonstrated to act as an HDACi and to be able to regulate gene transcription by blocking the activity of HDACs. Precisely for this reason, it has been proposed as a promising treatment for cancers and neurodegenerative disorders (Safdar & Ismail 2023).

This HDACi has exerted neuroprotective effects in several experimental models, through multiple mechanisms including enhancement of GLT-1 levels, anti-oxidative stress, and anti-inflammation. It suppressed lipid peroxidation and oxidative DNA damage in a rat model of ischemia-reperfusion injury (Suda et al. 2013), as well as reducing neuronal death by inhibiting cytochrome C release mediated by oxidative stress and endoplasmic reticulum stress in a rat model of spinal cord injury (Lee et al. 2014). VPA increased both GLT-1 expression and glutamate uptake in astrocyte cultures and was also able to decrease histone acetylation, thus alleviating Mn-induced dopaminergic neurotoxicity (Johnson et al. 2018). Moreover, VPA treatment attenuated seizure activity in a rat model of epilepsy by up-regulating GLT-1 expression and decreasing glutaminase expression levels (Taspinar et al. 2021). Similarly, in another study, rats were treated with a combination of VPA and CA in addition to each compound separately, and in all cases, the behavioural and neuronal deficits were alleviated; they even showed synergistic effects in combination (Liu et al. 2021).

Trichostatin A

Another HDAC inhibitor that has been studied to potentiate GLT-1 expression and quench oxidative damage is Trichostatin A (TSA), an antifungal antibiotic with different properties in mammalian cell culture (Vigushin et al. 2001).

In recent years, several in vitro experiments have been performed to determine its role in the regulation of GLT-1 expression. TSA increased hyperacetylation of histones and EAAT2 expression in a dose-dependent manner in glioma cells (Zschocke et al. 2007). Also, TSA treatment stimulated GLT-1 transcription in cultured astrocytes, which was associated with increased histone H3 and H4 acetylation (Allritz et al. 2009). In another similar study, GLT-1 expression was suppressed by treatment with MPP+, a mitochondrial Complex 1 inhibitor known to induce oxidative stress in neurodegenerative diseases (Gandhi & Abramov 2012), and TSA treatment was able to prevent this MPP+-induced downregulation of GLT-1. Related to this, it was hypothesized that oxidative damage might activate protein kinase C and cause internalization and down expression of GLT-1. TSA might have an antioxidant role, preventing ROS increase and contributing to GLT-1 upregulation (Wu et al. 2008).

However, some HDACi have shown unfavorable pharmacokinetic properties and compromised potency in some in vivo experiments (McClure et al. 2016, Li et al. 2018b ). Therefore, further research is still critical in order to determine the efficacy of these two compounds in the treatment of neurodegenerative diseases.

MicroRNAs

miRNAs are a class of short noncoding RNAs, about 18–25 nucleotides in length, that post-transcriptionally control gene expression through translational repression or mRNA degradation. Each miRNA has been shown to control the expression of more than one mRNA, and each mRNA may be regulated by several miRNAs (Cai et al. 2009). Given this important role in the regulation of gene expression, any imbalance in miRNA levels can lead to the development of many different diseases (Erson & Petty 2008).

So far, only a few miRNAs have been observed to regulate EAAT2 levels. Some of them, such as miR-543-3p, miR-30a-5p, and miRNA-107, appear to decrease its expression and function, thereby contributing to disease progression (Wu et al. 2019, Meng et al. 2021, Zhang et al. 2021). For this reason, inhibitors of these miRNAs could be potential therapeutic targets for neurodegenerative diseases.

In contrast, it has been suggested that other miRNAs may increase EAAT2 expression. In this sense, miR-124 has attracted considerable attention, since it has shown a positive relationship with GLT-1 levels both in vitro and in vivo, although it is not known whether this interaction is direct or not (Morel et al. 2013). Related to this, it has been proposed that miR-124 may regulate GLT-1 expression via the Akt and mTOR pathways, which play an important role in the regulation of inflammation, oxidative stress, and autophagy (Huang et al. 2019).

Since this aspect of GLT-1 regulation has not been explored in detail, it is reasonable to assume that many other miRNAs may be responsible for the upregulation of EAAT2 expression. Therefore, further research is needed in this complex area.

HSP90 inhibitors

Heat shock protein 90 (HSP90) is a chaperone involved in the correct assembly of many important signaling proteins and in the regulation of their functional stability, so it is essential for the maintenance of cellular homeostasis and stress response (Jackson 2012). HSP90 has two different isoforms: HSP90α, predominantly expressed in the respiratory system and reproductive organs; and HSP90β, highly expressed in all the main tissues. Given this different tissue distribution, it has been suggested that they may have different physiological functions (Maiti & Picard 2022). In fact, numerous studies have shown that altered cells are more dependent on the HSP90β isoform in some diseases, whereas in others they are more dependent on the HSP90α isoform (Kim et al. 2019). For instance, it has been observed that HSP90β induces endothelial cell-dependent tumor angiogenesis in hepatocellular carcinoma (Meng et al. 2017), and HSP90α mediates matrix metalloproteinase 2 activation, increasing breast cancer cell migration and invasion (Sims et al. 2011).

HSP90β has been reported to downregulate EAAT2 expression in both in vitro and in vivo experiments (Sha et al. 2017, Liang et al. 2023). That is why researchers are investigating different inhibitors of this isoform for the treatment of neurodegenerative disorders, in order to recover physiological levels of the glutamate transporter. In this regard, the HSP90β inhibitor 17-AAG (17-allylamino-17-demethoxy-geldanamycin) has aroused special interest and, for this reason, the majority of the current studies are focusing on it.

17-AAG

17-AAG is an analog of the antibiotic geldanamycin, which has been widely studied as a potent anticancer drug due to its ability to inhibit HSP90 (Zhang et al. 2013, Hong et al. 2020). 17-AAG has also shown a neuroprotective role in several experimental models, which has opened up the opportunity to use it for the treatment of neurological disorders.

Treatment with 17-AAG attenuated autophagic neuronal death and improved learning and memory functions in a rat model of global cerebral ischemia (Li et al. 2015). Also, it was able to protect against sevoflurane-induced apoptosis both in vitro and in vivo, by HSP70-dependent inhibition of apoptosis, oxidative stress, and pro-inflammatory signaling pathway (Liu et al. 2020). Interestingly, an up-regulation of HSP90β was observed in astrocytes of patients with temporal lobe epilepsy as well as in mouse models of rats, and treatment with 17-AGG suppressed spontaneous recurrent seizures and improved astrogliosis. Related to this, it was proposed that HSP90β may recruit GLT-1 to the proteasome and promote its degradation, and 17-AGG would prevent this by inhibiting HSP90β (Sha et al. 2017). This hypothesis was further explored in a mouse model of epilepsy; however, in this case, 17-AAG treatment did not have a remarkable therapeutic effect, despite successfully reducing HSP90β expression and increasing GLT-1 expression (Peng et al. 2019).

Allosteric modulators

Allosteric regulation is a process whereby the binding of one molecule in a specific location modifies the binding conditions of another molecule at a different location in the same molecule. In allostery, the ligand induces conformational changes that are propagated between the allosterically coupled binding sites of the target protein (Kern & Zuiderweg 2003).

It has been suggested that positive allosteric modulation of EAAT2 could be an interesting and novel therapeutic strategy for the treatment of neurological disorders characterized by glutamate excitotoxicity, by decreasing glutamate levels in the cleft (Kortagere et al. 2018). For this purpose, several pharmacological compounds have been studied.

Parawixin-1

Parawixin-1 is a compound purified from Parawixia bistriata spider venom, which has demonstrated a neuroprotective role through stimulation of glial glutamate transporter activity in several studies (Kurkinen 2022).

Parawixin-1 increased glutamate uptake and inhibited GABA uptake in a dose-dependent manner in synaptosomes from the cerebral cortex of rats. Interestingly, the researchers found that a single fraction of parawixin-1, termed PbTx1.2.3, was able to stimulate glutamate uptake without affecting GABA uptake, indicating that the active component of PbTx1.2.3 is specific for glutamate transport. Furthermore, it appears that this component mediates its effect by increasing V max for glutamate uptake reaction without changing the K M value. PbTx1.2.3 was tested in rats subjected to ischemia and reperfusion, and it protected neurons from excitotoxicity. In turn, they also observed that the venom itself was able to inhibit GABA uptake, suggesting that another of its components is responsible for GABA regulation (Fontana et al. 2003).

Fontana et al. attempted to elucidate the mechanism of action of parawixin-1 using COS-7 cells transfected with EAAT1, EAAT2, and EAAT3. Parawixin-1 increased glutamate uptake by up to 70% in cells expressing EAAT2, but not in cells expressing EAAT1 or EAAT3, demonstrating that it is specific for the EAAT2 transporter. Importantly, they found that this enhancement of glutamate uptake is not related to increased EAAT2 expression, but increased EAAT2 activity. They observed that parawixin-1 enhanced glutamate transport only when sodium was present and not potassium. This suggested that this compound may not effectively bind to the carrier oriented toward the cytoplasm, which is a state favored when external sodium is replaced by potassium. Related to this, parawixin-1 enhanced glutamate uptake by the wild-type EAAT2 but did not change transport in the EAAT2 mutant defective in the potassium-dependent reorientation step. As parawixin-1 does not compete with the primary substrate, it appears that this compound acts allosterically to facilitate potassium-dependent conformational changes, allowing the unoccupied glutamate-binding site to reorient back to an outward-facing configuration (Fontana et al. 2007).

In another study, the specificity of parawixin-1 was studied using chimeric proteins between EAAT2 and EAAT3 and mutants to determine the structure of its target. Two critical residues for selectivity and for the activity of the venom were identified in the transmembrane domain 2 (TM2): histidine-71 in EAAT2 and serine 45 in EAAT3. Subsequently, several neighboring amino acid residues in TM5 and TM8 were identified to also be important. These form a size-limited domain that may fit well with the estimated size of parawixin-1 (Mortensen et al. 2015).

GT949, GT951, and GT939

Based on the results obtained with parawixin-1, researchers subsequently attempted to find other allosteric regulators of EAAT2/GLT-1. By virtual screening using information derived from crystal structures of the bacterial homolog of EAAT2 (GltPh), they identified ten small molecules that interact with the proposed domain, of which three were positive allosteric modulators: GT949, GT951, and GT939. The first two molecules were studied in COS-7 cells transfected with EAAT2 and in cultured astrocytes, and in both cases, they were able to enhance glutamate uptake in a dose-dependent manner (Kortagere et al. 2018). The neuroprotective potential of GT949 was studied in primary culture models of excitotoxicity (neurons and glial cells subjected to glutamate treatment) and oxidative damage (neurons and glial cells subjected to hydrogen peroxide). In the excitotoxicity model, this compound significantly increased neuronal survival. However, no neuroprotection was observed in the oxidative stress model, which appeared to be due to damage to the glia and fragmentation of EAAT2 caused by hydrogen peroxide (Falcucci et al. 2019).

Natural compounds

Ginsenoside

Ginsenoside is the most active ingredient of ginseng, the root of a small herbaceous plant of the Araliaceae family called Panax ginseng C. A. Meyer. This natural compound has previously shown neuroprotective effects both in in vitro and in vivo experiments. Therefore, it has been proposed as a potential treatment for neurodegenerative disorders.

In rat hippocampal neurons, ginsenoside treatment prevented oxygen-glucose deprivation-induced apoptosis by reducing the intracellular production of ROS and malondialdehyde, as well as enhancing antioxidant activities of GPx, SOD, and catalase (CAT). This compound appears to stabilize the mitochondrial membrane potential and thus reduce apoptotic death (Ye et al. 2009). Similarly, ginsenoside also inhibited glutamate-induced cell death and reduced apoptosis in a dose-dependent manner in an in vitro model of rat cortical neurons (Li et al. 2010).

This compound has not only been shown to reduce oxidative stress and apoptosis but also to increase EAAT2 expression both in vitro and in vivo. Ginsenoside treatment enhanced mRNA expression and protein levels of GLT-1, as well as glutamate uptake, in cultured astrocytes and in a rat model. Interestingly, after oxygen-glucose deprivation, ginsenoside was also able to increase the levels of phosphorylated protein kinase B (PKB/Akt) and phospho-ERK1/2 (p-ERK1/2), whose signaling pathways are involved in cell proliferation and differentiation. Their phosphorylation activates NF-kB transcription factor and cAMP-response element binding protein (CREB), which are known to control GLT-1 transcription (Zhang 2013). It also increased GLT-1 expression and glutamate uptake, inhibited glutamate-induced excessive activation of NMDA, and decreased the release of cytochrome C in animal models of microperfusion and photothrombosis, thus reducing neuronal damage caused by mitochondrial stress (Wang et al. 2017). Furthermore, it was able to attenuate glutamate excitotoxicity by upregulating GLT-1 expression and function, as well as decreasing α-synuclein expression and astrocyte inflammation (astrogliosis) in a mouse model of Parkinson’s disease. Also, ginsenoside promoted nuclear translocation of NF-kB, which was related to increased GLT-1 expression (Zhang et al. 2018). In the same way, it restored decreased EAAT2 expression and overexpression of proinflammatory cytokines in a cardiac arrest and cardiopulmonary resuscitation rat model (Wu et al. 2023).

Pinostrobin

Pinostrobin is a bioflavonoid isolated from the rhizomes of the medicinal plant Boesenbergia rotunda, which has shown antioxidant, anti-inflammatory, and neuroprotective effects in several previous studies. Moreover, its potential as an EAAT2 enhancer is also being studied. This compound decreased oxidative damage and attenuated cognitive impairment in a rat model, in which increased neuronal density and glial fibrillary acidic protein expression were observed. In addition, it increased EAAT2 expression (Thongrong et al. 2023).

Although its relation to EAAT2 is still sparse, it is a very interesting candidate because it prevented β-amyloid peptide-induced neurotoxicity by inhibiting oxidative stress and intracellular calcium influx in an in vitro model of Alzheimer’s disease. β-amyloid peptide treatment elevated intracellular levels of ROS and calcium and decreased the activity of caspase-3 in PC12 cells, whereas pinostrobin treatment reverted these conditions (Xian et al. 2012). Similarly, it inhibited MPP+-induced apoptotic cascades in SH-SY5Y cells (decrease of ROS generation and upregulation of the antioxidants GPx, SOD, and CAT), and also alleviated the loss of dopaminergic neurons and locomotion deficiency induced by the neurotoxin, MPTP in a zebrafish model (Li et al. 2018a ). These effects were also observed in a study with MPTP-treated rats, in which pinostrobin not only increased the levels of SOD and GPx but also those of GDNF, a protein that promotes the survival of many types of neurons (Kongsui et al. 2023).

Conclusion

Glutamate transporter 1 (EAAT2/GLT-1) is a promising target for the treatment of neurodegenerative diseases, in which extensive glutamate excitotoxicity and oxidative stress occur. It has been proposed that neuroprotection could be achieved precisely by pharmacologically increasing the expression of EAAT2 and mitigating oxidative damage. For this reason, numerous drugs are being intensively studied as possible therapeutic strategies to prevent excitotoxicity, neurodegeneration, and oxidative stress associated with excess extracellular glutamate in these types of diseases. Although these drugs have so far shown promise as therapies for neurological disorders, further research is urgently needed to determine their safety and efficacy, as well as to fully elucidate their mechanism of action.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

The study was funded by ‘Fondo de Investigación Sanitaria’ (grant no. PI22/00507).

Author contribution statement

DDG, BRL, and MRL wrote the manuscript and drew the images; LB and RN performed the documentation search and analysis; FVP, JAN, and PGC provided financial support, and revised the manuscript.

References

  • Acred P, Brown DM, Turner DH & & Wilson MJ 1962 Pharmacology and chemotherapy of ampicillin - a new broad‐spectrum penicillin. British Journal of Pharmacology and Chemotherapy 18 356369. (https://doi.org/10.1111/j.1476-5381.1962.tb01416.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Adcock IM & & Mumby S 2016 Glucocorticoids. In Pharmacology and Therapeutics of Asthma and COPD. Handbook of Experimental Pharmacology, vol. 237, pp. 71196. Eds Page CP, & Barnes PJ. (https://doi.org/10.1007/164_2016_98)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alam MA & & Datta PK 2019 Epigenetic regulation of excitatory amino acid transporter 2 in Neurological Disorders. Frontiers in Pharmacology 10 1510. (https://doi.org/10.3389/fphar.2019.01510)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alasmari F, Abuhamdah S & & Sari Y 2015 Effects of ampicillin on cystine/glutamate antiporter and glutamate transporter 1 isoforms as well as ethanol drinking in male P rats. Neuroscience Letters 600 148152. (https://doi.org/10.1016/j.neulet.2015.06.015)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alasmari F, Alhaddad H, Wong W, Bell RL & & Sari Y 2020 Ampicillin/sulbactam treatment modulates NMDA receptor NR2B subunit and attenuates neuroinflammation and alcohol intake in male high alcohol drinking rats. Biomolecules 10 1030. (https://doi.org/10.3390/biom10071030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Al-Horani RA 2023 Riluzole and its prodrugs for the treatment of Alzheimer’s disease. Pharmaceutical Patent Analyst 12 7985. (https://doi.org/10.4155/ppa-2023-0001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alijanpour S, Miryounesi M & & Ghafouri-Fard S 2023 The role of excitatory amino acid transporter 2 (EAAT2) in epilepsy and other neurological disorders. Metabolic Brain Disease 38 116. (https://doi.org/10.1007/s11011-022-01091-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Allritz C, Bette S, Figiel M & & Engele J 2009 Endothelin-1 reverses the histone deacetylase inhibitor-induced increase in glial glutamate transporter transcription without affecting histone acetylation levels. Neurochemistry International 55 2227. (https://doi.org/10.1016/j.neuint.2008.12.020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Altaş M, Meydan S, Aras M, Yılmaz N, Ulutaş KT, Okuyan HM & & Nacar A 2013 Effects of ceftriaxone on ischemia/reperfusion injury in rat brain. Journal of Clinical Neuroscience 20 457461. (https://doi.org/10.1016/j.jocn.2012.05.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Althobaiti YS, Alshehri FS, Hakami AY, Hammad AM & & Sari Y 2019 Effects of clavulanic acid treatment on reinstatement to methamphetamine, glial glutamate transporters, and mGluR 2/3 expression in P rats exposed to ethanol. Journal of Molecular Neuroscience 67 115. (https://doi.org/10.1007/s12031-018-1194-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Arab AO, Alasmari F, Albaker AB, Alhazmi HA, Alameen AA, Alagail NM, Alwaeli SA, Rizwan Ahamad S, AlAsmari AF & & AlSharari SD 2023 Clavulanic acid improves memory dysfunction and anxiety behaviors through upregulating glutamatergic transporters in the nucleus accumbens of mice repeatedly exposed to khat extract. International Journal of Molecular Sciences 24 15657. (https://doi.org/10.3390/ijms242115657)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Autry AE, Grillo CA, Piroli GG, Rothstein JD, McEwen BS & & Reagan LP 2006 Glucocorticoid regulation of GLT-1 glutamate transporter isoform expression in the rat hippocampus. Neuroendocrinology 83 371379. (https://doi.org/10.1159/000096092)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Azbill RD, Mu X & & Springer JE 2000 Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Research 871 175180. (https://doi.org/10.1016/S0006-8993(0002430-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bacigaluppi M, Russo GL, Peruzzotti-Jametti L, Rossi S, Sandrone S, Butti E, de Ceglia R, Bergamaschi A, Motta C, Gallizioli M, et al.2016 Neural stem cell transplantation induces stroke recovery by upregulating glutamate transporter GLT-1 in astrocytes. The Journal of Neuroscience 36 1052910544. (https://doi.org/10.1523/JNEUROSCI.1643-16.2016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Barnes PJ 2014 Glucocorticoids. In History of Allergy. Chemical Immunology and Allergy, vol. 100, pp. 311316. Eds Bergmann KC, & Ring J. Karger Publishers. (https://doi.org/10.1159/000359984)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Beraldo DO 2013 Acute cholestatic hepatitis caused by amoxicillin/clavulanate. World Journal of Gastroenterology 19 87898792. (https://doi.org/10.3748/wjg.v19.i46.8789)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Berger UV & & Hediger MA 2006 Distribution of the glutamate transporters GLT-1 (SLC1A2) and GLAST (SLC1A3) in peripheral organs. Anatomy and Embryology 211 595606. (https://doi.org/10.1007/s00429-006-0109-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Biechele TL, Camp ND, Fass DM, Kulikauskas RM, Robin NC, White BD, Taraska CM, Moore EC, Muster J, Karmacharya R, et al.2010 Chemical-genetic screen identifies riluzole as an enhancer of Wnt/β-catenin signaling in melanoma. Chemistry and Biology 17 11771182. (https://doi.org/10.1016/j.chembiol.2010.08.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bisht R, Kaur B, Gupta H & & Prakash A 2014 Ceftriaxone mediated rescue of nigral oxidative damage and motor deficits in MPTP model of Parkinson’s disease in rats. NeuroToxicology 44 7179. (https://doi.org/10.1016/j.neuro.2014.05.009)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bolton GC, Allen GD, Davies BE, Filer CW & & Jeffery DJ 1986 The disposition of clavulanic acid in man. Xenobiotica 16 853863. (https://doi.org/10.3109/00498258609038967)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bridges RJ & & Esslinger CS 2005 The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity of the EAAT subtypes. Pharmacology and Therapeutics 107 271285. (https://doi.org/10.1016/j.pharmthera.2005.01.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Brumovsky PR 2013 VGLUTs in peripheral neurons and the spinal cord: time for a review. ISRN Neurology 2013 829753. (https://doi.org/10.1155/2013/829753)

  • Cai Y, Yu X, Hu S & & Yu J 2009 A brief review on the mechanisms of miRNA regulation. Genomics, Proteomics & Bioinformatics 7 147154. (https://doi.org/10.1016/S1672-0229(0860044-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Carbone M, Duty S & & Rattray M 2012 Riluzole elevates GLT-1 activity and levels in striatal astrocytes. Neurochemistry International 60 3138. (https://doi.org/10.1016/j.neuint.2011.10.017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Castañeda-Cabral JL, López-Ortega JG, Fajardo-Fregoso BF, Beas-Zárate C & & Ureña-Guerrero ME 2020 Glutamate induced neonatal excitotoxicity modifies the expression level of EAAT1 (GLAST) and EAAT2 (GLT-1) proteins in various brain regions of the adult rat. Neuroscience Letters 735 135237. (https://doi.org/10.1016/j.neulet.2020.135237)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chang KH, Yeh CM, Yeh CY, Huang CC & & Hsu KS 2013 Neonatal dexamethasone treatment exacerbates hypoxic-ischemic brain injury. Molecular Brain 6 18. (https://doi.org/10.1186/1756-6606-6-18)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cohen EM 1973 Dexamethasone. In Analytical Profiles of Drug Substances, vol. 2, pp. 163197. Ed Florey K. (https://doi.org/10.1016/S0099-5428(0860039-8)

  • Cole M 1982 Biochemistry and action of clavulanic acid. Scottish Medical Journal 27 S10S16. (https://doi.org/10.1177/00369330820270S103)

  • Cvetanovic M & & Gray M 2023 Contribution of glial cells to polyglutamine diseases: observations from patients and mouse models. Neurotherapeutics 20 4866. (https://doi.org/10.1007/s13311-023-01357-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Daśko M, de Pascual-Teresa B, Ortín I & & Ramos A 2022 HDAC inhibitors: innovative strategies for their design and applications. Molecules 27 715. (https://doi.org/10.3390/molecules27030715)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dawood KM, Dardeer HM, Abdel atty HA, El Hassan M, Rasslan MA, Mohamed SK, Farghaly OA & & Nafady A 2024 Design, assessment and antibacterial potency of novel pseudopolyrotaxanes based on cyclodextrin as drug carriers for amoxicillin and ceftriaxone. Journal of Molecular Structure 1296 136906. (https://doi.org/10.1016/j.molstruc.2023.136906)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Deng Y, Xu ZF, Liu W, Xu B, Yang HB & & Wei YG 2012 Riluzole-triggered GSH synthesis via activation of glutamate transporters to antagonize methylmercury-induced oxidative stress in rat cerebral cortex. Oxidative Medicine and Cellular Longevity 2012 534705. (https://doi.org/10.1155/2012/534705)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dharmadasa T & & Kiernan MC 2018 Riluzole, disease stage and survival in ALS. The Lancet Neurology 17 385386. (https://doi.org/10.1016/S1474-4422(1830091-7)

  • dos Santos Frizzo ME, Dall’Onder LP, Dalcin KB & & Souza DO 2004 Riluzole enhances glutamate uptake in rat astrocyte cultures. Cellular and Molecular Neurobiology 24 123128. (https://doi.org/10.1023/B:CEMN.0000012717.37839.07)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Duncan JS 2002 Neurotransmitters, drugs and brain function. British Journal of Clinical Pharmacology 53 648648. (https://doi.org/10.1046/j.1365-2125.2002.01607.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Engelsen B 2009 Neurotransmitter glutamate: its clinical importance. Acta Neurologica Scandinavica 74 337355. (https://doi.org/10.1111/j.1600-0404.1986.tb03524.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Erson AE & & Petty EM 2008 MicroRNAs in development and disease. Clinical Genetics 74 296306. (https://doi.org/10.1111/j.1399-0004.2008.01076.x)

  • Falcucci RM, Wertz R, Green JL, Meucci O, Salvino J & & Fontana ACK 2019 Novel positive allosteric modulators of glutamate transport have neuroprotective properties in an in vitro excitotoxic model. ACS Chemical Neuroscience 10 34373453. (https://doi.org/10.1021/acschemneuro.9b00061)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fan S, Xian X, Li L, Yao X, Hu Y, Zhang M & & Li W 2018 Ceftriaxone improves cognitive function and upregulates GLT-1-Related glutamate-glutamine cycle in APP/PS1 mice. Journal of Alzheimer’s Disease 66 17311743. (https://doi.org/10.3233/JAD-180708)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fontana ACK, Guizzo R, Beleboni RO, Meirelles e Silva AR, Coimbra NC, Amara SG, Santos WF & & Coutinho-Netto J 2003 Purification of a neuroprotective component of parawixia bistriata spider venom that enhances glutamate uptake. British Journal of Pharmacology 139 12971309. (https://doi.org/10.1038/sj.bjp.0705352)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fontana ACK, de Oliveira Beleboni R, Wojewodzic MW, Santos WF, Coutinho-Netto J, Grutle NJ, Watts SD, Danbolt NC & & Amara SG 2007 Enhancing glutamate transport: mechanism of action of parawixin1, a neuroprotective compound from Parawixia bistriata spider venom. Molecular Pharmacology 72 12281237. (https://doi.org/10.1124/mol.107.037127)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fumagalli E, Funicello M, Rauen T, Gobbi M & & Mennini T 2008 Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. European Journal of Pharmacology 578 171176. (https://doi.org/10.1016/j.ejphar.2007.10.023)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gandhi S & & Abramov AY 2012 Mechanism of oxidative stress in neurodegeneration. Oxidative Medicine and Cellular Longevity 2012 428010. (https://doi.org/10.1155/2012/428010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gao R, Ali T, Liu Z, Li A, Hao L, He L, Yu X & & Li S 2024 Ceftriaxone averts neuroinflammation and relieves depressive-like behaviors via GLT-1/TrkB signaling. Biochemical and Biophysical Research Communications 701 149550. (https://doi.org/10.1016/j.bbrc.2024.149550)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gegelashvili G & & Bjerrum OJ 2019 Glutamate transport system as a key constituent of glutamosome: molecular pathology and pharmacological modulation in chronic pain. Neuropharmacology 161 107623. (https://doi.org/10.1016/j.neuropharm.2019.04.029)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghanbarabadi M, Falanji F, Rad A, Chazani Sharahi N, Amoueian S, Amin M, Molavi M & & Amin B 2019 Neuroprotective effects of clavulanic acid following permanent bilateral common carotid artery occlusion in rats. Drug Development Research 80 11101119. (https://doi.org/10.1002/ddr.21595)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB & & Klein TE 2013 Valproic acid pathway. Pharmacogenetics and Genomics 23 236241. (https://doi.org/10.1097/FPC.0b013e32835ea0b2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ghosh P & & Saadat A 2023 Neurodegeneration and epigenetics: a review. Neurología 38 6268. (https://doi.org/10.1016/j.nrleng.2023.05.001)

  • Gill RK, Rawal RK & & Bariwal J 2015 Recent advances in the chemistry and biology of benzothiazoles. Archiv Der Pharmazie 348 155178. (https://doi.org/10.1002/ardp.201400340)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Grassi G, Cecchelli C, Vignozzi L & & Pacini S 2020 Investigational and experimental drugs to treat obsessive-compulsive disorder. Journal of Experimental Pharmacology 12 695706. (https://doi.org/10.2147/JEP.S255375)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Grewer C, Gameiro A & & Rauen T 2014 SLC1 glutamate transporters. Pflügers Archiv - European Journal of Physiology 466 324. (https://doi.org/10.1007/s00424-013-1397-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hammad AM, Alasmari F, Althobaiti YS & & Sari Y 2017 Modulatory effects of ampicillin/sulbactam on glial glutamate transporters and metabotropic glutamate receptor 1 as well as reinstatement to cocaine-seeking behavior. Behavioural Brain Research 332 288298. (https://doi.org/10.1016/j.bbr.2017.06.017)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hayashi M, Araki S, Arai N, Kumada S, Itoh M, Tamagawa K, Oda M & & Morimatsu Y 2002 Oxidative stress and disturbed glutamate transport in spinal muscular atrophy. Brain and Development 24 770775. (https://doi.org/10.1016/S0387-7604(0200103-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hong LJ, Chen AJ, Li FZ, Chen KJ & & Fang S 2020 The HSP90 inhibitor, 17-AAG, influences the activation and proliferation of T lymphocytes via AKT/GSK3β signaling in MRL/lpr mice. Drug Design, Development and Therapy 14 46054612. (https://doi.org/10.2147/DDDT.S269725)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huang WY, Jiang C, Ye HB, Jiao JT, Cheng C, Huang J, Liu J, Zhang R & & Shao JF 2019 miR-124 upregulates astrocytic glutamate transporter-1 via the Akt and mTOR signaling pathway post ischemic stroke. Brain Research Bulletin 149 231239. (https://doi.org/10.1016/j.brainresbull.2019.04.013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hung CC, Lin CH & & Lane HY 2021 Cystine/glutamate antiporter in schizophrenia: from molecular mechanism to novel biomarker and treatment. International Journal of Molecular Sciences 22 9718. (https://doi.org/10.3390/ijms22189718)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hurkacz M, Dobrek L & & Wiela-Hojeńska A 2021 Antibiotics and the nervous system—which face of antibiotic therapy is real, Dr. Jekyll (neurotoxicity) or Mr. Hyde (neuroprotection)? Molecules 26 7456. (https://doi.org/10.3390/molecules26247456)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hynd MR, Scott HL & & Dodd PR 2004 Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochemistry International 45 583595. (https://doi.org/10.1016/j.neuint.2004.03.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jackson SE 2012 Hsp90: structure and function. In Molecular Chaperones, vol. 328, pp. 155240. Ed Jackson S. (https://doi.org/10.1007/128_2012_356)

  • Jacobsson J, Persson M, Hansson E & & Rönnbäck L 2006 Corticosterone inhibits expression of the microglial glutamate transporter GLT-1 in vitro. Neuroscience 139 475483. (https://doi.org/10.1016/j.neuroscience.2005.12.046)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Johnson J, Pajarillo E, Karki P, Kim J, Son DS, Aschner M & & Lee E 2018 Valproic acid attenuates manganese-induced reduction in expression of GLT-1 and GLAST with concomitant changes in murine dopaminergic neurotoxicity. NeuroToxicology 67 112120. (https://doi.org/10.1016/j.neuro.2018.05.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kamal A, Syed MAH & & Mohammed SM 2015 Therapeutic potential of benzothiazoles: a patent review (2010–2014). Expert Opinion on Therapeutic Patents 25 335349. (https://doi.org/10.1517/13543776.2014.999764)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Karssen AM, Meijer OC & & de Kloet ER 2005 Corticosteroids and the blood–brain barrier. In Techniques in the Behavioral and Neural Sciences, vol. 15, pp. 329340. Eds Stecklet T, Kalin NH, & Reul JMHM. (https://doi.org/10.1016/S0921-0709(0580019-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kato T, Kusakizako T, Jin C, Zhou X, Ohgaki R, Quan L, Xu M, Okuda S, Kobayashi K, Yamashita K, et al.2022 Structural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2. Nature Communications 13 4714. (https://doi.org/10.1038/s41467-022-32442-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kern D & & Zuiderweg ERP 2003 The role of dynamics in allosteric regulation. Current Opinion in Structural Biology 13 748757. (https://doi.org/10.1016/j.sbi.2003.10.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim DJ, King JA, Zuccarelli L, Ferris CF, Koppel GA, Snowdon CT & & Ahn CH 2009 Clavulanic acid: a competitive inhibitor of beta-lactamases with novel anxiolytic-like activity and minimal side effects. Pharmacology, Biochemistry, and Behavior 93 112120. (https://doi.org/10.1016/j.pbb.2009.04.013)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim J, John J, Langford D, Walker E, Ward S & & Rawls SM 2016 Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice. Amino Acids 48 689696. (https://doi.org/10.1007/s00726-015-2117-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kim K, Lee HW, Lee EH, Park MI, Lee JS, Kim MS, Kim K, Roh MS, Pak MG, Oh JE, et al.2019 Differential expression of HSP90 isoforms and their correlations with clinicopathologic factors in patients with colorectal cancer. International Journal of Clinical and Experimental Pathology 12 978986.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kolahdouz M, Jafari F, Falanji F, Nazemi S, Mohammadzadeh M, Molavi M & & Amin B 2021 Clavulanic acid attenuating effect on the diabetic neuropathic pain in rats. Neurochemical Research 46 17591770. (https://doi.org/10.1007/s11064-021-03308-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Konaklieva M, Plotkin B & & Herbert T 2009 β-lactams as neuroprotective agents. Anti-Infective Agents in Medicinal Chemistry 8 2835. (https://doi.org/10.2174/187152109787047823)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kongsui R, Promsrisuk T, Klimaschewski L, Sriraksa N, Jittiwat J & & Thongrong S 2023 Pinostrobin mitigates neurodegeneration through an up-regulation of antioxidants and GDNF in a rat model of Parkinson’s disease. F1000Research 12 846. (https://doi.org/10.12688/f1000research.134891.2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kortagere S, Mortensen Ov, Xia J, Lester W, Fang Y, Srikanth Y, Salvino JM & & Fontana ACK 2018 Identification of novel allosteric modulators of glutamate transporter EAAT2. ACS Chemical Neuroscience 9 522534. (https://doi.org/10.1021/acschemneuro.7b00308)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kost GC, Selvaraj S, Lee YB, Kim DJ, Ahn CH & & Singh BB 2011 Clavulanic acid increases dopamine release in neuronal cells through a mechanism involving enhanced vesicle trafficking. Neuroscience Letters 504 170175. (https://doi.org/10.1016/j.neulet.2011.09.032)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kovermann P, Engels M, Müller F & & Fahlke C 2022 Cellular physiology and pathophysiology of EAAT anion channels. Frontiers in Cellular Neuroscience 15 815279. (https://doi.org/10.3389/fncel.2021.815279)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kumari S & & Deshmukh R 2021 β-lactam antibiotics to tame down molecular pathways of Alzheimer’s disease. European Journal of Pharmacology 895 173877. (https://doi.org/10.1016/j.ejphar.2021.173877)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kurkinen M 2022 Astrocyte glutamate transporter EAAT2 in Alzheimer dementia. In Glutamate and Neuropsychiatric Disorders, 1st ed., pp. 229259. Ed Pavlovic ZM. Springer International Publishing. (https://doi.org/10.1007/978-3-030-87480-3_7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lee JY, Maeng S, Kang SR, Choi HY, Oh TH, Ju BG & & Yune TY 2014 Valproic acid protects motor neuron death by inhibiting oxidative stress and endoplasmic reticulum stress-mediated cytochrome C release after spinal cord injury. Journal of Neurotrauma 31 582594. (https://doi.org/10.1089/neu.2013.3146)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lee KE, Cho KO, Choi YS & & Kim SY 2016 The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia. The Korean Journal of Physiology and Pharmacology 20 185192. (https://doi.org/10.4196/kjpp.2016.20.2.185)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li X, Liang J, Tang Y, Zhou J & & Guan Y 2010 Ginsenoside Rd prevents glutamate‐induced apoptosis in rat cortical neurons. Clinical and Experimental Pharmacology and Physiology 37 199204. (https://doi.org/10.1111/j.1440-1681.2009.05286.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li J, Yang F, Guo J, Zhang R, Xing X & & Qin X 2015 17-AAG post-treatment ameliorates memory impairment and hippocampal CA1 neuronal autophagic death induced by transient global cerebral ischemia. Brain Research 1610 8088. (https://doi.org/10.1016/j.brainres.2015.03.051)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li C, Tang B, Feng Y, Tang F, Pui-Man Hoi M, Su Z & & MingYuen Lee S 2018a Pinostrobin exerts neuroprotective actions in neurotoxin-induced Parkinson’s disease models through Nrf2 induction. Journal of Agricultural and Food Chemistry 66 83078318. (https://doi.org/10.1021/acs.jafc.8b02607)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li X, Peterson YK, Inks ES, Himes RA, Li J, Zhang Y, Kong X & & Chou CJ 2018b Class I HDAC inhibitors display different antitumor mechanism in leukemia and prostatic cancer cells depending on their p53 status. Journal of Medicinal Chemistry 61 25892603. (https://doi.org/10.1021/acs.jmedchem.8b00136)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liang T, Hu X, Zeng L, Zhou Z, Zhang J, Xu Z, Zeng J & & Xu P 2023 HSP90β regulates EAAT2 expression and participates in ischemia-reperfusion injury in rats. Molecular Medicine Reports 29 5. (https://doi.org/10.3892/mmr.2023.13128)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu M, Li M, Zhou Y, Zhou Q & & Jiang Y 2020 HSP90 inhibitor 17AAG attenuates sevoflurane-induced neurotoxicity in rats and human neuroglioma cells via induction of HSP70. Journal of Translational Medicine 18 166. (https://doi.org/10.1186/s12967-020-02332-w)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu C, Liao W, Li H, Tseng L, Wang W, Tung H, Lin P, Jao H, Liu W, Hung C, et al.2021 Treatment with the combination of clavulanic acid and valproic acid led to recovery of neuronal and behavioral deficits in an epilepsy rat model. Fundamental and Clinical Pharmacology 35 10321044. (https://doi.org/10.1111/fcp.12729)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu LZ, Fan SJ, Gao JX, Li WB & & Xian XH 2023 Ceftriaxone ameliorates hippocampal synapse loss by inhibiting microglial/macrophages activation in glial glutamate transporter-1 dependent manner in the APP/PS1 mouse model of Alzheimer’s disease. Brain Research Bulletin 200 110683. (https://doi.org/10.1016/j.brainresbull.2023.110683)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Magi S, Piccirillo S, Amoroso S & & Lariccia V 2019 Excitatory amino acid transporters (EAATs): glutamate transport and beyond. International Journal of Molecular Sciences 20 5674. (https://doi.org/10.3390/ijms20225674)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maiti S & & Picard D 2022 Cytosolic Hsp90 isoform-specific functions and clinical significance. Biomolecules 12 1166. (https://doi.org/10.3390/biom12091166)

  • Martin FJ, Amode MR, Aneja A, Austine-Orimoloye O, Azov AG, Barnes I, Becker A, Bennett R, Berry A, Bhai J, et al.2023 Ensembl 2023. Nucleic Acids Research 51 D933D941. (https://doi.org/10.1093/nar/gkac958)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Matthews DC, Mao X, Dowd K, Tsakanikas D, Jiang CS, Meuser C, Andrews RD, Lukic AS, Lee J, Hampilos N, et al.2021 Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer’s disease. Brain 144 37423755. (https://doi.org/10.1093/brain/awab222)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McClure JJ, Zhang C, Inks ES, Peterson YK, Li J & & Chou CJ 2016 Development of allosteric hydrazide-containing class I histone deacetylase inhibitors for use in acute myeloid leukemia. Journal of Medicinal Chemistry 59 99429959. (https://doi.org/10.1021/acs.jmedchem.6b01385)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meng J, Liu Y, Han J, Tan Q, Chen S, Qiao K, Zhou H, Sun T & & Yang C 2017 Hsp90β promoted endothelial cell-dependent tumor angiogenesis in hepatocellular carcinoma. Molecular Cancer 16 72. (https://doi.org/10.1186/s12943-017-0640-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Meng X, Zhong J, Zeng C, Yung KKL, Zhang X, Wu X & & Qu S 2021 MiR-30a-5p regulates GLT-1 function via a PKCα-mediated ubiquitin degradation pathway in a mouse model of Parkinson’s disease. ACS Chemical Neuroscience 12 15781592. (https://doi.org/10.1021/acschemneuro.1c00076)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mestikawy S, Wallén-Mackenzie Å, Fortin GM, Descarries L & & Trudeau LE 2011 From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nature Reviews Neuroscience 12 204216. (https://doi.org/10.1038/nrn2969)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miller BR, Dorner JL, Shou M, Sari Y, Barton SJ, Sengelaub DR, Kennedy RT & & Rebec GV 2008 Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington’s disease phenotype in the R6/2 mouse. Neuroscience 153 329337. (https://doi.org/10.1016/j.neuroscience.2008.02.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Miralles VJ, Martínez-López I, Zaragozá R, Borrás E, García C, Pallardó F & & Viña JR 2001 Na+ dependent glutamate transporters (EAAT1, EAAT2, and EAAT3) in primary astrocyte cultures: effect of oxidative stress. Brain Research 922 2129. (https://doi.org/10.1016/S0006-8993(0103124-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Morel L, Regan M, Higashimori H, Ng SK, Esau C, Vidensky S, Rothstein J & & Yang Y 2013 Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. Journal of Biological Chemistry 288 71057116. (https://doi.org/10.1074/jbc.M112.410944)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mortensen OV, Liberato JL, Coutinho-Netto J, Dos Santos WF & & Fontana ACK 2015 Molecular determinants of transport stimulation of EAAT2 are located at interface between the trimerization and substrate transport domains. Journal of Neurochemistry 133 199210. (https://doi.org/10.1111/jnc.13047)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Murphy TH, Miyamoto M, Sastre A, Schnaar RL & & Coyle JT 1989 Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2 15471558. (https://doi.org/10.1016/0896-6273(8990043-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nakagawa H, Yamada M, Tokiyoshi K, Miyawaki Y & & Kanayama T 1994 Penetration of potassium clavulanate/ticarcillin sodium into cerebrospinal fluid in neurosurgical patients. The Japanese Journal of Antibiotics 47 93101.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Naskar S, Datta S & & Chattarji S 2022 Riluzole prevents stress-induced spine plasticity in the hippocampus but mimics it in the amygdala. Neurobiology of Stress 18 100442. (https://doi.org/10.1016/j.ynstr.2022.100442)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Niciu MJ, Kelmendi B & & Sanacora G 2012 Overview of glutamatergic neurotransmission in the nervous system. Pharmacology, Biochemistry, and Behavior 100 656664. (https://doi.org/10.1016/j.pbb.2011.08.008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Obrenovitch TP, Urenjak J, Zilkha E & & Jay TM 2000 Excitotoxicity in neurological disorders — the glutamate paradox. International Journal of Developmental Neuroscience 18 281287. (https://doi.org/10.1016/S0736-5748(9900096-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Padhi S, Mazumder R & & Bisth S 2023 Development of trimethyl chitosan coated nanostructure lipid carriers to enhance the brain targeting capacity of ceftriaxone. Journal of Dispersion Science and Technology 44 17981808. (https://doi.org/10.1080/01932691.2022.2043161)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Pajarillo E, Rizor A, Lee J, Aschner M & & Lee E 2019 The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: potential targets for neurotherapeutics. Neuropharmacology 161 107559. (https://doi.org/10.1016/j.neuropharm.2019.03.002)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Peng YC, Wang S, Zhang Y, Huang LJ, Wang XL & & Peng Y 2019 Hsp90β inhibitors prevent GLT-1 degradation but have no beneficial efficacy on absence epilepsy. Journal of Asian Natural Products Research 21 905915. (https://doi.org/10.1080/10286020.2018.1530989)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Peterson AR, Garcia TA, Cullion K, Tiwari-Woodruff SK, Pedapati EV & & Binder DK 2021 Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy. Neurobiology of Disease 157 105443. (https://doi.org/10.1016/j.nbd.2021.105443)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Petrov PD, Soluyanova P, Sánchez-Campos S, Castell JV & & Jover R 2021 Molecular mechanisms of hepatotoxic cholestasis by clavulanic acid: role of NRF2 and FXR pathways. Food and Chemical Toxicology 158 112664. (https://doi.org/10.1016/j.fct.2021.112664)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ramandi D, Elahdadi Salmani M, Moghimi A, Lashkarbolouki T & & Fereidoni M 2021 Pharmacological upregulation of GLT-1 alleviates the cognitive impairments in the animal model of temporal lobe epilepsy. PLoS One 16 e0246068. (https://doi.org/10.1371/journal.pone.0246068)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rao PSS, Goodwani S, Bell RL, Wei Y, Boddu SHS & & Sari Y 2015 Effects of ampicillin, cefazolin and cefoperazone treatments on GLT-1 expressions in the mesocorticolimbic system and ethanol intake in alcohol-preferring rats. Neuroscience 295 164174. (https://doi.org/10.1016/j.neuroscience.2015.03.038)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Richards DM, Heel RC, Brogden RN, Speight TM & & Avery GS 1984 Ceftriaxone a review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs 27 469527. (https://doi.org/10.2165/00003495-198427060-00001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rimmele TS & & Rosenberg PA 2016 GLT-1: the elusive presynaptic glutamate transporter. Neurochemistry International 98 1928. (https://doi.org/10.1016/j.neuint.2016.04.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rimmele TS, Li S, Andersen JV, Westi EW, Rotenberg A, Wang J, Aldana BI, Selkoe DJ, Aoki CJ, Dulla CG, et al.2021 Neuronal loss of the glutamate transporter GLT-1 promotes excitotoxic injury in the hippocampus. Frontiers in Cellular Neuroscience 15 788262. (https://doi.org/10.3389/fncel.2021.788262)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Rinaldi T, Kulangara K, Antoniello K & & Markram H 2007 Elevated NMDA receptor levels and enhanced postsynaptic long-term potentiation induced by prenatal exposure to valproic acid. PNAS 104 1350113506. (https://doi.org/10.1073/pnas.0704391104)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Robinson MB 1998 Review article the family of sodium-dependent glutamate transporters: a focus on the GLT-1/EAAT2 subtype. Neurochemistry International 33 479491. (https://doi.org/10.1016/S0197-0186(9800055-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ronald De Koloet E 1997 Why dexamethasone poorly penetrates in brain. Stress 2 1320. (https://doi.org/10.3109/10253899709014734)

  • Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, et al.2005 β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433 7377. (https://doi.org/10.1038/nature03180)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Safdar A & & Ismail F 2023 A comprehensive review on pharmacological applications and drug-induced toxicity of valproic acid. Saudi Pharmaceutical Journal 31 265278. (https://doi.org/10.1016/j.jsps.2022.12.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Schubert D & & Piasecki D 2001 Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. Journal of Neuroscience 21 74557462. (https://doi.org/10.1523/JNEUROSCI.21-19-07455.2001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sha L, Wang X, Li J, Shi X, Wu L, Shen Y & & Xu Q 2017 Pharmacologic inhibition of Hsp90 to prevent GLT-1 degradation as an effective therapy for epilepsy. Journal of Experimental Medicine 214 547563. (https://doi.org/10.1084/jem.20160667)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shan D, Yates S, Roberts RC & & McCullumsmith RE 2012 Update on the neurobiology of schizophrenia: a role for extracellular microdomains. Minerva Psichiatrica 53 233249.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Shigeri Y, Seal RP & & Shimamoto K 2004 Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Research Reviews 45 250265. (https://doi.org/10.1016/j.brainresrev.2004.04.004)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Silakhori S, Hosseinzadeh H, Shaebani Behbahani F & & Mehri S 2019 Neuroprotective effect of clavulanic acid on trimethyltin (TMT)-induced cytotoxicity in PC12 cells. Drug and Chemical Toxicology 42 187193. (https://doi.org/10.1080/01480545.2018.1468772)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sims JD, McCready J & & Jay DG 2011 Extracellular heat shock protein (Hsp)70 and Hsp90α assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS One 6 e18848. (https://doi.org/10.1371/journal.pone.0018848)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Singh D, Gupta S, Verma I, Morsy MA, Nair AB & & Ahmed AF 2021 Hidden pharmacological activities of valproic acid: a new insight. Biomedicine and Pharmacotherapy 142 112021. (https://doi.org/10.1016/j.biopha.2021.112021)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sivasubramanian MK, Monteiro R, Balasubramanian P & & Subramanian M 2020 Oxidative stress‐induced senescence alters glutamate transporter expression in human brainstem astrocytes. The FASEB Journal 34 1. (https://doi.org/10.1096/fasebj.2020.34.s1.06566)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Soni N, Reddy BVK & & Kumar P 2014 GLT-1 transporter: an effective pharmacological target for various neurological disorders. Pharmacology, Biochemistry, and Behavior 127 7081. (https://doi.org/10.1016/j.pbb.2014.10.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Suárez C & & Gudiol F 2009 Antibióticos betalactámicos. Enfermedades Infecciosas y Microbiología Clínica 27 116129. (https://doi.org/10.1016/j.eimc.2008.12.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Suda S, Katsura K, Kanamaru T, Saito M & & Katayama Y 2013 Valproic acid attenuates ischemia-reperfusion injury in the rat brain through inhibition of oxidative stress and inflammation. European Journal of Pharmacology 707 2631. (https://doi.org/10.1016/j.ejphar.2013.03.020)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Suto N, Mieda T, Iizuka A, Nakamura K & & Hirai H 2016 Morphological and functional attenuation of degeneration of peripheral neurons by mesenchymal stem cell‐conditioned medium in spinocerebellar ataxia type 1‐knock‐in mice. CNS Neuroscience and Therapeutics 22 670676. (https://doi.org/10.1111/cns.12560)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Takahashi K, Foster JB & & Lin CLG 2015 Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cellular and Molecular Life Sciences 72 34893506. (https://doi.org/10.1007/s00018-015-1937-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Taspinar N, Hacimuftuoglu A, Butuner S, Togar B, Arslan G, Taghizadehghalehjoughi A, Okkay U, Agar E, Stephens R, Turkez H, et al.2021 Differential effects of inhibitors of PTZ‐induced kindling on glutamate transporters and enzyme expression. Clinical and Experimental Pharmacology and Physiology 48 16621673. (https://doi.org/10.1111/1440-1681.13575)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Thongrong S, Surapinit S, Promsrisuk T, Jittiwat J & & Kongsui R 2023 Pinostrobin alleviates chronic restraint stress-induced cognitive impairment by modulating oxidative stress and the function of astrocytes in the hippocampus of rats. Biomedical Reports 18 20. (https://doi.org/10.3892/br.2023.1602)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tikhonova MA, Amstislavskaya TG, Belichenko VM, Fedoseeva LA, Kovalenko SP, Pisareva EE, Avdeeva AS, Kolosova NG, Belyaev ND & & Aftanas LI 2018 Modulation of the expression of genes related to the system of amyloid-beta metabolism in the brain as a novel mechanism of ceftriaxone neuroprotective properties. BMC Neuroscience 19(Supplement 1) 13. (https://doi.org/10.1186/s12868-018-0412-5)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vallée A, Vallée JN, Guillevin R & & Lecarpentier Y 2020 Riluzole: a therapeutic strategy in Alzheimer’s disease by targeting the WNT/β-catenin pathway. Aging 12 30953113. (https://doi.org/10.18632/aging.102830)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • van Kan HJM, Groeneveld GJ, Kalmijn S, Spieksma M, van den Berg LH & & Guchelaar HJ 2005 Association between CYP1A2 activity and riluzole clearance in patients with amyotrophic lateral sclerosis. British Journal of Clinical Pharmacology 59 310313. (https://doi.org/10.1111/j.1365-2125.2004.02233.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vandenberg RJ & & Ryan RM 2013 Mechanisms of glutamate transport. Physiological Reviews 93 16211657. (https://doi.org/10.1152/physrev.00007.2013)

  • Vigushin DM, Ali S, Pace PE, Mirsaidi N, Ito K, Adcock I & & Coombes RC 2001 Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clinical Cancer Research 7 971976.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wang S, Li M, Guo Y, Li C, Wu L, Zhou XF, Luo Y, An D, Li S, Luo H, et al.2017 Effects of Panax notoginseng ginsenoside Rb1 on abnormal hippocampal microenvironment in rats. Journal of Ethnopharmacology 202 138146. (https://doi.org/10.1016/j.jep.2017.01.005)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Weersink RA, Alvarez‐Alvarez I, Medina‐Cáliz I, Sanabria‐Cabrera J, Robles‐Díaz M, Ortega‐Alonso A, García‐Cortés M, Bonilla E, Niu H, Soriano G, et al.2021 Clinical characteristics and outcome of drug‐induced liver injury in the older patients: from the young‐old to the oldest‐old. Clinical Pharmacology and Therapeutics 109 11471158. (https://doi.org/10.1002/cpt.2108)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wen ZH, Wu GJ, Chang YC, Wang JJ & & Wong CS 2005 Dexamethasone modulates the development of morphine tolerance and expression of glutamate transporters in rats. Neuroscience 133 807817. (https://doi.org/10.1016/j.neuroscience.2005.03.015)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wilkie CM, Barron JC, Brymer KJ, Barnes JR, Nafar F & & Parsons MP 2021 The effect of GLT-1 upregulation on extracellular glutamate dynamics. Frontiers in Cellular Neuroscience 15 661412. (https://doi.org/10.3389/fncel.2021.661412)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu JY, Niu F, Huang R & & Xu Y 2008 Enhancement of glutamate uptake in 1-methyl-4-phenylpyridinium-treated astrocytes by trichostatin A. NeuroReport 19 12091212. (https://doi.org/10.1097/WNR.0b013e328308b355)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu X, Meng X, Tan F, Jiao Z, Zhang X, Tong H, He X, Luo X, Xu P & & Qu S 2019 Regulatory mechanism of miR-543-3p on GLT-1 in a mouse model of Parkinson’s disease. ACS Chemical Neuroscience 10 17911800. (https://doi.org/10.1021/acschemneuro.8b00683)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu Z, Huang J, Bai X, Wang Q, Wang F, Xu J, Tang H, Yin C, Wang Y, Yu F, et al.2023 Ginsenoside-Rg1 mitigates cardiac arrest-induced cognitive damage by modulating neuroinflammation and hippocampal plasticity. European Journal of Pharmacology 938 175431. (https://doi.org/10.1016/j.ejphar.2022.175431)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xian YF, Ip SP, Lin ZX, Mao QQ, Su ZR & & Lai XP 2012 Protective effects of pinostrobin on β-amyloid-induced neurotoxicity in PC12 cells. Cellular and Molecular Neurobiology 32 12231230. (https://doi.org/10.1007/s10571-012-9847-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ye R, Li N, Han J, Kong X, Cao R, Rao Z & & Zhao G 2009 Neuroprotective effects of ginsenoside Rd against oxygen-glucose deprivation in cultured hippocampal neurons. Neuroscience Research 64 306310. (https://doi.org/10.1016/j.neures.2009.03.016)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yeh CY, Yeh CM, Yu TH, Chang KH, Huang CC & & Hsu KS 2017 Neonatal dexamethasone treatment exacerbates hypoxia/ischemia-induced white matter injury. Molecular Neurobiology 54 70837095. (https://doi.org/10.1007/s12035-016-0241-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yun J-Y, Park K-S, Kim J-H, Do S-H & & Zuo Z 2007 Propofol reverses oxidative stress-attenuated glutamate transporter EAAT3 activity: evidence of protein kinase C involvement. European Journal of Pharmacology 565 8388. (https://doi.org/10.1016/j.ejphar.2007.02.045)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zaitsev AV, Smolensky IV, Jorratt P & & Ovsepian SV 2020 Neurobiology, functions, and relevance of excitatory amino acid transporters (EAATs) to treatment of refractory epilepsy. CNS Drugs 34 10891103. (https://doi.org/10.1007/s40263-020-00764-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zarate CA & & Manji HK 2008 Riluzole in psychiatry: a systematic review of the literature. Expert Opinion on Drug Metabolism and Toxicology 4 12231234. (https://doi.org/10.1517/17425255.4.9.1223)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang X 2013 Ginsenoside Rd promotes glutamate clearance by up-regulating glial glutamate transporter GLT-1 via PI3K/AKT and ERK1/2 pathways. Frontiers in Pharmacology 4 152. (https://doi.org/10.3389/fphar.2013.00152)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang J, Zheng Z, Zhao Y, Zhang T, Gu X & & Yang W 2013 The heat shock protein 90 inhibitor 17-AAG suppresses growth and induces apoptosis in human cholangiocarcinoma cells. Clinical and Experimental Medicine 13 323328. (https://doi.org/10.1007/s10238-012-0208-3)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang YL, Liu Y, Kang XP, Dou CY, Zhuo RG, Huang SQ, Peng L & & Wen L 2018 Ginsenoside Rb1 confers neuroprotection via promotion of glutamate transporters in a mouse model of Parkinson’s disease. Neuropharmacology 131 223237. (https://doi.org/10.1016/j.neuropharm.2017.12.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang L, Wu R, Xu MJ, Sha J, Xu GY, Wu J & & Zhang PA 2021 MiRNA‐107 contributes to inflammatory pain by down‐regulating GLT‐1 expression in rat spinal dorsal horn. European Journal of Pain 25 12541263. (https://doi.org/10.1002/ejp.1745)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhang Z, Chen H, Geng Z, Yu Z, Li H, Dong Y, Zhang H, Huang Z, Jiang J & & Zhao Y 2022 Structural basis of ligand binding modes of human EAAT2. Nature Communications 13 3329. (https://doi.org/10.1038/s41467-022-31031-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zhou Y & & Danbolt NC 2014 Glutamate as a neurotransmitter in the healthy brain. Journal of Neural Transmission 121 799817. (https://doi.org/10.1007/s00702-014-1180-8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zoia CP, Tagliabue E, Isella V, Begni B, Fumagalli L, Brighina L, Appollonio I, Racchi M & & Ferrarese C 2005 Fibroblast glutamate transport in aging and in AD: correlations with disease severity. Neurobiology of Aging 26 825832. (https://doi.org/10.1016/j.neurobiolaging.2004.07.007)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zschocke J, Bayatti N, Clement AM, Witan H, Figiel M, Engele J & & Behl C 2005 Differential promotion of glutamate transporter expression and function by glucocorticoids in astrocytes from various brain regions. Journal of Biological Chemistry 280 3492434932. (https://doi.org/10.1074/jbc.M502581200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Zschocke J, Allritz C, Engele J & & Rein T 2007 DNA methylation dependent silencing of the human glutamate transporter EAAT2 gene in glial cells. Glia 55 663674. (https://doi.org/10.1002/glia.20497)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • Figure 1

    Representation of excitatory glutamatergic synapse. l-glutamate is released from the presynaptic neuron and subsequently binds in the postsynaptic neuron to AMPA receptors, which mediate fast excitatory potentials, and NMDA receptors, which possess a Ca2+-permeable cation channel. At the same time, l-glutamate is captured by the EAAT2 receptor on the surface of astrocytes, where it is converted to glutamine by glutamine synthetase. This glutamine is then released and used by neurons as a glutamate precursor (Figure created with BioRender.com).

  • Figure 2

    Representation of EAAT2 transporter structure in complex with glutamate. (A) Front view of the homotrimer. (B) Top view of the homotrimer. Each protomer of the homotrimer is composed, in turn, of transport and scaffold domains. The transport domain consists of two helical hairpins: HP1 and HP2 (light orange), and four transmembrane helices: TM3, TM6, TM7, and TM8 (dark orange). The scaffold domain consists of four transmembrane helices: TM1, TM2, TM4, and TM5 (blue) (Figure created with UCSF Chimera).

  • Figure 3

    Schematic structure of the SLC1A2 gene variants. SLC1A2 has around 50 different splice variants, which give rise to three distinct isoforms. (A) Transcript encoding EAAT2a represents the canonical sequence. (B) Transcript encoding EAAT2b has a deletion in the 5′ coding region (1–9). (C) Transcript encoding EAAT2c differs from the canonical one in the 3′ coding region (553–574) (Figure created with BioRender.com, based on information from Ensembl.org, release 111 – January 2024 (Martin et al. 2023)).

  • Figure 4

    Mechanism of action of histone deacetylases (HDACs). HDACs remove the acetyl groups from histone lysines, increasing the positive charge and affinity of histones for DNA. As a consequence, the DNA structure is condensed, and transcription is prevented. Histone acetyltransferases (HATs) do just the opposite: they transfer acetyl groups to histone lysines and promote transcription. When histone deacetylase inhibitors (HDACis) selectively inhibit HDACs, chromatin remains in a relaxed state, and gene transcription is allowed (Figure created with BioRender.com.).

  • Acred P, Brown DM, Turner DH & & Wilson MJ 1962 Pharmacology and chemotherapy of ampicillin - a new broad‐spectrum penicillin. British Journal of Pharmacology and Chemotherapy 18