Schizophrenia is a complex neuropsychiatric disorder composed of primary cluster-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. While traditional antipsychotics primarily target dopamine pathways, they provide limited efficacy against cognitive deficits and negative symptoms. Growing evidence implicates glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDA-R) hypofunction, in the pathophysiology of schizophrenia, making glutamate modulation a promising therapeutic approach. This review explores emerging glutamate-based treatment strategies, including NMDA receptor modulators, metabotropic glutamate receptor (mGluR) agents, glutamate transporter regulators, and kynurenine pathway inhibitors. We summarize preclinical and clinical findings on NMDA co-agonists (D-serine and glycine), glycine transporter inhibitors, D-amino acid oxidase inhibitors, and mGluR-targeted therapies, highlighting their mechanisms, efficacy, and limitations. In addition, we discuss novel interventions aimed at restoring glutamate homeostasis, including neuroinflammatory modulation and synaptic plasticity enhancers. Despite promising results, many glutamate-targeting therapies have yielded inconsistent clinical outcomes, underscoring the need for biomarker-driven patient selection and optimized treatment protocols. We propose that integrating glutamate modulators with existing antipsychotic regimens may enhance therapeutic response while minimizing side effects. Future research should focus on refining glutamate-based interventions, identifying predictive biomarkers, and addressing the heterogeneity in schizophrenia pathology. With continued advancements, glutamate modulation has the potential to transform schizophrenia treatment, particularly for cognitive and negative symptoms that remain largely unaddressed by current therapies.

Metabotropic glutamate receptor 4 (mGluR4) regulates disease by modulating neurotransmitter release and synaptic plasticity and has been implicated in various diseases, including neurodegenerative disorders and psychiatric conditions, where its dysregulation can impact synaptic function and neuronal signaling.

This review covers the patents and key literature concerning mGluR4 PAMs by utilizing the search engines: SciFinder, Google Patents, and PubMed from 2017 to 2024. It summarizes the key exemplified compounds, relevant SAR, and key biological data presented in the patents and primary literature. The key findings and potential path forward are also discussed.

The mGluR4 receptor serves as a novel target for the treatment of neurodegenerative disorders (namely Parkinson's disease), multiple sclerosis, and chronic pain along with other brain disorders. Two compounds have been advanced to early-stage clinical trials from Prexton Therapeutics and Appello Pharmaceuticals. The first compound from Prexton failed due to efficacy and the Appello compound has yet to have results disclosed. The results from this trial will be an important test for whether future mGluR4 PAMs are advanced into clinical trials.

Huntington's disease is a neurodegenerative disorder caused by an expanded CAG repeat mutation in the Huntingtin (HTT) gene. The mutation impacts neuronal protein homeostasis and cortical/striatal circuitry. SUMOylation is a post-translational modification with broad cellular effects including via modification of synaptic proteins. Here, we used an optimized SUMO protein-enrichment and mass spectrometry method to identify the protein SUMOylation/SUMO interaction proteome in the context of Huntington's disease using R6/2 transgenic and non-transgenic mice. Significant changes in the enrichment of SUMOylated and SUMO-interacting proteins were observed, including those involved in presynaptic function, cytomatrix at the active zone, cytoskeleton organization and glutamatergic signalling. Mitochondrial and RNA-binding proteins also showed altered enrichment. Modified SUMO-associated pathways in Huntington's disease tissue include clathrin-mediated endocytosis signalling, synaptogenesis signalling, synaptic long-term potentiation and SNARE signalling. To evaluate how modulation of SUMOylation might influence functional measures of neuronal activity in Huntington's disease cells in vitro, we used primary neuronal cultures from R6/2 and non-transgenic mice. A receptor internalization assay for the metabotropic glutamate receptor 7 (mGLUR7), a SUMO-enriched protein in the mass spectrometry, showed decreased internalization in R6/2 neurons compared to non-transgenic neurons. SiRNA-mediated knockdown of the E3 SUMO ligase protein inhibitor of activated STAT1 (Pias1), which can SUMO modify mGLUR7, reduced this Huntington's disease phenotype. In addition, microelectrode array analysis of primary neuronal cultures indicated early hyperactivity in Huntington's disease cells, while later time points demonstrated deficits in several measurements of neuronal activity within cortical neurons. Huntington's disease phenotypes were rescued at selected time points following knockdown of Pias1. Collectively, our results provide a mouse brain SUMOome resource and show that significant alterations occur within the post-translational landscape of SUMO-protein interactions of synaptic proteins in Huntington's disease mice, suggesting that targeting of synaptic SUMO networks may provide a proteostatic systems-based therapeutic approach for Huntington's disease and other neurological disorders.

Glutamate-induced neurotoxicity can be attenuated via paracrine mechanisms involving mesenchymal stem cells (MSCs). Conditioned medium (CM) from dental MSCs stimulates neuroprotective effects through trophic factors, and melatonin is a known enhancer of the efficacy of conditional media. Here, we investigated the protective effect of CM derived from stem cells from the apical papilla (SCAPs), supplemented without and with melatonin CM (SCAP-CM and Mel-CM), against glutamate-induced PC12 cell apoptosis via the inhibition of intracellular calcium influx and reactive oxygen species (ROS) production. The results showed that CM effectively reduced glutamate-induced intracellular calcium ion concentration, ROS production, and LDH levels in PC12 cells, elevated mitochondrial membrane potential, and inhibited Bax and Cytochrome c protein expression while increasing Bcl-2 protein expression. Moreover, CM significantly reduced the expression of caspase-9 and caspase-3 to inhibit glutamate-induced PC12 cell apoptosis. Notably, Mel-CM outperformed SCAP-CM in all aspects. This study demonstrates that melatonin can enhance the paracrine effects of stem cells and that Mel-CM mediates neuroprotection by inhibiting neuronal cell damage and apoptosis induced by glutamate-induced neurotoxicity.

The increasing prevalence of screen time among modern citizens has raised concerns regarding its potential impact on neuroinflammation and overall brain health. This review examines the complex interconnections between screen time and neuroinflammatory processes, particularly in children and adolescents. We analyze existing literature that explores how excessive digital media use can lead to alterations in neurobiological pathways, potentially exacerbating inflammatory responses in the brain. Key findings suggest that prolonged exposure to screens may contribute to neuroinflammation through mechanisms such as disrupted sleep patterns, diminished cognitive engagement, and increased stress levels. Similarly, we discuss the implications of these findings for mental health and cognitive development, emphasizing the need for a balanced approach to screen time. This review highlights the necessity for further research to elucidate the causal relationships and underlying mechanisms linking screen time and neuroinflammation, thereby informing guidelines for healthy media consumption.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aβ plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aβ plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aβ accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD.

Glutamate excitotoxicity is a central mechanism contributing to cellular dysfunction and death in various neurological disorders and diseases, such as stroke, traumatic brain injury, epilepsy, schizophrenia, addiction, mood disorders, Huntington's disease, Alzheimer's disease, Parkinson's disease, multiple sclerosis, pathologic pain, and even normal aging-related changes. This detrimental effect emerges from glutamate binding to glutamate receptors, including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, N-methyl-d-aspartate receptors, kainate receptors, and GluD receptors. Thus, excitotoxicity could be prevented by targeting glutamate receptors and their downstream signaling pathways. However, almost all the glutamate receptor antagonists failed to attenuate excitotoxicity in human patients, mainly due to the limited understanding of the underlying mechanisms regulating excitotoxicity. Transient receptor potential (TRP) channels serve as ancient cellular sensors capable of detecting and responding to both external and internal stimuli. The study of human TRP channels has flourished in recent decades since the initial discovery of mammalian TRP in 1995. These channels have been found to play pivotal roles in numerous pathologic conditions, including excitotoxicity. In this review, our focus centers on exploring the intricate interactions between TRP channels and glutamate receptors in excitotoxicity.

Regulation of messenger RNA (mRNA) transport and translation in neurons is essential for dendritic plasticity and learning/memory development. The trafficking of mRNAs along the hippocampal neuron dendrites remains translationally silent until they are selectively transported into the spines upon glutamate-induced receptor activation. However, the molecular mechanism(s) behind the spine entry of dendritic mRNAs under metabotropic glutamate receptor (mGluR)-mediated neuroactivation and long-term depression (LTD) as well as the fate of these mRNAs inside the spines are still elusive.

Different molecular and imaging techniques, e.g., immunoprecipitation (IP), RNA-IP, Immunofluorescence (IF)/fluorescence in situ hybridization (FISH), live cell imaging, live cell tracking of RNA using beacon, and mouse model study are used to elucidate a novel mechanism regulating dendritic spine transport of mRNAs in mammalian neurons.

We demonstrate here that brief mGluR1 activation-mediated dephosphorylation of pFMRP (S499) results in the dissociation of FMRP from TDP-43 and handover of TDP-43/Rac1 mRNA complex from the dendritic transport track on microtubules to myosin V track on the spine actin filaments. Rac1 mRNA thus enters the spines for translational reactivation and increases the mature spine density. In contrast, during mGluR1-mediated neuronal LTD, FMRP (S499) remains phosphorylated and the TDP-43/Rac1 mRNA complex, being associated with kinesin 1-FMRP/cortactin/drebrin, enters the spines owing to Ca2+-dependent microtubule invasion into spines, but without translational reactivation. In a VPA-ASD mouse model, this regulation become anomalous.

This study, for the first time, highlights the importance of posttranslational modification of RBPs, such as the neurodevelopmental disease-related protein FMRP, as the molecular switch regulating the dendrite-to-spine transport of specific mRNAs under mGluR1-mediated neurotransmissions. The misregulation of this switch could contribute to the pathogenesis of FMRP-related neurodisorders including the autism spectrum disorder (ASD). It also could indicate a molecular connection between ASD and neurodegenerative disease-related protein TDP-43 and opens up a new perspective of research to elucidate TDP-43 proteinopathy among patients with ASD.

Heavy metals are naturally occurring components of the Earth's crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and  extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO·), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O2·-), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO-). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (Cd), arsenic (As), mercury (Hg), lead (Pb), and chromium (Cr) and their roles in the development of gastrointestinal, pulmonary, kidney, reproductive, neurodegenerative (Alzheimer's and Parkinson's diseases), cardiovascular, and cancer (e.g. renal, lung, skin, stomach) diseases are discussed. A short account is devoted to the detoxification of heavy metals by chelation via the use of ethylenediaminetetraacetic acid (EDTA), dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercapto-1-propane sulfonic acid (DMPS), and penicillamine chelators.

Obsessive-Compulsive Disorder (OCD), a prevalent neuropsychiatric condition, affects approximately 2%-3% of the global population. This paper provides an extensive overview of OCD, detailing its clinical manifestations, neurobiological underpinnings, and therapeutic approaches. It examines OCD's classification shift in the DSM-5, the role of the cortico-striatothalamo- cortical pathway in its development, and the various factors contributing to its etiology, such as genes, environmental factors, and genetic predispositions. The challenges in diagnosing OCD and the effectiveness of both psychological and pharmacotherapeutic treatments are discussed. The paper also highlights the significant overlap between OCD and other mental health disorders, emphasizing its impact on global disability. Moreover, the role of genetic factors in OCD, including twin studies and gene association studies, is elaborated, underscoring the complex interplay of hereditary and environmental influences in its manifestation. The review further delves into the polygenic nature of OCD, illustrating how multiple genes contribute to its development, and explores the implications of genetic studies in understanding the disorder's complexity. Additionally, this research study delves into the concept of polygenic inheritance in complex diseases, highlighting the role of multiple genes in increasing OCD risk. A Genome-wide Association Study (GWAS) is employed to assess Single Nucleotide Polymorphisms (SNPs) to unearth genetic associations with OCD. This comprehensive analysis provides valuable insights into OCD's genetic landscape, paving the way for enhanced diagnostic approaches and treatment modalities.

Gamma-glutamate is an important excitatory neurotransmitter in the central nervous system (CNS), which plays an important role in transmitting synapses, plasticity, and other brain activities. Nevertheless, alterations in the glutamatergic signaling pathway are now accepted as a central element in Alzheimer's disease (AD) pathophysiology. One of the most prevalent types of dementia in older adults is AD, a progressive neurodegenerative illness brought on by a persistent decline in cognitive function. Since AD has been shown to be multifactorial, a variety of pharmaceutical targets may be used to treat the condition. N-methyl-D-aspartic acid receptor (NMDAR) antagonists and acetylcholinesterase inhibitors (AChEIs) are two drug classes that the Food and Drug Administration has authorized for the treatment of AD. The AChEIs approved to treat AD are galantamine, donepezil, and rivastigmine. However, memantine is the only non-competitive NMDAR antagonist that has been authorized for the treatment of AD. This review aims to outline the involvement of glutamate (GLU) at the molecular level and the signaling pathways that are associated with AD to demonstrate the drug target therapeutic potential of glutamate and its receptor. We will also consider the opinion of the leading authorities working in this area, the drawback of the existing therapeutic strategies, and the direction for the further investigation.

Propofol and midazolam are the current standard of care for prolonged sedation in Intensive Care Units (ICUs). However, the effects and mechanism of these sedatives in brain tissue are unclear. Herein, the development of an ICU patient-on-a-chip platform to elucidate those effects is reported. The humanized neural tissue compartment combines mast cells differentiated from human induced pluripotent stem cells (hiPSCs) with cerebral organoids in a three-dimensional (3D) matrix, which is covered with a membrane populated with human cerebral microvascular endothelial cells (hCMEC/D3) that separates the tissue chamber from the vascular lumen, where sedatives were infused for four days to evaluate neurotoxicity and cell-mediated immune responses. Subsequent to propofol administration, gene expressions of CD40 and TNF-α in mast cells, AIF1 in microglia and GFAP/S100B/OLIG2/MBP in macroglia were elevated, as well as NOS2, CD80, CD40, CD68, IL6 and TNF-α mediated proinflammation is noted in cerebral organoids, which resulted in higher expressions of GJB1, GABA-A and NMDAR1 in the tissue construct of the platform. Besides, midazolam administration stimulated expression of CD40 and CD203c+ reactivated mast cell proliferation and compromised BBB permeability and decreased TEER values with higher barrier disruption, whereas increased populations of CD11b+ microglia, higher expressions of GFAP/DLG4/GJB1 and GABA-A-/NMDAR1- identities, as well as glutamate related neurotoxicity and IL1B, IFNG, IFNA1, IL6 genes mediated proinflammation, resulting in increased apoptotic zones are observed in cerebral organoids. These results suggest that different sedatives cause variations in cell type activation that modulate different pathways related to neuroinflammation and neurotoxicity in the ICU patient-on-chip platform.

Metabotropic glutamate receptors (mGluRs) are part of the G protein-coupled receptors (GPCRs) family. They are coupled to Gαq (group I) or Gi/o (groups II and III) proteins, which result in the generation of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) or the inhibition of adenylyl cyclase, respectively. mGluRs have been implicated in anxiety, depression, learning, and synaptic plasticity. Similarly, CB1 cannabinoid receptors (CB1Rs), also GPCRs, play roles in cognitive function and mood regulation through Gαi/o-mediated inhibition of adenylyl cyclase. Both mGluRs and CB1Rs exhibit surface labeling and undergo endocytosis. Given the similar cellular distribution and mechanisms of action, this review complies with fundamental data on the potential interactions and mutual regulation of mGluRs and CB1Rs in the context of depression, anxiety, and cognition, providing pioneering insights into their interplay.

The group III metabotropic glutamate receptors (mGluRs), comprising mGluR4, mGluR6, mGluR7, and mGluR8, offer neuroprotective potential in mitigating excitotoxicity during ischemic brain injury, particularly in neonatal contexts. They are G-protein coupled receptors that inhibit adenylyl cyclase and reduce neurotransmitter release, mainly located presynaptically and acting as autoreceptors. This review aims to examine the differential expression and function of group III mGluRs across various brain regions such as the cortex, hippocampus, and cerebellum, with a special focus on the neonatal stage of development. Glutamate excitotoxicity plays a crucial role in the pathophysiology of brain ischemia in neonates. While ionotropic glutamate receptors are traditional targets for neuroprotection, their direct inhibition often leads to severe side effects due to their critical roles in normal neurotransmission and synaptic plasticity. Group III mGluRs provide a more nuanced and potentially safer approach by modulating rather than blocking glutamatergic transmission. Their downstream signaling cascade results in the regulation of intracellular calcium levels, neuronal hyperpolarization, and reduced neurotransmitter release, effectively decreasing excitotoxic signaling without completely suppressing essential glutamatergic functions. Importantly, the neuroprotective effects of group III mGluRs extend beyond direct modulation of glutamate release influencing glial cell function, neuroinflammation, and oxidative stress, all of which contribute to secondary injury cascades in brain ischemia. This comprehensive analysis of group III mGluRs multifaceted neuroprotective potential provides valuable insights for developing novel therapeutic strategies to combat excitotoxicity in neonatal ischemic brain injury.

N-methyl-D-aspartate receptors (NMDARs) are critical components of the mammalian central nervous system, involved in synaptic transmission, plasticity, and neurodevelopment. This review focuses on the structural and functional characteristics of NMDARs, with a particular emphasis on the GRIN2 subunits (GluN2A-D). The diversity of GRIN2 subunits, driven by alternative splicing and genetic variants, significantly impacts receptor function, synaptic localization, and disease manifestation. The temporal and spatial expression of these subunits is essential for typical neural development, with each subunit supporting distinct phases of synaptic formation and plasticity. Disruptions in their developmental regulation are linked to neurodevelopmental disorders, underscoring the importance of understanding these dynamics in NDD pathophysiology. We explore the physiological properties and developmental regulation of these subunits, highlighting their roles in the pathophysiology of various NDDs, including ASD, epilepsy, and schizophrenia. By reviewing current knowledge and experimental models, including mouse models and human-induced pluripotent stem cells (hiPSCs), this article aims to elucidate different approaches through which the intricacies of NMDAR dysfunction in NDDs are currently being explored. The comprehensive understanding of NMDAR subunit composition and their mutations provides a foundation for developing targeted therapeutic strategies to address these complex disorders.

Alzheimer's disease (AD) is characterized by significant alterations in hippocampal function and structure, but the molecular mechanisms underlying the hippocampal region remain elusive. We integrated multiple transcriptome datasets including human or rat hippocampus (GSE173955, GSE129051, GSE84422) to identify candidate genes. Subsequent analyses including gene ontology analysis and protein-protein interaction mapping were performed to identify key genes and pathways. We found that glutamate ionotropic receptor NMDA-type subunit 3A (GRIN3A) and glutamate metabotropic receptor 8 (GRM8), which are related to the glutamatergic system, were the top two annotated genes and directly related to MAPT, which encodes a tau protein. Since there is no direct evidence of interaction between tauopathy and these genes in AD, further transcriptomic data (GSE125957, GSE56772) from tau transgenic mice and experimental validations through primary rat hippocampal neurons and induced pluripotent stem cell (iPSC)-derived brain organoids were performed. Interestingly, we identified that decreased NR3A (encoded by GRIN3A) and mGluR8 (encoded by GRM8) are correlated with tauopathy and loss of postsynaptic function in AD. Taken together, our results identified a novel tauopathy biomarker GRIN3A in AD. Furthermore, our findings suggest that an integrated approach combining public databases and diverse experimental validations can contribute to the advancement of precision medicine therapies.

Objective: The modulating effects of Cucurbita pepo seed oil (CPSO) on dyslipidemia and neuronal dysfunction in tramadol toxicity were studied. Methods: Fifty-six albino rats were divided into seven groups of eight rats each after a 2-week acclimatization period. All animals had unrestricted access to water and feed, and treatments were administered orally once daily for 42 days. Glutamate dehydrogenase and glutaminase activities were assessed using brain homogenate, while lipid profiles were analyzed in serum samples. Results: Tramadol toxicity was evidenced by significant (P < 0.05) increases in brain glutamate dehydrogenase along with significant (P < 0.05) decreases in the activities of glutaminase in the group administered only tramadol. Also, serum levels of total cholesterol, LDL-C and triglycerides also increased significantly (P < 0.05) following administration of tramadol with decreased level of HDL-C (P < 0.05). However, treatment with CPSO significantly restored the activities and levels of the altered biochemical parameters in a dose-dependent manner. The results of the biochemical investigation using the lipid profile and the enzymes of glutamate metabolism were corroborated by the results obtained from the histopathological examination of the brain. Conclusion: The results of this study therefore suggest that tramadol-induced dyslipidemia and neuronal dysfunction be managed and prevented by the administration of Cucurbita pepo seed oil.

Proteins, which are ubiquitous in cells and critical to almost all cellular functions, are indispensable for life. Fluorescence imaging of proteins is key to understanding their functions within their native milieu, as it provides insights into protein localization, dynamics, and trafficking in living systems. Consequently, the selective labeling of target proteins with fluorophores has emerged as a highly active research area, encompassing bioorganic chemistry, chemical biology, and cell biology. Various methods for selectively labeling proteins with fluorophores in cells and tissues have been established and are continually being developed to visualize and characterize proteins. This review highlights research findings reported since 2018, with a focus on the selective labeling of cellular proteins with small organic fluorophores and their biological applications in studying protein-associated biological events. We also discuss the strengths and weaknesses of each labeling approach for their utility in living systems.

Aging is characterized by the decline in many of the individual's capabilities. It has been recognized that the brain undergoes structural and functional changes during aging that are occasionally associated with the development of neurodegenerative diseases. In this sense, altered glutamatergic neurotransmission, which involves the release, binding, reuptake, and degradation of glutamate (Glu) in the brain, has been widely studied in physiological and pathophysiological aging. In particular, changes in glutamatergic neurotransmission are exacerbated during neurodegenerative diseases and are associated with cognitive impairment, characterized by difficulties in memory, learning, concentration, and decision-making. Thus, in the present manuscript, we aim to highlight the relevance of glutamatergic neurotransmission during cognitive impairment to develop novel strategies to prevent, ameliorate, or delay cognitive decline. To achieve this goal, we provide a comprehensive review of the changes reported in glutamatergic neurotransmission components, such as Glu transporters and receptors during physiological aging and in the most studied neurodegenerative diseases. Finally, we describe the current therapeutic strategies developed to target glutamatergic neurotransmission.

Acute organophosphorus compound (OP) poisoning induces symptoms of the cholinergic crises with the occurrence of severe epileptic seizures. Seizures are induced by hyperstimulation of the cholinergic system, but are enhanced by hyperactivation of the glutamatergic system. Overstimulation of muscarinic cholinergic receptors by the elevated acetylcholine causes glutamatergic hyperexcitation and an increased influx of Ca2+ into neurons through a type of ionotropic glutamate receptors, N-methyl-d-aspartate (NMDA) receptors (NMDAR). These excitotoxic signaling processes generate reactive oxygen species, oxidative stress, and activation of the neuroinflammatory response, which can lead to recurrent epileptic seizures, neuronal cell death, and long-term neurological damage. In this review, we illustrate the NMDAR structure, complexity of subunit composition, and the various receptor properties that change accordingly. Although NMDARs are in normal physiological conditions important for controlling synaptic plasticity and mediating learning and memory functions, we elaborate the detrimental role NMDARs play in neurotoxicity of OPs and focus on the central role NMDAR inhibition plays in suppressing neurotoxicity and modulating the inflammatory response. The limited efficacy of current medical therapies for OP poisoning concerning the development of pharmacoresistance and mitigating proinflammatory response highlights the importance of NMDAR inhibitors in preventing neurotoxic processes and points to new avenues for exploring therapeutics for OP poisoning.

The metabotropic glutamate receptor (mGluR, GRM) family is involved in multiple signaling pathways and regulates neurotransmitter release. However, the evolutionary history, distribution, and function of the mGluRs family in lampreys have not been determined. Therefore, we identified the mGluRs gene family in the genome of Lethenteron reissneri, which has been conserved throughout vertebrate evolution. We confirmed that Lr-GRM3, Lr-GRM5, and Lr-GRM7 encode three types of mGluRs in lamprey. Additionally, we investigated the distribution of Lr-GRM3 within this species by qPCR and Western blotting. Furthermore, we conducted RNA sequencing to investigate the molecular function of Lr-GRM3 in lamprey. Our gene expression profile revealed that, similar to that in jawed vertebrates, Lr-GRM3 participates in multiple signal transduction pathways and influences synaptic excitability in lampreys. Moreover, it also affects intestinal motility and the inflammatory response in lampreys. This study not only enhances the understanding of mGluRs' gene evolution but also highlights the conservation of GRM3's role in signal transduction while expanding our knowledge of its functions specifically within lampreys. In summary, our experimental findings provide valuable insights for studying both the evolution and functionality of the mGluRs family.

Metabotropic glutamate receptors (mGluRs) play a pivotal role in the neuroendocrine-immune regulation. In this study, eight mGluRs were identified in the Pacific Oyster Crassostrea gigas, which were classified into three subfamilies based on genetic similarity. All CgmGluRs harbor variable numbers of PBP1 domains at the N-terminus. The sequence and structural features of CgmGluRs are highly similar to mGluRs in other species. A uniformly upregulated expression of CgmGluRs was observed during D-shaped larval stage compared to early D-shaped larval stage. The transcripts of CgmGluRs were detectable in various tissues of oyster. Different CgmGluR exhibited diverse expression patterns response against different PAMP stimulations, among which CgmGluR5 was significantly downregulated under these stimulations, reflecting its sensitivity and broad-spectrum responsiveness to microbes. Following LPS stimulation, the mRNA expression of CgmGluR5 and CgCALM1 in haemocytes was suppressed within 6 h and returned to normal levels by 12 h. Inhibition of CgmGluR5 activity resulted in a significant reduction in CgCALM1 expression after 12 h. Further KEGG enrichment analysis suggested that CgmGluR5 might modulate calcium ion homeostasis and metabolic pathways by regulating CgCALM1. This research delivers the systematic analysis of mGluR in the Pacific Oyster, offering insights into evolutionary characteristics and immunoregulatory function of mGluR in mollusks.

Metabotropic glutamate (mGlu) receptors play a key role in modulating most synapses in the brain. The mGlu7 receptors inhibit presynaptic neurotransmitter release and offer therapeutic possibilities for post-traumatic stress disorders or epilepsy. Screening campaigns provided mGlu7-specific allosteric modulators as the inhibitor XAP044 (Gee et al. J. Biol. Chem. 2014). In contrast to other mGlu receptor allosteric modulators, XAP044 does not bind in the transmembrane domain but to the extracellular domain of the mGlu7 receptor and not at the orthosteric site. Here, we identified the mode of action of XAP044, combining synthesis of derivatives, modeling and docking experiments, and mutagenesis. We propose a unique mode of action of these inhibitors, preventing the closure of the Venus flytrap agonist binding domain. While acting as a noncompetitive antagonist of L-AP4, XAP044 and derivatives act as apparent competitive antagonists of LSP4-2022. These data revealed more potent XAP044 analogues and new possibilities to target mGluRs.

Patients with asthma experience elevated rates of mental illness. However, the molecular links underlying such lung-brain crosstalk remain ambiguous. Hypothalamic dysfunction is observed in many psychiatric disorders, particularly those with an inflammatory component due to many hypothalamic regions being unprotected by the blood-brain barrier. To gain a better insight into such neuropsychiatric sequelae, this study investigated gene expression differences in the hypothalamus following lung inflammation (asthma) induction in mice, using RNA transcriptome profiling. BALB/c mice were challenged with either bacterial lipopolysaccharide (LPS, E. coli) or ovalbumin (OVA) allergens or saline control (n = 7 per group), and lung inflammation was confirmed via histological examination of postmortem lung tissue. The majority of the hypothalamus was micro-dissected, and total RNA was extracted for sequencing. Differential expression analysis identified 31 statistically significant single genes (false discovery rate FDR5%) altered in expression following LPS exposure compared to controls; however, none were significantly changed following OVA treatment, suggesting a milder hypothalamic response. When gene sets were examined, 48 were upregulated and 8 were downregulated in both asthma groups relative to controls. REACTOME enrichment analysis suggests these gene sets are involved in signal transduction metabolism, immune response and neuroplasticity. Interestingly, we identified five altered gene sets directly associated with neurotransmitter signaling. Intriguingly, many of these altered gene sets can influence mental health and or/neuroinflammation in humans. These findings help characterize the links between asthma-induced lung inflammation and the brain and may assist in identifying relevant pathways and therapeutic targets for future intervention.

The world has witnessed a revolution in therapeutics with the development of biological medicines such as antibodies and antibody fragments, notably nanobodies. These nanobodies possess unique characteristics including high specificity and modulatory activity, making them promising candidates for therapeutic applications. Identifying their binding mode is essential for their development. Experimental structural techniques are effective to get such information, but they are expensive and time-consuming. Here, we propose a computational approach, aiming to identify the epitope of a nanobody that acts as an agonist and a positive allosteric modulator at the rat metabotropic glutamate receptor 5. We employed multiple structure modeling tools, including various artificial intelligence algorithms for epitope mapping. The computationally identified epitope was experimentally validated, confirming the success of our approach. Additional dynamics studies provided further insights on the modulatory activity of the nanobody. The employed methodologies and approaches initiate a discussion on the efficacy of diverse techniques for epitope mapping and later nanobody engineering.

G protein-coupled receptors (GPCRs) are a large family of cell surface receptors that play a critical role in nervous system function by transmitting signals between cells and their environment. They are involved in many, if not all, nervous system processes, and their dysfunction has been linked to various neurological disorders representing important drug targets. This overview emphasises the GPCRs of the nervous system, which are the research focus of the members of ERNEST COST action (CA18133) working group 'Biological roles of signal transduction'. First, the (patho)physiological role of the nervous system GPCRs in the modulation of synapse function is discussed. We then debate the (patho)physiology and pharmacology of opioid, acetylcholine, chemokine, melatonin and adhesion GPCRs in the nervous system. Finally, we address the orphan GPCRs, their implication in the nervous system function and disease, and the challenges that need to be addressed to deorphanize them.

Memory problems are often the first signs of cognitive impairment related to Alzheimer's disease (AD), and stem cells and stem cell-derived exosomes (EXOs) have been studied for their therapeutic potential to improve the disease signs. While many studies have shown the anti-inflammatory and immunomodulatory effects of stem cells and exosomes on improving memory in different AD models, there is still insufficient data to determine how they modulate neural plasticity to enhance spatial memory and learning ability. Therefore, we conducted a study to investigate the effects of exosomes derived from 3D-cultured human Unrestricted Somatic Stem Cells (hUSSCs) on spatial memory and neuroplasticity markers in a sporadic rat model of AD. Using male Wistar rats induced by intracerebral ventricle injection of streptozotocin, we demonstrated that intranasal administration of hUSSC-derived exosomes could decrease Aβ accumulation and improve learning and memory in the Morris water maze test. We also observed an increase in the expression of pre-synaptic and post-synaptic molecules involved in neuronal plasticity, including NMDAR1, integrin β1, synaptophysin, pPKCα, and GAP-43, in the hippocampus. Our findings suggest that intranasal administration of exosomes can ameliorate spatial learning and memory deficits in rats, at least in part, by increasing the expression of neuroplasticity proteins. These results may encourage researchers to further investigate the molecular pathways involved in memory improvement after stem cell and exosome therapy, with the goal of increasing the efficacy and safety of exosome-based treatments for AD.

Parkinson's disease is a neurodegenerative disorder characterized by slow movement, tremors, and stiffness caused due to loss of dopaminergic neurons caused in the brain's substantia nigra. The concentration of dopamine is decreased in the brain. Parkinson's disease may be happened because of various genetic and environmental factors. Parkinson's disease is related to the irregular expression of the monoamine oxidase (MAO) enzyme, precisely type B, which causes the oxidative deamination of biogenic amines such as dopamine. MAO-B inhibitors, available currently in the market, carry various adverse effects such as dizziness, nausea, vomiting, lightheadedness, fainting, etc. So, there is an urgent need to develop new MAO-B inhibitors with minimum side effects. In this review, we have included recently studied compounds (2018 onwards). Agrawal et al. reported MAO-B inhibitors with IC50 0.0051 µM and showed good binding affinity. Enriquez et al. reported a compound with IC50 144 nM and bind with some critical amino acid residue Tyr60, Ile198, and Ile199. This article also describes the structure-activity relationship of the compounds and clinical trial studies of related derivatives. These compounds may be used as lead compounds to develop potent compounds as MAO-B inhibitors.

Epilepsy is one of the most common, severe, chronic, potentially life-shortening neurological disorders, characterized by a persisting predisposition to generate seizures. It affects more than 60 million individuals globally, which is one of the major burdens in seizure-related mortality, comorbidities, disabilities, and cost. Different treatment options have been used for the management of epilepsy. More than 30 drugs have been approved by the US FDA against epilepsy. However, one-quarter of epileptic individuals still show resistance to the current medications. About 90% of individuals in low and middle-income countries do not have access to the current medication. In these countries, plant extracts have been used to treat various diseases, including epilepsy. These medicinal plants have high therapeutic value and contain valuable phytochemicals with diverse biomedical applications. Epilepsy is a multifactorial disease, and therefore, multitarget approaches such as plant extracts or extracted phytochemicals are needed, which can target multiple pathways. Numerous plant extracts and phytochemicals have been shown to treat epilepsy in various animal models by targeting various receptors, enzymes, and metabolic pathways. These extracts and phytochemicals could be used for the treatment of epilepsy in humans in the future; however, further research is needed to study the exact mechanism of action, toxicity, and dosage to reduce their side effects. In this narrative review, we comprehensively summarized the extracts of various plant species and purified phytochemicals isolated from plants, their targets and mechanism of action, and dosage used in various animal models against epilepsy.

Metabotropic glutamate receptors (mGluRs) are class C G protein-coupled receptors that function as obligate dimers in regulating neurotransmission and synaptic plasticity in the central nervous system. The mGluR1 subtype has been shown to be modulated by the membrane lipid environment, particularly cholesterol, though the molecular mechanisms remain elusive. In this study, we employed all-atom molecular dynamics simulations to investigate the effects of cholesterol on the conformational dynamics of the mGluR1 seven-transmembrane (7TM) domain in an inactive state model. Simulations were performed with three different cholesterol concentrations (0%, 10%, and 25%) in a palmitoyl-oleoyl phosphatidylcholine (POPC) lipid bilayer system. Our results demonstrate that cholesterol induces conformational changes in the mGluR1 dimer more significantly than in the individual protomers. Notably, cholesterol modulates the dynamics and conformations of the TM1 and TM2 helices at the dimer interface. Interestingly, an intermediate cholesterol concentration of 10% elicits more pronounced conformational changes compared to both cholesterol-depleted (0%) and cholesterol-enriched (25%) systems. Specific electrostatic interaction unique to the 10% cholesterol system further corroborate these conformational differences. Given the high sequence conservation of the 7TM domains across mGluR subtypes, the cholesterol-dependent effects observed in mGluR1 are likely applicable to other members of this receptor family. Our findings provide atomistic insights into how cholesterol modulates the conformational landscape of mGluRs, which could impact their function and signaling mechanisms.

Many central nervous system diseases are closely related to nerve damage caused by dysregulation of the endogenous neurotransmitter glutamate. Exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) play an important role in improving injury and regeneration functions. However, its mechanism remains unknown. Therefore, the aim of this study is to investigate whether and how BMSC-Exos improve neurotoxicity caused by glutamate and to fill the gap in the literature. In this study, glutamate-treated HT22 cells were first exposed to mouse-derived BMSC-Exos at different concentrations to observe their effects on HT22 apoptosis. Next, we treated glutamate-treated HT22 cells with mouse-derived BMSC-Exos. We then inhibited the PI3K/Akt/mTOR signaling pathways using the PI3K/Akt inhibitor and the mTOR inhibitor, respectively, and observed the protective effect of mouse-derived BMSC-Exos on HT22 cells treated with glutamate. Our results show that BMSC-Exos reduced apoptosis triggered by glutamate stimulation, increased cell vitality, and decreased the levels of proapoptotic proteins while increasing the levels of anti-apoptotic proteins. The protective effect of BMSC-Exos was weakened when PI3K/Akt inhibitor and mTOR inhibitor were added. To sum up, we draw the following conclusions: BMSC-Exos can reduce neuronal apoptosis and apoptosis-related protein expression after glutamate stimulation by regulating the PI3K/Akt/mTOR signaling pathway.

mGluR2 receptors are widely expressed in limbic brain regions associated with memory, including the hippocampal formation, retrosplenial and frontal cortices, as well as subcortical regions including the mammillary bodies. mGluR2/3 agonists have been proposed as potential therapeutics for neurological and psychiatric disorders, however, there is still little known about the role of these receptors in cognitive processes, including memory consolidation. To address this, we assessed the effect of the mGluR2/3 agonist, eglumetad, on spatial memory consolidation in both mice and rats. Using the novel place preference paradigm, we found that post-sample injections of eglumetad impaired subsequent spatial discrimination when tested 6 h later. Using the immediate early gene c-fos as a marker of neural activity, we showed that eglumetad injections reduced activity in a network of limbic brain regions including the hippocampus and mammillary bodies. To determine whether the systemic effects could be replicated with more targeted manipulations, we performed post-sample infusions of the mGluR2/3 agonist 2R,4R-APDC into the mammillary bodies. This impaired novelty discrimination on a place preference task and an object-in-place task, again highlighting the role of mGluR2/3 transmission in memory consolidation and demonstrating the crucial involvement of the mammillary bodies in post-encoding processing of spatial information.

The number of elderly people is projected to double in the next 50 years worldwide, resulting in an increased prevalence of neurodegenerative diseases. Aging causes changes in brain tissue homeostasis, thus contributing to the development of neurodegenerative disorders. Current treatments are not entirely effective, so alternative treatments or adjuvant agents are being actively sought. Antioxidant properties of phenolic compounds are of particular interest for neurodegenerative diseases whose psychopathological mechanisms strongly rely on oxidative stress at the brain level. Moreover, phenolic compounds display other advantages such as the permeability of the blood-brain barrier (BBB) and the interesting molecular mechanisms that we reviewed in this work. We began by briefly outlining the physiopathology of neurodegenerative diseases to understand the mechanisms that result in irreversible brain damage, then we provided an overall classification of the phenolic compounds that would be addressed later. We reviewed in vitro and in vivo studies, as well as some clinical trials in which neuroprotective mechanisms were demonstrated in models of different neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), ischemia, and traumatic brain injury (TBI).

Neither psychological nor neuroscientific investigations have been able to fully explain the paradox that placebo is designed to be inert in randomized controlled trials (RCTs), yet appears to be effective in evaluations of clinical interventions in all fields of medicine and alternative medicine. This article develops the Neuroplasticity Placebo Theory, which posits that neuroplasticity in fronto-limbic areas is the unifying factor in placebo response (seen in RCTs) and placebo effect (seen in clinical interventions) where it is not intended to be inert. Depression is the disorder that has the highest placebo response of any medical condition and has the greatest potential for understanding how placebos work: recent developments in understanding of the pathophysiology of depression suggest that fronto-limbic areas are sensitized in depression which is associated with a particularly strong placebo phenomenon. An innovative linkage is made between diverse areas of the psychology and the translational psychiatry literature to provide supportive evidence for the Neuroplasticity Placebo Theory. This is underpinned by neuro-radiological evidence of fronto-limbic change in the placebo arm of antidepressant trials. If placebo stimulates neuroplasticity in fronto-limbic areas in conditions other than depression - and results in a partially active treatment in other areas of medicine - there are far reaching consequences for the day-to-day use of placebo in clinical practice, the future design of RCTs in all clinical conditions, and existing unwarranted assertions about the efficacy of antidepressant medications. If fronto-limbic neuroplasticity is the common denominator in designating placebo as a partially active treatment, the terms placebo effect and placebo response should be replaced by the single term "placebo treatment."

Ischemic stroke ranks among the foremost clinical causes of mortality and disability, instigating neuronal degeneration, fatalities, and various sequelae. While standard treatments, such as intravenous thrombolysis and endovascular thrombectomy, prove effective, they come with limitations. Hence, there is a compelling need to develop neuroprotective agents capable of improving the functional outcomes of the nervous system. Numerous preclinical studies have demonstrated that lithium can act in multiple molecular pathways, including glycogen synthase kinase 3(GSK-3), the Wnt signaling pathway, the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) signaling pathway, brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), and glutamate receptors. Through these pathways, lithium has been shown to affect inflammation, autophagy, apoptosis, ferroptosis, excitotoxicity, and other pathological processes, thereby improving central nervous system (CNS) damage caused by ischemic stroke. Despite these promising preclinical findings, the number of clinical trials exploring lithium's efficacy remains limited. Additional trials are imperative to thoroughly ascertain the effectiveness and safety of lithium in clinical settings. This review delineates the mechanisms underpinning lithium's neuroprotective capabilities in the context of ischemic stroke. It elucidates the intricate interplay between these mechanisms and sheds light on the involvement of mitochondrial dysfunction and inflammatory markers in the pathophysiology of ischemic stroke. Furthermore, the review offers directions for future research, thereby advancing the understanding of the potential therapeutic utility of lithium and establishing a theoretical foundation for its clinical application.

Glutamate, an excitatory neurotransmitter, is essential for neuronal function, and it acts on ionotropic or metabotropic glutamate receptors (mGluRs). A disturbance in glutamatergic signaling is a hallmark of many neurodegenerative diseases. Developing disease-modifying treatments for neurodegenerative diseases targeting glutamate receptors is a promising avenue. The understudied group III mGluR 4, 6-8 are commonly found in the presynaptic membrane, and their activation inhibits glutamate release. Thus, targeted mGluRs therapies could aid in treating neurodegenerative diseases. This review describes group III mGluRs and their pharmacological ligands in the context of amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, and Huntington's diseases. Attempts to evaluate the efficacy of these drugs in clinical trials are also discussed. Despite a growing list of group III mGluR-specific pharmacological ligands, research on the use of these drugs in neurodegenerative diseases is limited, except for Parkinson's disease. Future efforts should focus on delineating the contribution of group III mGluR to neurodegeneration and developing novel ligands with superior efficacy and a favorable side effect profile for the treatment of neurodegenerative diseases.

Introduction: The anticancer drug doxorubicin (DOX) is used for various malignancies. However, it also causes cognitive impairment in cancer survivors. In order to determine the mechanisms underlying the acute effects of DOX, we assessed the mRNA and protein expression of glutamate receptors and proteins involved in cognitive function and apoptosis. Methods: Fear-conditioning memory tests were performed in rats after a single intraperitoneal injection of DOX (25 mg/kg) to evaluate short-term memory function. Rat brain samples were collected, and GluA1 mRNA and protein expression; NR2A and NR2B mRNA expression; and COX-2, NF-kB, TNF-α, and MDA, Bax, and caspase-3 levels were assessed via reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assays. Results: We observed a decreased number of entries in Y-maze, decreased exploration time to the novel object in the novel object recognition (NOR), and decreased freezing time in the fear-conditioning memory tests in DOX-treated rats relative to those in control rats, demonstrating cognitive impairment. GluA1, NR2B, and NR2A expression and MDA, NF-κB, Bax, COX-2, TNF-α, and caspase-3 levels in the brain were significantly elevated in DOX-treated rats. Conclusion: DOX induced cognitive impairment in the rats via neuronal toxicity by upregulating AMPAR and NMDAR expression and increasing neuroinflammation, oxidative stress, and apoptosis in the brain.

Adipose-derived stem cells (ADSCs) have incredible potential as an avenue to better understand and treat neurological disorders. While they have been successfully differentiated into neural stem cells and neurons, most such protocols involve 2D environments, which are not representative of in vivo physiology. In this study, human ADSCs were cultured in 1.1 kPa polyethylene-glycol 3D hydrogels for 10 days with B27, CultureOne (C1), and N2 neural supplements to examine the neural differentiation potential of ADSCs using both chemical and mechanical cues. Following treatment, cell viability, proliferation, morphology, and proteome changes were assessed. Results showed that cell viability was maintained during treatments, and while cells continued to proliferate over time, proliferation slowed down. Morphological changes between 3D untreated cells and treated cells were not observed. However, they were observed among 2D treatments, which exhibited cellular elongation and co-alignment. Proteome analysis showed changes consistent with early neural differentiation for B27 and C1 but not N2. No significant changes were detected using immunocytochemistry, potentially indicating a greater differentiation period was required. In conclusion, treatment of 3D-cultured ADSCs in PEG-based hydrogels with B27 and C1 further enhances neural marker expression, however, this was not observed using supplementation with N2.

Two of the most prevalent neurodegenerative disorders (NDDs), Alzheimer's disease (AD) and Parkinson's disease (PD), present significant challenges to healthcare systems worldwide. While the etiologies of AD and PD differ, both diseases share commonalities in synaptic dysfunction, thereby focusing attention on the role of neurotransmitters. The possible functions that platelets may play in neurodegenerative illnesses including PD and AD are becoming more acknowledged. In AD, platelets have been investigated for their ability to generate amyloid-ß (Aß) peptides, contributing to the formation of neurotoxic plaques. Moreover, platelets are considered biomarkers for early AD diagnosis. In PD, platelets have been studied for their involvement in oxidative stress and mitochondrial dysfunction, which are key factors in the disease's pathogenesis. Emerging research shows that platelets, which release glutamate upon activation, also play a role in these disorders. Decreased glutamate uptake in platelets has been observed in Alzheimer's and Parkinson's patients, pointing to a systemic dysfunction in glutamate handling. This paper aims to elucidate the critical role that glutamate receptors play in the pathophysiology of both AD and PD. Utilizing data from clinical trials, animal models, and cellular studies, we reviewed how glutamate receptors dysfunction contributes to neurodegenerative (ND) processes such as excitotoxicity, synaptic loss, and cognitive impairment. The paper also reviews all current medications including glutamate receptor antagonists for AD and PD, highlighting their mode of action and limitations. A deeper understanding of glutamate receptor involvement including its systemic regulation by platelets could open new avenues for more effective treatments, potentially slowing disease progression and improving patient outcomes.

Ammonium ion (NH4 + ) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH4 + -induced brain injury exists so far. Excitotoxicity is a well-known phenomenon in the brain of hyperammonemic cases. The hyperactivation of the N-Methyl- d-aspartate (NMDA) receptors by agents such as glutamate, an NH4 + metabolite, could cause excitotoxicity. Excitotoxicity is connected with events such as oxidative stress and neuroinflammation. Hence, utilizing NMDA receptor antagonists could prevent neurological complications of NH4 + neurotoxicity. In the current study, C57BL6/J mice received acetaminophen (APAP; 800 mg/kg, i.p) to induce HE. Hyperammonemic animals were treated with ketamine (0.25, 0.5, and 1 mg/kg, s.c) as an NMDA receptor antagonist. Animals' brain and plasma levels of NH4 + were dramatically high, and animals' locomotor activities were disturbed. Moreover, several markers of oxidative stress were significantly increased in the brain. A significant increase in brain tissue levels of TNF-α, IL-6, and IL-1β was also detected in hyperammonemic animals. It was found that ketamine significantly normalized animals' locomotor activity, improved biomarkers of oxidative stress, and decreased proinflammatory cytokines. The effects of ketamine on oxidative stress biomarkers and inflammation seem to play a key role in its neuroprotective mechanisms in the current study.

Developing biological based approaches for preventing suicide has become a priority. In recent years, there has been a surge in studies investigating the role of the glutamatergic system in suicide, although it remains unclear.

We evaluated changes in the gene expression of the metabotropic glutamate receptor 5 (mGluR5) and its scaffolding proteins Homer1a and p11 in the dorsolateral prefrontal cortex (DLPFC), amygdala (AMY), and hippocampus (HIP) of 28 suicide decedents (S) (with no clinical psychiatric history or treatment with anxiolytics or antidepressants) and 26 controls (C) by real-time PCR (qPCR). Indeed, we measured BDNF gene expression and VGluT1 and VGAT immunoreactivities in the HIP by qPCR and immunohistochemistry, respectively. Cases and controls matched for age (C: 48.6 ± 11.6 years; S: 46.9 ± 14.5 years) and postmortem interval (PMI; C: 20.1 ± 13h; S: 16.9 ± 5h).

In DLPFC, S had lower p11 gene expression levels, but no differences were found in mGluR5 or Homer1a. In the AMY and HIP, mGluR5 and Homer1a were increased, p11 and BDNF were reduced. In the HIP, there were less VGAT-ir and more VGluT1-ir.

Future studies are necessary to evaluate protein levels, and determine the cell types and potential compensatory mechanisms in a larger sample including S diagnosed with psychiatric disorders, females and different ethnicities.

This study identified significant alterations in mGluR5, Homer1a, p11, BDNF and excitatory/inhibitory balance in corticolimbic brain areas of S. These results further characterize the biological basis of suicide, contributing to the identification of potential biomarkers for suicide prevention.