Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection

Abstract

Recent advances in neuroscience have illuminated the central role of glutamate dysregulation in various neurological disorders. The glutamatergic system has emerged as a central player in the pathophysiology of various neurological disorders. The dysregulation of glutamate signaling, leading to excitotoxicity and neuronal cell death, has been a focal point in understanding the underlying mechanisms of these conditions. This has prompted a paradigm shift in neuroprotection research, with a growing emphasis on targeting ionotropic glutamate receptors (iGluRs) to restore glutamatergic homeostasis. This review provides a comprehensive overview of recent advancements in the field of iGluR‐targeted neuroprotection. We further investigate the implications of glutamate dysregulation in the central nervous system (CNS) disorders, highlighting the complex interplay between excitotoxicity and neuroprotection. We elucidate the multifaceted factors that render neurons vulnerable to excitotoxic damage, emphasizing the need for innovative therapeutic approaches. This review provides an extensive survey of the burgeoning field of iGluR‐targeted neuroprotection. It showcases the significant potential of a wide array of compounds, encompassing both natural and synthetic agents, to modulate iGluRs and ameliorate excitotoxicity and oxidative stress‐induced neuronal damage. These compounds have demonstrated impressive neuroprotective effects in diverse experimental models, from glutamate‐induced toxicity to traumatic brain injuries. We advocate for further research and clinical investigations to harness the full therapeutic potential of iGluR modulation, heralding a promising era in neuroprotection and CNS disorder management.

Glutamate dysregulation leads to neurological disorders, which has prompted a paradigm shift towards neuroprotection targeting ionotropic glutamate receptors (iGluRs). Neurons may be less susceptible to excitotoxic damage with interventions targeting iGluRs. In this work we highlight natural and synthetic compounds with remarkable neuroprotective effects in various experimental models. This opens a broad research scenery to fully exploit their beneficial potential in CNS disorders.

Highlights

• Targeting ionotropic glutamate receptors (iGluRs) holds significant promise for restoring glutamatergic balance in CNS disorders.

• Personalized therapies based on biomarkers and genomic profiling are on the horizon, revolutionizing neuroprotection.

• Potential for preventing and delaying neurodegenerative diseases through iGluR modulation.

1. INTRODUCTION: GLUTAMATE AND EXCITOTOXICITY IN THE CENTRAL NERVOUS SYSTEM (CNS)

The CNS is a complex network of neurons and neurotransmitters that coordinate various functions critical for human cognition and behavior. Glutamate, a nonessential amino acid, acts as the principal excitatory neurotransmitter in the CNS, mediating the majority of excitatory synaptic transmission. ¹ Its role in synaptic plasticity and information processing makes it indispensable for learning, memory, and overall cognitive function. However, maintaining a delicate balance of glutamate is vital, as excessive levels can lead to excitotoxicity—a pathophysiological process in which prolonged activation of glutamate receptors results in harmful effects on neurons. ² , ³ The primary glutamate receptors responsible for excitotoxicity are ionotropic glutamate receptors (iGluRs), ⁴ , ⁵ specifically N‐methyl‐d‐aspartate (NMDA) receptors, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors, and kainate receptors (KARs). ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹

Excitotoxicity is characterized by an influx of calcium ions into neurons, leading to the activation of various cell signaling pathways, oxidative stress, mitochondrial dysfunction, and ultimately, cell death. This phenomenon has been implicated in the pathogenesis of various CNS disorders, ¹² including stroke, epilepsy, traumatic brain injury (TBI), ¹³ neurodegenerative diseases, and other neuroinflammatory conditions. Several studies have demonstrated that during neurodegenerative conditions there is a notable dysregulation in glutamate levels in specific CNS regions. ¹⁴ , ¹⁵ This glutamate dysregulation is closely associated with excitotoxicity, ¹⁶ , ¹⁷ leading to neuronal damage and progressive cognitive impairment. The consequences of excitotoxicity are far‐reaching and can have devastating effects on neuronal integrity and circuitry. Thus, understanding the intricate interplay between glutamate signaling and excitotoxicity has become a focal point in CNS research. Identifying effective neuroprotective strategies to mitigate excitotoxic damage is of paramount importance in developing therapeutic interventions for CNS disorders. ¹⁸ , ¹⁹ , ²⁰

The paramount field of glutamate research has witnessed substantial contributions, as evident in recent literature. Hansen et al. ⁶ reported a comprehensive overview of iGluRs, emphasizing their critical role in brain function and their implication in various psychiatric and neurologic disorders. It covers aspects such as structure, function, pharmacology, and therapeutic implications, spanning more than three decades of research. In addition, Moroz et al. ²¹ delves into the evolutionary history of glutamatergic signaling, offering insights into the selection of l‐glutamate as a signaling molecule and the diverse families of iGluRs across eukaryotes. Moving to the realm of posttranslational modifications, Hayashi ²² focuses on the palmitoylation of iGluRs, elucidating its regulatory role in synaptic expression, localization, and membrane trafficking. The review underscores the conservation of this modification mechanism and its implications for neural communication, memory formation, and disorders such as epileptic seizures. Complementary, Burada et al. ²³ emphasize the important roles of GluD1 and GluD2 receptors in synapse formation and maintenance, with implications for disorders like schizophrenia and autism spectrum disorder (ASD). In this review, we delve into the role of glutamate as a key excitatory neurotransmitter in the CNS and its implications in excitotoxicity. We explore literature to establish the relationship between excitotoxicity and CNS pathologies. Additionally, we discuss the potential of targeting iGluRs as a promising approach to restore glutamatergic homeostasis and protect against excitotoxicity‐induced neuronal damage. Elucidating the intricate mechanisms underlying glutamate‐induced excitotoxicity may provide new avenues for developing neuroprotective agents and advancing our understanding of CNS disorders, ultimately leading to improved therapeutic strategies for patients suffering from these debilitating conditions.

2. GLUTAMATE AND EXCITATORY NEUROTRANSMISSION: UNVEILING THE RECEPTOR LANDSCAPE

Glutamate is the most abundant excitatory neurotransmitter in the CNS and plays a pivotal role in various physiological processes. As an amino acid, glutamate is synthesized from glutamine through enzymatic conversion by glutaminase and is stored in synaptic vesicles within presynaptic terminals during the glutamate‐glutamine cycle. The cycle involves the transfer of ammonia (NH₃) between these two amino acids. In mammals, ammonia is produced in multiple metabolic reactions, crosses the blood‐brain barrier with facileness ²⁴ and must be efficiently eliminated to prevent neurotoxicity. ²⁵ While the liver primarily detoxifies ammonia through urea synthesis, in the brain, a significant portion is detoxified by incorporating it into glutamine via astrocytic glutamine synthetase. The synthesized glutamine is released from astrocytes and transferred to neurons, where it is converted back to glutamate, contributing to the glutamate‐glutamine cycle (Figure 1).

Figure 1.

Representative schematic of the glutamate–glutamine cycle in an astrocyte. The cycle begins with the neutralization of circulating ammonia in the astrocyte through reaction with glutamate to form glutamine by the enzyme glutamine synthetase. Glutamine is transported to the extracellular environment, where it can be directed to the cerebrospinal fluid or transferred to neurons. In neurons, glutamine is degraded to glutamate and ammonia via the enzyme glutaminase phosphate‐activated glutaminase (GLS‐1), contributing to the neurotransmitter glutamate and maintaining glutamate homeostasis in the central nervous system. Excitatory amino acid transporters (EAATs) facilitate the uptake of glutamate from the synaptic cleft, while phosphate‐activated glutaminase (PAG) converts glutamine to glutamate as part of the glutaminolysis pathway in mitochondria. GluRs, glutamate receptors.

The glutamate–glutamine cycle does not follow a stoichiometric reaction, with some glutamate lost in other pathways, impacting energy metabolism and neurotransmitter synthesis. Although astrocytes supply glutamine to neurons, they also contribute to metabolizing it, maintaining physiological glutamine levels. This cycle is vital for maintaining glutamate homeostasis in the brain, preventing excitotoxicity. Upon neuronal activation, glutamate is released into the synaptic cleft, where it interacts with postsynaptic receptors, transmitting excitatory signals to neighboring neurons. The primary receptors for glutamate are iGluRs and metabotropic glutamate receptors (mGluRs). iGluRs are ligand‐gated ion channels that mediate fast excitatory neurotransmission. The three major subtypes of iGluRs include NMDA receptors, AMPA receptors, and KARs. ⁵ , ¹¹ , ²⁶

The reception and transport of glutamate in brain cells, such as neurons and astrocytes, is a vital part of CNS function. ²⁷ Glutamate uptake is mediated by five glutamate transporters proteins, Na⁺‐dependent high‐affinity glutamate transporters, also identified as excitatory amino acid transporters (EAATs). ²⁸ Neurons and astrocytes express glutamate transporters EEATs and glutamate receptors (GluR) that split into two families: iGluRs and mGluRs. Resident immune cells of the CNS, called microglia, also express mGluRs ²⁹ and have been shown to have an immune response when GluRs AMPA or NMDA are activated in them. ³⁰ Dysfunction of GluR in microglia may cause neurodegeneration. ³¹ Glutamate enters immune cells via the EAAT. Under physiological conditions, macrophages do not express any of the EAAT subtypes. Nevertheless, under inflammatory conditions, EAAT expression is elevated by lipopolysaccharide and tumor necrosis factor‐a. mGluR5a activation mediates the acute upregulation of glutamate absorption through EAAT in reactive astrocytes. ³²

The complexity of glutamate regulation underscores the challenges in developing targeted medications. Only few prescription medications been developed specifically for glutamate or GluRs over the past decades and others for example nerinetide have been advanced in clinical phase studies. ³³ Unlike neurotransmitters with less complex synaptic regulation, such as dopamine and serotonin, glutamate's pervasive role and pathways in the CNS contribute to the difficulty in finding precise intervention points. Notably, several enzymes utilizing glutamate as a substrate are localized in mitochondria. Distinct carriers—AGC1, AGC2, GC1, and GC2 ³⁴ —facilitate glutamate translocation within mitochondria. Moreover, in glutamatergic nerve terminals, vesicular glutamate transporters play a fundamental role by transporting glutamate into synaptic vesicles. This process is distinct from plasma membrane transporters and contributes to the regulation of extracellular glutamate concentration. The equilibrium kept by these transporters, supporting a significant gradient of glutamate across cell membranes, theoretically maintains low extracellular glutamate concentrations. However, studies using NMDA receptors as probes suggest that resting extracellular glutamate concentrations might be higher, ³⁵ raising intriguing questions about the dynamic interplay of transporters in different synaptic conditions.

2.1. NMDA receptors

The NMDA receptors are fundamental players in excitatory neurotransmission and synaptic plasticity within the CNS. These receptors are crucial for normal brain function and have been a subject of considerable interest among neurophysiologists and pharmacologists. ³⁶ NMDA receptors are unique among iGluRs, because they require both glutamate binding and postsynaptic depolarization to relieve the magnesium block from their ion channels, allowing calcium influx into the neuron. ³⁷ Understanding the evolution and unique properties of NMDAs is essential to grasp their functional significance in the CNS. Recent advancements in genomics and structural biology have enabled a comprehensive analysis of the evolution of iGluR genes, particularly the NMDAs, offering insights into the molecular framework shaping their architecture and functionalities. ³⁸ Researchers have traced the differences and similarities between NMDAs and other iGluRs by combining data from phylogeny, atomic structure, and physiological and mechanistic studies. Distinctive properties of NMDAs, such as ligand binding and gating, permeation, allosteric modulation, and intracellular signaling, have been emphasized. ³⁹ Moreover, NMDAs have been implicated in various neurological disorders ³⁶ and mutations in their subunits have been linked to neurodevelopmental conditions like intellectual disability, ASDs, and epilepsy. ⁴⁰ The role of NMDAs in excitotoxicity, a pathological process characterized by excessive calcium entry into cells, has led to investigations of neuroprotective agents, including novel steroidal NMDA receptor inhibitors. ²⁰ These agents show potential in combating excitotoxicity‐induced neuronal damage and offer therapeutic prospects for glutamate‐related CNS diseases. The evolution and molecular properties of NMDAs hold significance in understanding their role in synaptic plasticity and CNS function across distinct species. Mutations in NMDA subunits have appeared as potential contributors to neurodevelopmental disorders, underscoring the importance of further research and targeted therapeutic approaches in addressing glutamate‐related neurological conditions.

2.2. AMPA receptors (AMPARs)

AMPA (α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate) and kainic acid receptors (AMPARs) are essential iGluRs that play a significant role in rapid excitatory neurotransmission and synaptic plasticity in the CNS. ⁴¹ They exist as heteromers composed of various subunits, with the prevalent configuration being tetrameric assemblies of GluA1 to GluA4 subunits. Recent studies have offered determining insights into the structural organization of AMPAR heteromers, revealing a novel compact conformation with an alternating arrangement of the four subunits around a central axis. ⁴² This unique configuration has been confirmed through crystal structures of GluA2/3 and GluA2/4 N‐terminal domains. Furthermore, cryogenic electron microscopy has allowed the determination of the intact GluA2/3 receptor structure in ligand‐free states, providing snapshots of gating transitions in the nominal absence of ligand. ⁴² AMPARs are known as the principal mediators of fast synaptic transmission at central synapses, responsible for the rapid transduction of excitatory signals. Their biogenesis involves the regulation of kinetic and conductance properties, which are influenced by posttranscriptional RNA editing, splice variation, posttranslational modification, and subunit composition. The diversity and functional specificity of AMPARs are further enhanced by the presence of auxiliary subunits. ⁴³ These auxiliary proteins contribute to the assembly, trafficking, and functional heterogeneity of AMPARs, adding a layer of complexity to their functional repertoire. Understanding the subunit structure, stoichiometry, and interactions with auxiliary proteins is determining for understanding the heterogeneity and functionality of AMPARs. The specific configuration of AMPAR heteromers tailors their synaptic signaling and plasticity roles, making them vital components in the intricate neural networks that underlie learning, memory, and cognition. As a major target for pharmacological interventions, unraveling the mechanisms underlying AMPAR regulation and function holds great promise for the development of therapeutic strategies targeting neurological and neuropsychiatric disorders associated with glutamatergic dysfunction. Further research in this area will undoubtedly deepen our understanding of AMPAR architecture and signaling, opening up new avenues for therapeutic interventions in the CNS. ⁴³

2.3. KARs

KARs also contribute to synaptic transmission and have been implicated in various CNS functions, including neuroprotection and neuronal excitability regulation. KARs are a subtype iGluRs that contribute significantly to the fast‐excitatory branch of neurotransmission. KARs mediate the synaptic response to the neurotransmitter glutamate, acting as ligand‐gated ion channels that regulate the flow of ions across the neuronal membrane in response to glutamate binding. ⁴⁴ In their resting and desensitized states, KAR ion channels are closed, and the ligand‐binding domain layers adopt distinct conformations. The process of desensitization, where KARs become refractory to further activation, involves the establishment of a ring‐like structure in the ligand‐binding domains. This desensitization ring formation results in a pseudo‐fourfold symmetric arrangement of the ligand‐binding domains, which must be disrupted for the receptor to return to its resting state, thus completing the gating cycle. ⁴⁵ Dysfunctions in KARs have been associated with conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. However, compared to other GluRs, such as AMPARs, progress in understanding KARs has been hampered by a lack of specific and selective pharmacological tools. Nevertheless, recent advances in the field have shed light on the function and regulation of KARs, including the discovery of competitive and noncompetitive KAR antagonists that hold therapeutic potential. ⁴⁶ Additionally, cryo‐electron microscopy structures have provided insights into the allosteric modulation of KARs by small molecules, such as positive allosteric modulators like BPAM344 and negative allosteric modulators like antiepileptic drug perampanel. ⁴⁷ These findings offer promising directions for exploring KARs as potential drug targets to address CNS disorders and pave the way for further research in understanding the complexities of KAR biology and its implications in neuronal communication and modulation.

2.4. EAATs

Glutamate signaling is tightly regulated to maintain proper neurotransmission and prevent excitotoxicity. Glutamate uptake transporters, such as EAATs, efficiently clear glutamate from the synaptic cleft, ensuring rapid termination of excitatory signaling. Any disruption in glutamate clearance mechanisms can lead to an accumulation of glutamate in the extracellular space, setting the stage for excitotoxicity. The balance between glutamatergic excitation and inhibition through neurotransmission is critical for normal CNS function. However, excessive activation of iGluRs and the later overexcitation of neurons can lead to excitotoxicity, a phenomenon strongly associated with various neurological disorders. Understanding the delicate regulation of glutamatergic neurotransmission and the involvement of iGluRs in CNS pathologies is fundamental for the development of targeted neuroprotective strategies.

In the following sections, we explore the implications of excitotoxicity in CNS disorders. Although abnormal glutamate levels in the CNS have consequences related to neurodegenerative diseases of high incidence worldwide, it is not clear that therapeutic interventions restore glutamatergic homeostasis during ongoing neurodegeneration. In the last decade, evidence has accumulated for therapeutic interventions in which the expression of iGluRs, is a biomarker of effectiveness in arresting the disease process. For this reason, this work focuses on the review of interventions targeting nervous system diseases that evaluate the expression of iGluRs as biomarkers.

3. IMPLICATIONS FOR EXCITOTOXICITY AND NEUROPROTECTION IN CNS DISORDERS

In the last decade, several studies have offered significant insights into the role of excitotoxicity in various CNS disorders and the potential for neuroprotection through targeted interventions. ⁴⁸ , ⁴⁹ , ⁵⁰ , ⁵¹ , ⁵² , ⁵³ These studies have shed light on the involvement of iGluRs in excitotoxicity, a critical process leading to neuronal damage and death in diverse neurological conditions. Excitotoxicity is characterized by excessive glutamate‐mediated neuronal cell death, appeared as a determining factor in the pathogenesis of various CNS disorders.

The studies have explored various neuroprotective strategies aimed at attenuating excitotoxicity and preserving neuronal integrity. Compounds like memantine and apigenin‐8‐C‐glycoside (AP8CG) have shown potential in reducing NMDA and AMPAR activation, offering neuroprotection in animal models of CNS disorders. ⁴⁸ , ⁴⁹ The administration of the glutamate transporter enhancer (2S, 3S)‐3‐[3‐[4‐(trifluoromethyl)benzoylamino]benzyloxy]aspartate has demonstrated a neuroprotective effect by preventing excessive glutamate accumulation and excitotoxicity in diabetic retinopathy. ⁵¹ In the context of ischemic brain injury, the use of the p38 mitogen‐activated protein kinase (MAPK) inhibitor SB203580 has shown promising results in reducing excitotoxicity and neuronal death. ⁵³ The therapeutic potential of erythropoietin (EPO) in attenuating glutamate‐induced excitotoxicity has been explored, with promising findings in animal models of diabetic encephalopathy. ⁵⁰

3.1. Neurovascular disorders

3.1.1. Ischemic stroke

Ischemic stroke, a leading cause of mortality and disability worldwide, is strongly associated with excitotoxicity. Increased activation of NMDA receptors and AMPARs has been seen in ischemic brain injury, leading to heightened excitotoxicity and subsequent neuronal death. ⁴⁸ Notably, Tat‐NR2B9c, a synthetic eicosapeptide now known as nerinetide, has proved therapeutic benefits in humans. This interfering peptide is designed to dissociate NMDA receptors from PSD‐95, thereby disrupting interactions within the NMDA complex. ⁵⁴ In the same sense, the researchers have investigated the neuroprotective effects of genistein, a primary isoflavonoid, in in vitro models of cerebral ischemia using primary neurons from 1‐day‐old Wistar rats. They conducted several experiments to assess the impact of genistein on neuronal survival and apoptosis. First, the conventional 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay was used to measure cell viability after exposure to oxygen–glucose deprivation (OGD) with or without genistein treatment for different time points (3, 6, 24, and 48 h). The results showed that genistein treatment improved cell viability in the OGD‐induced ischemic condition. Next, the researchers performed the terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling (TUNEL) assay to evaluate apoptotic cells. They found that the OGD group showed a higher apoptosis index compared to the control group, while the OGD + genistein group showed a reduction in the apoptosis index, indicating the antiapoptotic effect of genistein. Additionally, the expression levels of two iGluR subunits, GluR2 and NR2, were assessed using immunocytochemistry. The results proved that GluR2 expression was significantly decreased in the OGD group but restored in the OGD + genistein group. On the other hand, NR2 expression was increased in the OGD group but reduced in the presence of genistein, suggesting that genistein modulates the expression of these iGluRs in response to cerebral ischemia. Overall, the findings from reference indicate that this phytoestrogen exerts neuroprotective effects by enhancing cell viability, reducing apoptosis, and regulating the expression of iGluRs. This suggests that genistein may play a role in mitigating excitotoxicity, a process linked to excessive glutamate release and neuronal damage. These findings highlight the potential significance of targeting iGluRs as a therapeutic approach to mitigate the consequences of ischemic stroke.

3.1.2. Diabetic retinopathy

Similarly, in diabetic retinopathy, excess glutamate levels in retinal tissues have been linked to excitotoxicity and retinal neuronal cell death. ⁵¹ Investigating interventions that modulate glutamatergic signaling and prevent excitotoxicity could hold promise for preserving retinal function in diabetic patients. The neuroprotective effects of EPO were investigated in the context of diabetic retinal damage induced by glutamate neurotoxicity. The study aimed to decide if EPO could offer neuroprotection against glutamate‐induced toxicity in diabetic rat retinas. Male Sprague–Dawley rats were divided into three experimental groups, with diabetic rats in Groups 2 and 3. Glutamate levels in the retina were quantified, showing a 20.9% increase in Group 2 compared to the control group, whereas Group 3, treated with EPO, exhibited a 13.8% reduction compared to Group 2. The TUNEL assay revealed an increase in cells with DNA damage in diabetic rats without EPO treatment (Group 2), whereas few or no damaged cells were observed in group 3, indicating the neuroprotective effects of EPO. Immunofluorescence assays detected changes in the expression levels of NMDA receptor (NR1) and KAR (KA1) subunits. Diabetic rats without EPO treatment showed elevated expression levels of NR1 (29.2%) and KA1 (21.0%) compared to the control group. However, EPO‐treated diabetic rats exhibited decreased expression of NR1 (24.1%) and KA1 (9.4%) compared to Group 2. These findings suggest that EPO may exert a neuroprotective function against glutamate‐induced toxicity in the diabetic retina, highlighting its potential as a therapeutic agent for mitigating neurodegenerative effects in diabetic retinopathy.

3.1.3. Ischemic brain injury

Moreover, the role of excitotoxicity in ischemic brain injury, where enhanced glutamate signaling, and excitotoxicity contribute to neuronal death have investigated. ⁵³ The researchers have investigated the role of p38 MAPKs in excitotoxicity and neuronal apoptosis. Excitotoxicity occurs when excessive levels of glutamate lead to overstimulation of iGluRs, causing an influx of calcium ions and triggering neurotoxic pathways, leading to neuronal death. The study used the p38 inhibitor SB203580 to explore its neuroprotective effects in an excitotoxic injury model induced by monosodium glutamate (MSG) in neonatal Wistar rats. The results demonstrated rapid and significant activation of p38 in the MSG group compared to the control group. However, in the group treated with SB203580, p38 activity decreased in a dose‐dependent manner, suggesting that the inhibitor effectively countered the p38 activation induced by MSG. Regarding iGluR expression, an increase in the NMDA receptor subunit NR1 was observed in the MSG group compared to the control group. However, in the MSG + SB203580 group, NR1 expression decreased, indicating that the p38 inhibitor mitigated the upregulation of NMDA receptors induced by MSG. Additionally, the AMPAR subunit GluR2 expression decreased in the MSG group, but this decrease was reversed in the MSG + SB203580 group, approaching levels similar to the control group. These findings suggest that excitotoxicity‐induced neurodegeneration involves the activation of p38 MAPKs and the dysregulation of NMDA and AMPARs. The use of SB203580 as a p38 inhibitor demonstrated neuroprotective effects, attenuating excitotoxicity and its associated neuronal apoptosis. The study sheds light on the complex molecular mechanisms underlying excitotoxicity, implicating p38 MAPKs and iGluRs as potential therapeutic targets for neuroprotection against excitotoxic injury in cerebral ischemia and other CNS disorders. Understanding these pathways is necessary for developing effective therapies to combat excitotoxicity‐related neurodegenerative diseases.

3.2. Neurological and metabolic disorders

3.2.1. Epilepsy

In the context of epilepsy, the upregulation of iGluRs, particularly NMDA and KARs, has been implicated in the generation and propagation of seizures. ⁴⁸ Enhanced glutamate‐mediated excitatory neurotransmission is thought to contribute to the hypersynchronization of neuronal networks underlying epileptic foci. The researchers investigated the antiepileptic potential of two phenolic compounds, chlorogenic acid (CA) and vitexin/AP8CG, known for their antioxidant properties and neuroprotective effects. They conducted experiments on male Swiss albino mice divided into five groups, where epilepsy was induced in all groups except the control. The mice were treated with pilocarpine, and then the effects of AP8CG and CA were evaluated. The results showed that pilocarpine induced seizures in all groups, with significant increases in seizure duration and frequency. However, treatment with AP8CG and CA reduced these parameters, with the pilocarpine + CA group achieving the best results, with 83.33% of animals being seizure‐free. The expression levels of NMDA receptors and KARs (KA1) were quantified, and pilocarpine treatment led to an increase in NMDA expression, which were attenuated in the presence of AP8CG and CA. Furthermore, changes in glutamate and γ‐aminobutyric acid (GABA) levels in the hippocampus were observed. Pilocarpine increased glutamate levels and decreased GABA levels, whereas treatment with AP8CG and CA reversed these changes, with CA showing the closest results to the control group. These findings suggest that AP8CG and CA may exert their antiepileptic effects by modulating NMDA receptors and restoring glutamate and GABA levels, which play determining roles in excitotoxicity and epilepsy pathogenesis. the study provides valuable insights into the potential therapeutic use of these compounds in epilepsy management. ⁴⁹

3.2.2. Diabetic encephalopathy

In the same sense, diabetic encephalopathy, a complication of diabetes mellitus affecting the brain, has been associated with excitotoxicity‐induced neuronal apoptosis. Studies have shown that elevated glutamate levels in the cerebral cortex led to excitotoxicity and cognitive impairment. ⁵⁰ The modulation of glutamate homeostasis and iGluR activity might represent potential neuroprotective targets for managing diabetic encephalopathy. In this study, the researchers investigated the neuroprotective effects of curcumin in diabetic encephalopathy by analyzing NMDA and AMPAR‐mediated excitotoxicity in the cerebral cortex of diabetic rats. Adult male Wistar rats were divided into four groups, with all except the control group receiving streptozotocin to induce diabetes. The rats were treated with insulin or curcumin, and their cerebral cortex was extracted for analysis. The study found that untreated diabetic rats exhibited a significant increase in glutamate levels compared to the control group, indicating excitotoxicity. However, the group treated with curcumin showed the most promising results, reducing glutamate levels closer to the control group. Furthermore, immunohistochemical analysis revealed increased expression of the NMDA receptor subunit NR1 and AMPAR subunit GluR4 in diabetic rats. However, treatment with insulin or curcumin reversed this increased expression, with curcumin demonstrating the most significant decrease in expression levels. These findings suggest that curcumin may ameliorate excitotoxicity in the cerebral cortex of diabetic rats by modulating NMDA and AMPAR‐mediated pathways. The study highlights the potential therapeutic role of curcumin in protecting against neuronal damage and indicates its relevance in the management of diabetic encephalopathy. ⁵⁰

3.2.3. Multiple sclerosis (MS)

In MS, an autoimmune demyelinating disease of the CNS, increased expression of iGluRs has been associated with inflammation and demyelination. ⁵² The study aimed to investigate the role of NMDA receptors in experimental autoimmune encephalomyelitis (EAE), an animal model used to understand the pathomechanisms of MS. The researchers explored the effects of NMDA receptor antagonists, memantine, and amantadine, as potential therapies for EAE. Female Lewis rats were divided into three experimental groups, with Groups 2 and 3 induced with EAE using guinea pig spinal cord homogenate and complete Freund's adjuvant. The antagonists were administered daily for 7 days, starting 5 days after EAE induction. Neurological symptoms of EAE were monitored using a scoring system. The results showed that EAE symptoms peaked on Day 13 and significantly decreased thereafter. Both memantine and amantadine administration reduced the severity of symptoms, with memantine demonstrating a more substantial effect The dysregulation of glutamatergic signaling pathways may contribute to disease progression and neurodegeneration in MS. Targeting iGluRs might present a novel therapeutic approach to attenuate excitotoxicity and potentially slow down MS progression. ⁵³

The dysregulation of iGluRs and glutamate signaling contributes to neuronal damage and cell death in these conditions, emphasizing the importance of maintaining glutamatergic homeostasis. Targeted interventions aimed at modulating iGluRs, and glutamate levels hold promise for mitigating excitotoxicity and preserving neuronal function in CNS disorders. A comprehensive understanding of the intricate interactions between glutamate signaling and neurodegenerative processes is essential for advancing therapeutic approaches to combat CNS disorders and promote neuroprotection. Table 1 presents the expression levels of the iGluRs in the different experimental conditions compared to control groups. The findings from these studies collectively demonstrate the promise of targeted interventions in mitigating excitotoxicity and preserving neuronal integrity. These therapeutic approaches aim to restore glutamatergic homeostasis and protect against excitotoxic neuronal cell death by selectively modulating iGluRs or glutamate levels.

Table 1.

Expression levels of iGluRs.

Ref.	Substance tested	iGluR	Expression levels (% of the untreated group compared to control)	Expression levels (% of the treated group compared to control)
[47]	Genistein, an isoflavonoid derived from soy products.	NR2	↑50.5% (3 h); ↑105.2% (48 h)	↑3.2% (3 h); ↑73.4% (48 h)
		GluR2	↓42.5% (3 h); ↓54.1% (48 h)	↓11.5%(3 h); ↓47.1%(48 h)
[48]	Apigenin 8‐C‐glucoside and CA, which are antioxidant agents	NMDAR	↑195%	↑95% (AP8CG); ↑40% (CA)
[49]	Curcumin, also known as diferuloylmethane, is an active component in the golden spice turmeric (Curcuma longa) and in Curcuma xanthorrhiza oil	NR1	↑85.9%	↑17.7%
		GluR4	↑83%	↑19.4%
[50]	EPO, is a recombinant form of human EPO used to increase differentiation of progenitor cells to red blood cells in the treatment of anemia	NR1	↑29.2%	↑5.1%
		KA1	↑21%	↑11.6%
[52]	Monosodium l‐glutamate SB203580 (p38 inhibitor)	NR1	↑36.3% (8 d postnatal); ↑10.8% (14 d postnatal)	↑24.2% (8 d postnatal); ↑0.6% (14 d postnatal)
		GluR2	↑163.6% (8 d postnatal); ↓54.5% (14 d postnatal)	↑184.8% (8 d postnatal); ↑11.1% (14 d postnatal)

Note: NR2 is a specific subunit of the NMDA receptor, an iGluR that plays a determining role in synaptic plasticity and learning in the CNS. GluR2 is a specific subunit of the AMPA receptor, an iGluR that mediates fast excitatory neurotransmission in the CNS. NMDA receptor is a type of iGluR that is essential for learning, memory, and synaptic plasticity in the CNS. NR1 is a specific subunit of the NMDA receptor, which forms a heteromeric complex with other subunits to create functional NMDA receptors in the CNS. GluR4 is a specific subunit of the AMPA receptor, involved in mediating fast excitatory neurotransmission and synaptic plasticity in the CNS. KA1 is a specific subunit of kainate receptors, a type of iGluR that modulates neuronal circuitry in the CNS. Untreated group: This group represents the baseline or control condition where subjects or samples are not exposed to any specific treatment or drug. It serves as a reference to compare the natural or unaltered expression levels of iGluRs. Treated group: This group consists of subjects or samples that have been exposed to a specific treatment or drug. The purpose of this group is to observe how the treatment influences the expression levels of iGluRs compared to the untreated baseline. The treatment could involve the administration of drugs, compounds, or other interventions aimed at modulating glutamate receptor expression.

Abbreviations: AMPA, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid; AP8CG, apigenin‐8‐C‐glycoside; CA, chlorogenic acid; CNS, central nervous system; EPO, erythropoietin; GluR2, glutamate receptor subtype 2; GluR4, glutamate receptor subtype 4; iGluRs, ionotropic glutamate receptors; KA1, kainate receptor subtype 1; NMDA, N‐methyl‐d‐aspartate; NR1, NMDA receptor subtype 1; NR2, NMDA receptor subtype 2.

3.3. Neuroprotection through targeted interventions

Given the detrimental consequences of excitotoxicity in various CNS disorders, there is a growing interest in developing targeted interventions to protect neurons from glutamate‐induced damage. At present, there are no established therapies to treat or impede the advancement of these conditions, and current interventions primarily offer symptomatic relief. Within this framework, natural compounds emerge as potential candidates for addressing neurodegeneration due to their diverse range of pharmacological and biological effects. Accumulating scientific evidence is pointing to natural extracts playing a key role in neuroprotection. Their considerable versatility positions them as promising options in the exploration of drug development and discovery for various CNS disorders. ⁵⁵ In the pursuit of effective neuroprotective interventions, several studies have shed light on potential substances and compounds for therapeutic applications.

The neuroprotective effects of Artemisia absinthium extract against glutamate‐induced toxicity in PC12 cells were investigated. ⁵⁶ PC12 cells were pretreated with A. absinthium extract before exposure to glutamate‐induced toxicity. The results demonstrated that A. absinthium extract significantly attenuated the loss of cell viability, reduced reactive oxygen species (ROS) accumulation, and inhibited lipid peroxidation in glutamate‐injured PC12 cells. Additionally, the extract reduced cell apoptosis, indicating its potential as a neuroprotective agent against glutamate‐induced neurotoxicity. These extracts displayed antioxidant properties, preserved mitochondrial membrane potential, and modulated the expression of survival factors, indicating potential therapeutic avenues for neurodegenerative diseases.

In the context of TBI, branched‐chain amino acids (BCAAs) emerged as promising neuroprotectants, as shown in ⁵⁷ where the authors explored the protective effect of BCAAs on TBI and their potential to enhance the rate of recovery. The study utilized a mouse model of TBI induced by a weight‐drop method. The mice were divided into groups receiving pretreatment, posttreatment, or pre‐ + posttreatment with BCAAs. The results showed that pretreated and pre‐ + posttreated mice exhibited significantly better motor recovery and cognitive function compared to the untreated group. These groups also showed reduced levels of astrocytes, suggesting a neuroprotective effect of BCAAs in TBI. The study demonstrated that BCAAs are neuroprotective and may enhance recovery after TBI, potentially through their role in glutamate homeostasis. Pretreatment with BCAAs significantly improved motor and cognitive recovery in mouse models of TBI, suggesting their prophylactic role in contact sports and emergent use scenarios.

Moreover, the neuroprotective effects of melatonin in mitigating glutamate‐induced excitotoxicity in retinal ganglion cells (RGCs) was investigated. ⁵⁸ The study proved that melatonin treatment effectively protected RGCs from NMDA‐induced injury by reducing oxidative stress and maintaining mitochondrial membrane potential. Moreover, melatonin was found to modulate intracellular calcium influx and inhibit MAPK phosphorylation, highlighting its potential therapeutic application for the treatment of glaucoma and other neurodegenerative conditions. These findings underscore the significance of melatonin as a potential neuroprotective agent with promising implications for the management of neurodegenerative diseases. In a similar vein, in ⁵⁹ the neuroprotective potential of Garcinia cowa extracts against glutamate‐mediated hippocampal neuronal HT22 cell death was explored. The study showed six novel polyoxygenated xanthones from the extracts, with garcicowanone F showing remarkable neuroprotective activity, promoting more than 80% cell viability in a concentration‐dependent manner. The extracts also showed strong antioxidant properties, suggesting a potential therapeutic avenue for the treatment of various neurodegenerative diseases.

In Ref. [60], the study aimed to investigate the neuroprotective effects of the neuropeptide Y (NPY) on human neuroblastoma SH‐SY5Y cells under glutamate excitotoxicity and endoplasmic reticulum (ER) stress conditions. The researchers exposed SH‐SY5Y cells to glutamate and tunicamycin, an ER stress‐inducing agent, to induce cell damage. The results showed that NPY treatment significantly increased cell viability and reduced apoptosis in the glutamate and tunicamycin‐induced neuronal injury models. Further analysis revealed that NPY treatment suppressed the activation of proapoptotic pathways, including ERK1/2 and JNK/BAD, while enhancing the activation of survival pathways such as AKT and CREB. These findings show that NPY exerts neuroprotective effects by modulating cell survival and apoptotic signaling pathways, making it a potential therapeutic target for neurodegenerative disorders.

Recently, researchers have investigated the neuroprotective effects of dexmedetomidine in glutamate‐stimulated neuronal injury using the microRNA‐433/Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (miR‐433/JAK2/STAT3) pathway. ⁶¹ The study utilized synaptosomes and HT22 cells as in vitro models. The results revealed that dexmedetomidine treatment suppressed glutamate‐induced neuronal injury and reduced apoptosis in HT22 cells. Dexmedetomidine also upregulated the expression of miR‐433, which in turn inhibited the activation of the JAK2/STAT3 pathway. These findings suggest that dexmedetomidine exerts its neuroprotective effects by modulating the miR‐433/JAK2/STAT3 pathway, providing new insights into potential therapeutic strategies for neuroprotection in excitotoxic conditions. In Ref. [62], the researchers delved into the neuroprotective effects of black pepper (Piper nigrum L.) and its bioactive compounds in age‐related neurological disorders. Black pepper has long been used in traditional medicine for various ailments, and its potential therapeutic benefits have been a subject of interest. The study highlighted the antioxidant, anti‐inflammatory, and neuroprotective properties of black pepper and its active ingredient, piperine. It was found that black pepper and piperine have the ability to modulate cell survival signaling and protect against oxidative stress, inflammation, and protein misfolding—all of which are key players in age‐related neurological disorders. Whereas in Ref. [63], the researchers focused on understanding the asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimer's disease (AD). They employed a novel approach by using the glutamate biosensor iGluSnFR, restricted to either the CA3 or CA1 neurons to visualize glutamate dynamics at pre‐ and postsynaptic microenvironments, respectively. The results revealed that the inhibition of the primarily astrocytic glutamate transporter‐1 (GLT‐1) resulted in slower glutamate clearance rates at presynaptic membranes. Interestingly, GLT‐1 expression was found to be reduced early in the AD model, leading to impaired glutamate clearance, and disrupted presynaptic short‐term plasticity. This discovery shed light on the critical role of astrocytes in regulating glutamate dynamics and synaptic function in AD, highlighting new avenues for potential neuroprotective interventions targeting astrocytic function.

In Ref. [64], the neuroprotective potential of farrerol, a flavonoid found in certain plants, against glutamate‐induced apoptosis in HT22 cells were investigated. The study explored the impact of farrerol on oxidative stress and mitochondrial damage induced by glutamate. The results showed that farrerol effectively inhibited ROS expression, reduced apoptosis, and protected mitochondrial integrity in HT22 cells exposed to glutamate‐induced toxicity. Additionally, farrerol was found to regulate the Nrf2/heme oxygenase‐1 (HO‐1) signaling pathway, promoting cellular antioxidant defenses, and mitigating oxidative stress‐induced neuronal damage. These findings provide valuable evidence for farrerol's potential as a neuroprotective agent, warranting further investigations for its application in neurodegenerative disease models. The same cell line was used in, ⁶⁵ where the researchers examined the neuroprotective effects of the ethanol extract of Polyscias fruticosa (EEPF) against glutamate‐mediated neuronal toxicity. The study aimed to elucidate the molecular mechanisms underlying EEPF's neuroprotective actions. The results demonstrated that EEPF treatment significantly increased cell viability and reduced apoptosis in HT22 cells exposed to glutamate‐induced toxicity. Moreover, EEPF treatment suppressed intracellular calcium levels and ROS accumulation, providing further evidence of its antioxidative and neuroprotective properties. The study also revealed that EEPF modulated various signaling pathways associated with cell survival and apoptosis, suggesting a multifaceted mechanism for its neuroprotective effects. These findings suggest that EEPF holds promise as a natural neuroprotective agent with potential therapeutic applications in neurodegenerative disorders. In the same way, the potential neuroprotective effects of the plant extract Arecae pericarpium on oxidative stress‐induced neuronal cell death was investigated using HT22 cells. ⁶⁶ A. pericarpium is known for its anti‐migraine, antidepressant, and antioxidative properties in traditional herbal medicine. The researchers used a glutamate excitotoxicity model in HT22 cells to induce oxidative stress and neuronal cell death. The results showed that pretreatment with A. Pericarpium extract significantly protected HT22 cells against glutamate‐induced injury by reducing intracellular ROS levels, supporting mitochondrial membrane potential and upregulating the phosphoinositide 3‐kinase/protein kinase B (Akt) pathway. These findings prove the potential of A. Pericarpium as a neuroprotective agent against oxidative stress‐induced neurotoxicity and call for further investigation into its therapeutic benefits for neurodegenerative disorders.

The evidence accumulated over the years highlights the promising potential of various natural substances in neuroprotection against glutamate‐induced toxicity and oxidative stress‐induced neuronal cell death. Each substance demonstrated significant neuroprotective effects in different experimental models, including glutamate‐induced toxicity, TBI, and excitotoxic conditions (Table 2). The modulation of various cellular pathways, such as apoptosis, survival signaling, and neurotransmitter homeostasis, contributes to the neuroprotective mechanisms of these substances.

Table 2.

Neuroprotective effects of natural substances in various experimental models.

Reference	Neuroprotective substance and tested on (animals/cell line)	Expression	Remarkable results
[56]	Artemisia absinthium Extract—PC12 cells	Markedly attenuated glutamate‐induced cytotoxicity, reduced ROS generation, lipid peroxidation, and cell apoptosis	Neuroprotective against glutamate‐induced injury
[57]	BCAAs—adult mice	Improved motor recovery and cognitive function after TBI, associated with BCAAs’ role in glutamate homeostasis	Potential preventive and neuroprotective role for TBI
[58]	Melatonin—R28 cells and mouse RGCs	Protected R28 cells and RGCs from glutamate excitotoxicity, reduced cellular Ca2+ influx, and inhibited ROS generation	Therapeutic potential for glaucoma treatment
[59]	Garcinia cowa, polyoxygenated xanthones—HT22 cells	Garcicowanones and norcowanol exhibited significant neuroprotective effects against glutamate‐mediated HT22 cell death	Potential neuroprotective agents
[60]	NPY—human neuroblastoma SH‐SY5Y cells	NPY increased cell viability and suppressed apoptosis induced by glutamate, regulated proapoptotic signaling pathways	Potential neuroprotective role of NPY in glutamate excitotoxicity
[61]	Dexmedetomidine—neuronal injury model	Dexmedetomidine ameliorated Glu‐induced neuronal injury via miR‐433/JAK2/STAT3 pathway	Potential therapeutic option for neuronal injury
[62]	Black pepper and its bioactive compounds—age‐related neurological disorders	Black pepper compounds showed neuroprotective properties against ANDs in experimental models	Potential therapeutic agents for ANDs
[63]	Asymmetric glutamate dysregulation—mouse, model of AD	GLT‐1 dysfunction affected the presynapse more than the postsynapse, potentially implicating presynaptic impairments in brain diseases	Relevant to understanding presynaptic impairments in AD
[64]	Farrerol—HT22 cells	Farrerol inhibited ROS expression, apoptosis, mitochondrial damage, and caspase activation in HT22 cells induced by glutamate	Potential therapeutic option with neuroprotective and antioxidant effects
[65]	EEPF—HT22 cells	EEPF treatment protected HT22 cells against glutamate‐mediated cell death, improved cell viability, and suppressed apoptosis	Potential neuroprotective agent against glutamate‐mediated neurotoxicity
[66]	APE—HT22 cells	APE protected HT22 cells against glutamate‐induced injury, reduced oxidative stress and apoptosis	Potential neuroprotective agent via PI3K/Akt‐mediated Nrf‐2/HO‐1 signaling pathway
[67]	Glutamatergic therapeutic drugs—bipolar disorder	Glutamatergic drugs showed neuroprotective and neuroplastic potential in bipolar disorder	Potential for novel therapeutic approaches
[68]	Valeric acid—Alzheimer‐induced rats	Valeric acid increased hippocampal neurotransmitter levels (ACH, GABA, glutamate, dopamine, and serotonin) in AD model rats	Potential neuroprotective agent in AD management

Abbreviations: APE, Arecae pericarpium ethanol extract; BCAAs, branched‐chain amino acids; EEPF, ethanol extract of Polyscias fruticosa; GABA, γ‐aminobutyric acid; GLT‐1, glutamate transporter‐1; HO‐1, heme oxygenase‐1; miR433/JAK2/STAT3, microRNA‐433/Janus kinase 2/signal transducer and activator of transcription 3; NPY, neuropeptide Y; PI3K, phosphoinositide 3‐kinase; RGC, retinal ganglion cell; ROS, reactive oxygen species; TBI, traumatic brain injury.

These studies provide valuable insights into the underlying molecular mechanisms of these substances and their potential applications as neuroprotective agents in the context of neurodegenerative diseases.

This table summarizes the findings from various studies investigating neuroprotective substances and their effects on neuronal cells or animal models under glutamate‐mediated neurotoxicity conditions.

4. INNOVATIVE APPROACHES TO IGLURS MODULATION

Recent advancements in the field of iGluRs research have witnessed notable innovation, particularly in the exploration of novel therapeutic strategies. Researchers have increasingly focused on investigating drug combinations that target iGluRs. Combination therapy aims to achieve enhanced therapeutic efficacy and potentially mitigate adverse effects associated with single‐agent treatments by synergistically modulating glutamatergic neurotransmission along with other relevant pathways. Additionally, there has been significant progress in the development of cell‐targeted therapies, leveraging advancements in molecular biology and gene editing techniques to precisely modulate iGluR activity in specific cell populations. Moreover, the emergence of new technologies, such as CRISPR‐based approaches, has provided unprecedented tools for studying iGluRs with high spatial and temporal resolution, opening new avenues for therapeutic intervention. ⁶⁹ , ⁷⁰ , ⁷¹ , ⁷²

Drug combination is a novel new research approach to the role of iGluRs in health. For example, the influence of the combination of nicotine with other substances on GluRs has been studied. ⁷³ Nicotine triggers the release of glycine from the rat hippocampus through α7‐nAChR activation, leading to increased glutamate release. Additionally, the deficits in attentional processing induced by MK‐801 can be prevented by nicotine. However, the combination of nicotine and clozapine, both partial agonists at NMDA receptors, does not mitigate MK‐801‐induced deficits, suggesting opposing mechanisms of action. On the contrary, the combined treatment of 1MeTIQ and MK‐801 showed promising results in mitigating glutamate‐induced neurotoxicity. ⁷⁴ MK‐801, known for its NMDA receptor inhibition, triggered glutamate release and oxidative stress, leading to cell death. However, coadministration of 1MeTIQ effectively attenuated these toxic effects, demonstrating its potential as a neuroprotective agent. Notably, the combination therapy significantly inhibited glutamate release in the rat hippocampus, highlighting its efficacy in modulating excitotoxicity.

Recent research has focused on elucidating the intricate dynamics of combining substances to modulate excitotoxicity mediated by glutamatergic neurotransmission, particularly in AD pathology. Several preclinical and clinical studies have provided compelling evidence supporting the rationale for combination therapy in AD. ⁷⁵ For instance, the simultaneous blockade of NMDA receptors alongside acetylcholinesterase inhibition has demonstrated synergistic neuroprotective effects in experimental models of AD, suggesting a complementary mechanism of action that could translate into improved cognitive outcomes in patients. Moreover, the integration of neuroprotective agents with anti‐inflammatory drugs or antioxidants may offer additional benefits by attenuating neuroinflammation and oxidative stress, thereby preserving neuronal function and delaying disease progression. In the same sense, recent investigations demonstrated that the combination of angiotensin receptor blockers (ARBs) and ceftriaxone offers promising neuroprotective effects in conditions such as ischemic stroke. ⁷⁶ ARBs and ceftriaxone synergistically enhance neuroprotection, suggesting a novel therapeutic strategy for ischemic stroke and related neurodegenerative disorders. These findings suggest a promising therapeutic approach for managing glutamate‐mediated neurodegenerative disorders. However, the design and implementation of combination therapy regimens necessitate careful consideration of factors such as drug interactions, dosing schedules, and safety profiles to optimize therapeutic outcomes while minimizing the risk of adverse events. ³⁵

iGluRs are emerging as promising targets for therapeutic interventions tailored to specific cell types within the nervous system. ⁷⁷ There's a growing focus on the role of iGluRs in cell‐targeted therapy. A recent study has underscored the association between iGluRs and cell‐targeted therapies, heralding a departure from conventional treatment strategies for CNS diseases. ⁷⁸ This study delved into the multifaceted roles of iGluRs across various cell types within the nervous system, including oligodendrocytes, microglia, and endothelial cells, revealing novel insights into their involvement in disease pathogenesis. This represents innovative therapeutic approaches that harness the power of iGluR modulation to precisely target diseased cells while sparing healthy ones. Moreover, a recent study sheds light on the novel application of iGluRs beyond CNS diseases. Although iGluRs are primarily known for their role in neuronal signaling, emerging evidence suggests their involvement in immune cell regulation within the tumor microenvironment (TME). ⁷⁹ Specifically, both NMDA and AMPA receptors, subtypes of iGluRs, have been found to be expressed by immune cells such as T cells and macrophages. Despite limited research on the role of iGluRs in the TME, studies have demonstrated their potential impact on immune cell function. For instance, the activation of AMPA receptors in macrophages has been linked to the production of pro‐inflammatory cytokines, implicating iGluRs in immune response modulation. iGluRs have been shown to influence T‐cell adhesion and migration, suggesting a broader role in immune cell behavior. Moreover, within the innovative landscape of cell‐targeted therapies, iGluRs emerges as a novel frontier in combatting retinal neurodegeneration. ⁸⁰ Notably, NMDA is central to the excitotoxicity implicated in retinal neurodegeneration. Through targeted interventions with iGluR antagonists, particularly in experimental models of glaucoma, ischemia, and retinitis pigmentosa, significant efficacy has been demonstrated. However, bridging the gap from preclinical success to clinical application necessitates further exploration, addressing challenges such as disease heterogeneity and the identification of reliable disease progression markers. This interplay between iGluRs and immune cells within the TME presents a promising target for novel cell‐targeted therapies in cancer treatment. Further investigation into the mechanisms underlying iGluR‐mediated immune modulation could pave the way for innovative therapeutic strategies aimed at harnessing the immune system to combat cancer. The interplay between iGluRs and cell‐targeted therapies represents a promising target for new technologies to develop novel cellular therapies to combat various diseases.

5. CONCLUDING REMARKS: TARGETING IGLURS FOR RESTORING GLUTAMATERGIC HOMEOSTASIS

In this review, we have explored the promising potential of targeting iGluRs as a viable strategy for restoring glutamatergic homeostasis in various CNS disorders. Glutamate, being the principal excitatory neurotransmitter in the brain, plays a determining role in synaptic transmission and plasticity. However, excessive glutamate release and dysregulation of iGluRs have been linked to neurodegenerative diseases, stroke, and other CNS disorders. Through the analysis of multiple research studies, we have gained valuable insights into the neuroprotective effects of various compounds that modulate iGluRs. The amalgamation of synthetic agonists and natural extracts showcases the rich tapestry of therapeutic potential in this field. Although the journey to fully comprehend the intricate mechanisms underlying iGluR modulation remains ongoing, the captivating findings presented herein offer compelling evidence for the pursuit of novel therapeutic strategies to reinstate glutamatergic balance and enhance the quality of life for patients grappling with CNS disorders.

In conclusion, the exploration of targeting iGluRs for restoring glutamatergic homeostasis represents a promising frontier in the field of neuroprotection and CNS disorder management. The future of targeting iGluRs for restoring glutamatergic homeostasis holds great promise and potential in the field of neuroprotection and CNS disorders management. As research continues to advance, significant breakthroughs are likely to occur in the understanding of the molecular and cellular mechanisms involved in glutamatergic system regulation. One key direction for the future lies in the development of more specific and personalized therapies targeting iGluRs. Through precision medicine approaches, biomarkers and genetic profiles can be identified to tailor treatments for each individual based on their unique response to therapy. Furthermore, investigations into natural compounds and plant‐derived products will remain relevant in the search for neuroprotective agents. Studies on plant extracts and their bioactive components offer a valuable source of new therapeutic candidates, with the potential to address the intricate interactions of the glutamatergic system and restore homeostasis in pathological conditions. Advancements in technology will also play a determining role in shaping the future of this research. The utilization of more sophisticated approaches such as nanomedicine will enable the development of more efficient drug delivery systems and enhance the bioavailability of neuroprotective agents. Further research and clinical trials are needed to fully explore the therapeutic efficacy and safety of these natural compounds, paving the way for new interventions aimed at neuroprotection.

AUTHOR CONTRIBUTIONS

Jorge Y. Magdaleno Roman led the data curation process, conducted formal analysis, and contributed equally to the investigation, methodology development, validation, visualization, and writing and editing of the manuscript. Christian Chapa González played a leading role in conceptualization, methodology development, project administration, resource allocation, and supervision. Additionally, he contributed equally to data curation, formal analysis, investigation, validation, visualization, and both the original drafting and subsequent review and editing of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Not applicable.

Magdaleno Roman JY, Chapa González C. Glutamate and excitotoxicity in central nervous system disorders: ionotropic glutamate receptors as a target for neuroprotection. Neuroprotection. 2024;2:137‐150. 10.1002/nep3.46

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.