Accumulation Of Glutamate Research Articles

A New Perspective in the Treatment of Ischemic Stroke: Ferroptosis.

Ischemic stroke is a common neurological disease. Currently, there are no Food and Drug Administration-approved drugs that can maximize the improvement in ischemic stroke-induced nerve damage. Hence, treating ischemic stroke remains a clinical challenge. Ferroptosis has been increasingly studied in recent years, and it is closely related to the pathophysiological process of ischemic stroke. Iron overload, reactive oxygen species accumulation, lipid peroxidation, and glutamate accumulation associated with ferroptosis are all present in ischemic stroke. This article focuses on describing the relationship between ferroptosis and ischemic stroke and summarizes the relevant substances that ameliorate ischemic stroke-induced neurological damage by inhibiting ferroptosis. Finally, the problems in the treatment of ischemic stroke targeting ferroptosis are discussed, hoping to provide a new direction for its treatment.

Increased A1 astrocyte activation-driven hippocampal neural network abnormality mediates delirium-like behavior in aged mice undergoing cardiac surgery.

Delirium is the most common neurological complication after cardiac surgery with adverse impacts on surgical outcomes. Advanced age is an independent risk factor for delirium occurrence but its underlying mechanisms are not fully understood. Although increased A1 astrocytes and abnormal hippocampal networks are involved in neurodegenerative diseases, whether A1 astrocytes and hippocampal network changes are involved in the delirium-like behavior of aged mice remains unknown. In the present study, a mice model of myocardial ischemia-reperfusion mimicking cardiac surgery and various assessments were used to investigate the different susceptibility of the occurrence of delirium-like behavior between young and aged mice and the underlying mechanisms. The results showed that surgery significantly increased hippocampal A1 astrocyte activation in aged compared to young mice. The high neuroinflammatory state induced by surgery resulted in glutamate accumulation in the extrasynaptic space, which subsequently decreased the excitability of pyramidal neurons and increased the PV interneurons inhibition through enhancing N-methyl-D-aspartate receptors' tonic currents in the hippocampus. These further induced the abnormal activities of the hippocampal neural networks and consequently contributed to delirium-like behavior in aged mice. Notably, the intraperitoneal administration of exendin-4, a glucagon-like peptide-1 receptor agonist, downregulated A1 astrocyte activation and alleviated delirium-like behavior in aged mice, while IL-1α, TNF-α, and C1q in combination administered intracerebroventricularly upregulated A1 astrocyte activation and induced delirium-like behavior in young mice. Therefore, our study suggested that cardiac surgery increased A1 astrocyte activation which subsequently impaired the hippocampal neural networks and triggered delirium development.

Increased glucose metabolism and impaired glutamate transport in human astrocytes are potential early triggers of abnormal extracellular glutamate accumulation in hiPSC-derived models of Alzheimer's disease.

Glutamate recycling between neurons and astrocytes is essential to maintain neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in excitotoxicity and neuronal death, have been described as a potential mechanism in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter metabolism in different human brain cells, particularly astrocytes, has been poorly investigated at the early stages of AD. We sought to investigate glucose and glutamate metabolism in AD by employing human induced pluripotent stem cell (hiPSC)-derived astrocytes and neurons carrying mutations in the amyloid precursor protein (APP) or presenilin-1 (PSEN-1) gene as found in familial types of AD (fAD). Methods such as live-cell bioenergetics and metabolic mapping using [13C]-enriched substrates were used to examine metabolism in the early stages of AD. Our results revealed greater glycolysis and glucose oxidative metabolism in astrocytes and neurons with APP or PSEN-1 mutations, accompanied by an elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or PSEN-1 mutations exhibited reduced expression of the excitatory amino acid transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with enhanced glutamate release specifically in neurons with a PSEN-1 mutation. These results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations possibly linked to toxic glutamate accumulation. Our findings further identify metabolic imbalances that may occur in the early phases of AD pathophysiology.

New bithiophene derivative attenuated Alzheimer’s disease induced by aluminum in a rat model via antioxidant activity and restoration of neuronal and synaptic transmission

BackgroundOne of the hypotheses that leads to an increased incidence of Alzheimer’s disease (AD) is the accumulation of aluminum in the brain’s frontal cortex. The present study aimed to evaluate the therapeutic role of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. MethodologyAdult male rats were divided into six groups, 18 rats each. Group 1: naïve animals, group 2: animals received a daily oral administration of bithiophene dissolved in DMSO (1 mg/kg) for 30 days every other day, groups 3–6: animals received a daily oral administration of AlCl3 (100 mg/kg/day) for 45 consecutive days. Groups 4 and 5 received an oral administration of low or high dose of the bithiophene (0.5 or 1 mg/kg, respectively). Group 6; Animals were treated with a daily oral dose of memantine (20 mg/kg) for 30 consecutive days. Main findingsAl disturbed the antioxidant milieu, elevated the lipid peroxidation, and depleted the antioxidants. It also disturbed the synaptic neurotransmission by elevating the activities of acetylcholine esterase and monoamine oxidase resulting in the depletion of dopamine and serotonin and accumulation of glutamate and norepinephrine. Al also deteriorated the expression of genes involved in apoptosis and the production of amyloid-β plaques as well as phosphorylation of tau. The new bithiophene at the low dose reversed most of the previous deleterious effects of aluminum in the cerebral cortex and was in many instances superior to the reference drug; memantine. ConclusionTaking together, the bithiophene modulated the AD etiology through antioxidant activity, prevention of neuronal and synaptic loss, and probably mitigating the formation of amyloid-β plaques and phosphorylation of tau.

Cyclopropane fatty acid and accumulation of glutamate contributed to higher freeze-drying resistance for Bifidobacterium animalis than Bifidobacterium adolescentis

Low-temperature vacuum drying is one of the most important ways to product the probiotic powders. But different strains showed different freeze-drying resistance during the whole cycle. In order to find out what caused the different freeze-drying survival rate between Bifidobacterium animalis (B. animalis) CCFM1155 and Bifidobacterium adolescentis (B. adolescentis) CCFM8630. Focus on the differences on the strains’ own structure, the results showed B. animalis CCFM1155 had thicker cell wall than B. adolescentis CCFM8630. Cyclopropane fatty acid was reported to modulate the permeability and fluidity of the membrane, but the B. adolescentis CCFM8630 deficiency the cfa which controlled the synthesis of cyclopropane fatty acid caused lower freeze-drying survival rate of the strain. Generally, the B. adolescentis CCFM8630 accumulated more γ-aminobutyric acid (GABA) to overcome the acidic environment. However, after maintaining a constant culture pH, the content of the glutamate was increased in the B. adolescentis CCFM8630 and the freeze-drying survival rate of the strain was also increased. In summary, our research revealed that fatty acids and intracellular substance differences caused the different of freeze-drying survival resistance between B. animalis CCFM1155 and B. adolescentis CCFM8630.

Salinity alleviates arsenicstress-induced oxidative damage via antioxidative defense and metabolic adjustment in the root of the halophyte Salvadora persica.

Arsenic tolerance in the halophyte Salvadora persica is achieved by enhancing antioxidative defense and modulations of various groups of metabolites like amino acids, organic acids, sugars, sugar alcohols, and phytohormones. Salvadora persica is a facultative halophyte that thrives under high saline and arid regions of the world. In present study, we examine root metabolic responses of S. persica exposed to individual effects of high salinity (750mM NaCl), arsenic (600µM As), and combined treatment of salinity and arsenic (250mM NaCl + 600µM As) to decipher its As and salinity resistance mechanism. Our results demonstrated that NaCl supplementation reduced the levels of reactive oxygen species (ROS) under As stress. The increased activities of antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR) maintained appropriate levels of ROS [superoxide (O2•-) and hydrogen peroxide (H2O2)] under salinity and/or As stress. The metabolites like sugars, amino acids, polyphenols, and organic acids exhibited higher accumulations when salt was supplied with As. Furthermore, comparatively higher accumulations of glycine, glutamate, and cystine under combined stress of salt and As may indicate its role in glutathione and phytochelatins (PCs) synthesis in root. The levels of phytohormones such as salicylate, jasmonate, abscisic acid, and auxins were significantly increased under high As with and without salinity stress. The amino acid metabolism, glutathione metabolism, carbohydrate metabolism, tricarboxylic acid cycle (TCA cycle), phenylpropanoid biosynthesis, and phenylalanine metabolism are the most significantly altered metabolic pathways in response to NaCl and/or As stress. Our study decoded the important metabolites and metabolic pathways involved in As and/or salinity tolerance in root of the halophyte S. persica providing clues for development of salinity and As resistance crops.

Transcriptome and Biochemical Analyses of a Chlorophyll-Deficient Bud Mutant of Tea Plant (Camellia sinensis).

Tea leaf-color mutants have attracted increasing attention due to their accumulation of quality-related biochemical components. However, there is limited understanding of the molecular mechanisms behind leaf-color bud mutation in tea plants. In this study, a chlorina tea shoot (HY) and a green tea shoot (LY) from the same tea plant were investigated using transcriptome and biochemical analyses. The results showed that the chlorophyll a, chlorophyll b, and total chlorophyll contents in the HY were significantly lower than the LY's, which might have been caused by the activation of several genes related to chlorophyll degradation, such as SGR and CLH. The down-regulation of the CHS, DFR, and ANS involved in flavonoid biosynthesis might result in the reduction in catechins, and the up-regulated GDHA and GS2 might bring about the accumulation of glutamate in HY. RT-qPCR assays of nine DEGs confirmed the RNA-seq results. Collectively, these findings provide insights into the molecular mechanism of the chlorophyll deficient-induced metabolic change in tea plants.

Kainic Acid-Induced Excitotoxicity Leads to the Activation of Heat Shock Response.

Heat shock response (HSR) which is regulated by heat shock factor 1 (HSF1) is the most important mechanism and the major regulator that prevents protein aggregation in neurodegenerative diseases. Excitotoxicity, which is the accumulation of excess glutamate in synaptic cleft, is observed in age-dependent neurodegenerative diseases and also in stroke, epilepsy, and brain trauma. Only a few studies in the literature show the link between excitotoxicity and HSR. In this study, we aimed to show the molecular mechanism underlying this link. We applied heat shock (HS) treatment and induced excitotoxicity with kainic acid (KA) in neuroblastoma (SHSY-5Y) and glia (immortalized human astrocytes (IHA)) cells. We observed that, only in SHSY-5Y cells, heat shock preconditioning increases cell survival after KA treatment. GLT-1 mRNA expression is increased as a result of KA treatment and HS due to the elevation of HSF1 binding to GLT-1 promoter which was induced by HSF1 phosphorylation and sumolation in SHSY-5Y cells. Additionally, glutamine synthetase and glutaminase expressions are increased after HS preconditioning in SHSY-5Y cells indicating that HS activates glutamate metabolism modulators and accelerates the glutamate cycle. In glia cells, we did not observe the effect of HS preconditioning. In summary, heat shock preconditioning might be protective against excitotoxicity-related cell death and degeneration.

Combined transcriptomics and metabolomics analysis reveals the molecular mechanism of heat tolerance of Le023M, a mutant in Lentinulaedodes

Lentinula edodes, one of the most highly regarded edible mushrooms in China, is susceptible to damage from high temperatures. However, a mutant strain derived from L. edodes, known as Le023M, has shown exceptional thermotolerance. Compared to the original strain Le023, Le023M exhibited accelerated mycelial recovery following heat stress. Through RNA-seq analysis, the majority of differentially expressed genes (DEGs) were found to be associated with functions such as “protein refolding”, “protein unfolding”, “protein folding”, and “response to heat”, all of which are closely linked to heat shock proteins. Furthermore, qRT-PCR results revealed significant accumulation of heat shock-related genes in Le023M under heat stress. GC-MS analysis indicated elevated levels of trehalose, aspartate, and glutamate in Le023M when subjected to heat stress. The highly expressed genes involved in these metabolic pathways were predominantly found in Le023M. Collectively, these findings highlight the following: (i) the crucial role of heat shock proteins (HSPs) in the thermo-resistant mechanisms of Le023M; (ii) the potential of trehalose accumulation in Le023M to enhance mycelium resistance to heat stress; and (iii) the induction of aspartate and glutamate accumulation in response to heat stress. These results shed light on the molecular mechanisms underlying the thermotolerance of Le023M, providing valuable insights for further understanding and improving heat stress response in L. edodes. The findings also highlight the potential applications of Le023M in the cultivation and production of L. edodes under high-temperature conditions.

Neuropharmacological insight into preventive intervention in posttraumatic epilepsy based on regulating glutamate homeostasis.

Posttraumatic epilepsy (PTE) is one of the most critical complications of traumatic brain injury (TBI), significantly increasing TBI patients' neuropsychiatric symptoms and mortality. The abnormal accumulation of glutamate caused by TBI and its secondary excitotoxicity are essential reasons for neural network reorganization and functional neural plasticity changes, contributing to the occurrence and development of PTE. Restoring glutamate balance in the early stage of TBI is expected to play a neuroprotective role and reduce the risk of PTE. To provide a neuropharmacological insight for drug development to prevent PTE based on regulating glutamate homeostasis. We discussed how TBI affects glutamate homeostasis and its relationship with PTE. Furthermore, we also summarized the research progress of molecular pathways for regulating glutamate homeostasis after TBI and pharmacological studies aim to prevent PTE by restoring glutamate balance. TBI can lead to the accumulation of glutamate in the brain, which increases the risk of PTE. Targeting the molecular pathways affecting glutamate homeostasis helps restore normal glutamate levels and is neuroprotective. Taking glutamate homeostasis regulation as a means for new drug development can avoid the side effects caused by direct inhibition of glutamate receptors, expecting to alleviate the diseases related to abnormal glutamate levels in the brain, such as PTE, Parkinson's disease, depression, and cognitive impairment. It is a promising strategy to regulate glutamate homeostasis through pharmacological methods after TBI, thereby decreasing nerve injury and preventing PTE.

Fenpropathrin Induces GLT-1 Ubiquitination and Increases IL-6 Secretion through the Mdm2-p53 Pathway.

Human exposure to fenpropathrin, a widely used pesticide, is linked to Parkinson's-like symptoms in the body. However, a specific pathogenic mechanism is still unclear. This study found that fenpropathrin increased the expression of murine double minute 2 (Mdm2) and reduced the expression of p53. Fenpropathrin stimulated the expression of neural precursor cell expressed, developmentally down-regulated 4-like (Nedd4L) and promoted the secretion of the inflammatory cytokine interleukin-6 (IL-6) through the Mdm2-p53 pathway. Nedd4L, a ubiquitin ligase, mediated the ubiquitination degradation of glutamate transporter 1 (GLT-1), resulting in glutamate accumulation and excitotoxicity aggravation. Our findings elucidate part of the pathogenic mechanism of fenpropathrin toxicity and provide scientific evidence to help develop guidance for pesticide control and environmental protection.

The Regulation of GLT-1 Degradation Pathway by SIRT4.

Glial cells give rise to glioblastoma multiform as a primary brain tumor. In glioblastomas, neurons are destroyed via excitotoxicity which is the accumulation of excess glutamate in synaptic cavity. Glutamate Transporter 1 (GLT-1) is the main transporter that absorbs the excessive glutamate. Sirtuin 4 (SIRT4) was shown to have a potential protective role against excitotoxicity in previous studies. In this study, the regulation of dynamic GLT-1 expression by SIRT4 was analyzed in glia (immortalized human astrocytes) and glioblastoma (U87) cells. The expression of GLT-1 dimers and trimers were reduced and the ubiquitination of GLT-1 was increased in glioblastoma cells when SIRT4 was silenced; however GLT-1 monomer was not affected. In glia cells, SIRT4 reduction did not affect GLT-1 monomer, dimer, trimer expression or the ubiquitination of GLT-1. The phosphorylation of Nedd4-2 and the expression of PKC did not change in glioblastoma cells when SIRT4 was silenced but increased in glia cells. We also showed that SIRT4 deacetylates PKC in glia cells. In addition, GLT-1 was shown to be deacetylated by SIRT4 which might be a priority for ubiquitination. Therefore, we conclude that GLT-1 expression is regulated differently in glia and glioblastoma cells. SIRT4 activators or inhibitors of ubiquitination may be used to prevent excitotoxicity in glioblastomas.

Vesicular glutamate transporters are H+-anion exchangers that operate at variable stoichiometry

Vesicular glutamate transporters accumulate glutamate in synaptic vesicles, where they also function as a major Cl- efflux pathway. Here we combine heterologous expression and cellular electrophysiology with mathematical modeling to understand the mechanisms underlying this dual function of rat VGLUT1. When glutamate is the main cytoplasmic anion, VGLUT1 functions as H+-glutamate exchanger, with a transport rate of around 600 s−1 at −160 mV. Transport of other large anions, including aspartate, is not stoichiometrically coupled to H+ transport, and Cl- permeates VGLUT1 through an aqueous anion channel with unitary transport rates of 1.5 × 105 s−1 at −160 mV. Mathematical modeling reveals that H+ coupling is sufficient for selective glutamate accumulation in model vesicles and that VGLUT Cl- channel function increases the transport efficiency by accelerating glutamate accumulation and reducing ATP-driven H+ transport. In summary, we provide evidence that VGLUT1 functions as H+-glutamate exchanger that is partially or fully uncoupled by other anions.

Low Temperature Delays the Effects of Ischemia in Bergmann Glia and in Cerebellar Tissue Swelling.

Cerebral ischemia results in oxygen and glucose deprivation that most commonly occurs after a reduction or interruption in the blood supply to the brain. The consequences of cerebral ischemia are complex and involve the loss of metabolic ATP, excessive K+ and glutamate accumulation in the extracellular space, electrolyte imbalance, and brain edema formation. So far, several treatments have been proposed to alleviate ischemic damage, yet few are effective. Here, we focused on the neuroprotective role of lowering the temperature in ischemia mimicked by an episode of oxygen and glucose deprivation (OGD) in mouse cerebellar slices. Our results suggest that lowering the temperature of the extracellular 'milieu' delays both the increases in [K+]e and tissue swelling, two dreaded consequences of cerebellar ischemia. Moreover, radial glial cells (Bergmann glia) display morphological changes and membrane depolarizations that are markedly impeded by lowering the temperature. Overall, in this model of cerebellar ischemia, hypothermia reduces the deleterious homeostatic changes regulated by Bergmann glia.

Identification of pH-specific protein expression responses by Campylobacter jejuni strain NCTC 11168

In this study a data dependent acquisition label-free based proteomics approach was used to identify pH-dependent proteins that respond in a growth phase independent manner in Campylobacter jejuni reference strain NCTC 11168. NCTC 11168 was grown within its pH physiological normal growth range (pH 5.8, 7.0 and 8.0, μ = ∼0.5 h−1) and exposed to pH 4.0 shock for 2 h. It was discovered that gluconate 2-dehydrogenase GdhAB, NssR-regulated globins Cgb and Ctb, cupin domain protein Cj0761, cytochrome c protein CccC (Cj0037c), and phosphate-binding transporter protein PstB all show acidic pH dependent abundance increases but are not activated by sub-lethal acid shock. Glutamate synthase (GLtBD) and the MfrABC and NapAGL respiratory complexes were induced in cells grown at pH 8.0. The response to pH stress by C. jejuni is to bolster microaerobic respiration and at pH 8.0 this is assisted by accumulation of glutamate the conversion of which could bolster fumarate respiration. The pH dependent proteins linked to growth in C. jejuni NCTC 11168 aids cellular energy conservation maximising growth rate and thus competitiveness and fitness.

Abstract 6033: RA123, a new GLS1 allosteric inhibitor demonstrates in vitro and in vivo activity in multiple myeloma models

Abstract The conditional essential amino acid glutamine is utilized by tumors to sustain bioenergetic requirements in a nutrient-poor microenvironment. Based on this specific tumor need, efforts have been made to target the glutamine metabolism using glutaminase inhibitors. In this study, we present in vitro and in vivo studies demonstrating activities and target engagement of a new specific GLS1 allosteric inhibitor (RA123). In vitro, RA123 was tested in imid-resistant, CD38 low RPMI8226 multiple myeloma cell line using the ATP Cell titer Glo assay over a 72h treatment period. In vivo, RA123 was tested in mice xenografted with RPMI8226 multiple myeloma cell line. Compound was given at three different under a BID (twice a day) regimen. Tumor growth under treatment was monitored by caliper measurement for 20 days. A terminal PK/PD study on the same model was setup measuring impact of the drug on the glutamine and glutamate tumor content post 24 hours after the last administration. Over the same period, PK measurements were planned to document drug exposure in the plasma and in the tumor. Finally, in a stand-alone study, target engagement was documented using imaging modality. [18F]FSPG PET radiotracer was used to visualize and quantify impact of RA123 on tumor (RPMI8226) glutamate pool. RA123 was given at three doses under a BID regimen. Treatment was administered for 3 days, and PET signal was recorded at baseline and at end of day 3. In vitro study demonstrated that RA123 was able to induce cell killing of RPMI8226 after 72 hours of treatment. These data translated in vivo by a dose-dependent effect on cell growth. In a terminal PK/PD study, RA123 confirmed a dose-dependent impact on glutamine and glutamate tumor levels which correlated with both plasma and tumor exposure. Further confirmation of target engagement was observed with reduced PET uptake post- RA123 treatment at the three doses tested. In conclusion, this study demonstrated that RA123, a new specific GLS1 allosteric inhibitor was able to impact multiple myeloma tumor cell growth both in vitro and in vivo. This effect was associated with reduced glutamate pools and accumulation of glutamine levels within the tumor cells. Citation Format: Christophe Henry, Dimitri Gorge-Bernat, Pascal Pannier, Isabelle Meaux, Jane Cheng, Fangxian Sun, Olivier Pasquier, Philippe Lienard, Erwan Jouannot, Thierry Gouyon, Geneviève Estenne-Bouhtou, Bailin Zhang, Bérangère Thiers, Laurent Debussche, David Machnik. RA123, a new GLS1 allosteric inhibitor demonstrates in vitro and in vivo activity in multiple myeloma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6033.

An integrated multi-level analysis reveals learning-memory deficits and synaptic dysfunction in the rat model exposure to austere environment

Austere environment existing in tank, submarine and vessel has many risk factors including high temperature and humidity, confinement, noise, hypoxia, and high level of carbon dioxide, which may cause depression and cognitive impairment. However, the underlying mechanism is not fully understood yet. We attempt to investigate the effects of austere environment (AE) on emotion and cognitive function in a rodent model. After 21 days of AE stress, the rats exhibit depressive-like behavior and cognitive impairment. Compared with control group, the glucose metabolic level of the hippocampus is significantly decreased using whole-brain positron emission tomography (PET) imaging, and the density of dendritic spines of the hippocampus is remarkably reduced in AE group. Then, we employ a label-free quantitative proteomics strategy to investigate the differentially abundant proteins in rats' hippocampus. It is striking that the differentially abundant proteins annotated by KEGG enrich in oxidative phosphorylation pathway, synaptic vesicle cycle pathway and glutamatergic synapses pathway. The synaptic vesicle transport related proteins (Syntaxin-1A, Synaptogyrin-1 and SV-2) are down-regulated, resulting in the accumulation of intracellular glutamate. Furthermore, the concentration of hydrogen peroxide and malondialdehyde is increased while the activity of superoxide dismutase and complex I and IV of mitochondria is decreased, indicating that oxidative damage to hippocampal synapses is associated with the cognitive decline. The results of this study offer direct evidence, for the first time, that austere environment can substantially cause learning and memory deficits and synaptic dysfunction in a rodent model via behavioral assessments, PET imaging, label-free proteomics, and oxidative stress tests. SignificanceThe incidence of depression and cognitive decline in military occupations (for example, tanker and submariner) is significantly higher than that of global population. In the present study, we first established novel model to simulate the coexisting risk factors in the austere environment. The results of this study offer the direct evidences, for the first time, that the austere environment can substantially cause learning and memory deficits by altering plasticity of the synaptic transmission in a rodent model via proteomic strategy, PET imaging, oxidative stress and behavioral assessments. These findings provide valuable information to better understand the mechanisms of cognitive impairment.

The initiator of neuroexcitotoxicity and ferroptosis in ischemic stroke: Glutamate accumulation.

Glutamate plays an important role in excitotoxicity and ferroptosis. Excitotoxicity occurs through over-stimulation of glutamate receptors, specifically NMDAR, while in the non-receptor-mediated pathway, high glutamate concentrations reduce cystine uptake by inhibiting the System Xc-, leading to intracellular glutathione depletion and resulting in ROS accumulation, which contributes to increased lipid peroxidation, mitochondrial damage, and ultimately ferroptosis. Oxidative stress appears to crosstalk between excitotoxicity and ferroptosis, and it is essential to maintain glutamate homeostasis and inhibit oxidative stress responses in vivo. As researchers work to develop natural compounds to further investigate the complex mechanisms and regulatory functions of ferroptosis and excitotoxicity, new avenues will be available for the effective treatment of ischaemic stroke. Therefore, this paper provides a review of the molecular mechanisms and treatment of glutamate-mediated excitotoxicity and ferroptosis.

Ferroptosis is a new therapeutic target for spinal cord injury.

Spinal cord injury is a serious traumatic disease. As Ferroptosis has been increasingly studied in recent years, it has been found to be closely related to the pathophysiological processes of spinal cord injury. Iron overload, reactive oxygen species accumulation, lipid peroxidation and glutamate accumulation associated with Ferroptosis are all present in spinal cord injury, and thus Ferroptosis is thought to be involved in the pathological processes secondary to spinal cord injury. This article highlights the relationship between Ferroptosis and spinal cord injury, lists substances that improve spinal cord injury by inhibiting Ferroptosis, and concludes with a discussion of the problems that may be encountered in the clinical translation of Ferroptosis inhibitors as a means of enabling their faster use in clinical treatment.

Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

Brain injury is accompanied by neuroinflammation, accumulation of extracellular glutamate and mitochondrial dysfunction, all of which cause neuronal death. The aim of this study was to investigate the impact of these mechanisms on neuronal death.Patients from the neurosurgical intensive care unit suffering aneurysmal subarachnoid hemorrhage (SAH) were recruited retrospectively from a respective database. In vitro experiments were performed in rat cortex homogenate, primary dissociated neuronal cultures, B35 and NG108-15 cell lines. We employed methods including high resolution respirometry, electron spin resonance, fluorescent microscopy, kinetic determination of enzymatic activities and immunocytochemistry.We found that elevated levels of extracellular glutamate and nitric oxide (NO) metabolites correlated with poor clinical outcome in patients with SAH. In experiments using neuronal cultures we showed that the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the glutamate-dependent segment of the tricarboxylic acid (TCA) cycle, is more susceptible to the inhibition by NO than mitochondrial respiration. Inhibition of OGDHC by NO or by succinyl phosphonate (SP), a highly specific OGDHC inhibitor, caused accumulation of extracellular glutamate and neuronal death. Extracellular nitrite did not substantially contribute to this NO action. Reactivation of OGDHC by its cofactor thiamine (TH) reduced extracellular glutamate levels, Ca2+ influx into neurons and cell death rate. Salutary effect of TH against glutamate toxicity was confirmed in three different cell lines.Our data suggest that the loss of control over extracellular glutamate, as described here, rather than commonly assumed impaired energy metabolism, is the critical pathological manifestation of insufficient OGDHC activity, leading to neuronal death.