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).
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).
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).
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.
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.
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