Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke

Shen, Zihuan; Xiang, Ming; Chen, Chen; Ding, Fan; Wang, Yuling; Shang, Chang; Xin, Laiyun; Zhang, Yang; Cui, Xiangning

doi:10.1016/j.biopha.2022.113125

Cited by 102 publications

(58 citation statements)

References 391 publications

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“…After a few minutes of cerebral blood vessel occlusion, the continuous supply of oxygen, glucose, and other substrates is abruptly ceased especially in the core region of ischemia, leading to a consequent reduction of ATP production [ 31 , 32 ]. Such a decline dissipates the transmembrane gradient while also impairing the Na + /K + -ATPase (NKA), Na + /Ca 2+ exchange (NCX), and Ca 2+ -ATPase pump function [ 7 , 33 ]. These cellular changes further activate voltage-gated Ca 2+ channels (VGCC) and increase presynaptic Ca 2+ overload, ultimately causing exocytosis of excitatory amino acids into the synaptic cleft [ 30 , 34 , 35 ].…”

Section: Morphological and Functional Changes Of Synapse In Strokementioning

confidence: 99%

“…The rapid clearance of glutamate in the outer space of brain cells helps to stop excitatory transmission, and once glutamate uptake and metabolism are impaired, it will have a significant impact on excitotoxicity and related neuropathology [ 7 ]. Therefore, enhanced glutamate uptake and metabolism can protect neurons against neuronal injury after cerebral ischemia through various mechanisms, including (i) neurons and astrocytes via transporter protein up taking the accumulated glutamate in external fluid; (ii) glutamate being converted to glutamine or glutathione by metabolic enzymes to accelerate metabolism and prevent oxidative stress; (iii) relying on endothelial regulation to promote excess glutamate into the blood and reduce the content in the brain.…”

Section: Glutamate Uptake and Metabolic Inhibition Aggravating Synapt...mentioning

confidence: 99%

“…With the advance in the pathophysiology of ischemic stroke over the past decade, the highly complex mechanism of ischemic cell death has become increasingly clear at the cellular and molecular levels [ 6 ]. Numerous pathways underlie responses of brain tissue to cerebral ischemia, among which excitotoxicity is one of the earliest hallmarks and plays an essential role in the pathogenesis of post-ischemic stroke damage [ 7 , 8 ]. It is well known that neuron cells especially the hippocampus are sensitive to changes in glutamate levels [ 7 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Numerous pathways underlie responses of brain tissue to cerebral ischemia, among which excitotoxicity is one of the earliest hallmarks and plays an essential role in the pathogenesis of post-ischemic stroke damage [ 7 , 8 ]. It is well known that neuron cells especially the hippocampus are sensitive to changes in glutamate levels [ 7 , 9 ]. Following cerebral ischemia, largely increased glutamate emanates from nerve terminals and astrocytes due to anoxic depolarizations within minutes, accompanied by impaired reuptake, ultimately leading to excessive accumulation in the ischemic regions of the brain [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Fan

Xie

Xing

et al. 2022

IJMS

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Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).

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Section: Morphological and Functional Changes Of Synapse In Strokementioning

confidence: 99%

Section: Glutamate Uptake and Metabolic Inhibition Aggravating Synapt...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Fan

Xie

Xing

et al. 2022

IJMS

View full text Add to dashboard Cite

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“…Inside neurons, intrinsic apoptosis pathways depend on the expression and activation of Bax proteins specifically [ 42 , 43 ]. Once neurons receive death signals–like increased Ca 2+ levels, p53 activation, and FADD protein activation–to initiate the death cascade, BH3-only proteins can activate Bax and Bak proteins that stimulate Ca 2+ mitochondrial entry via mitochondria calcium uniporters [ 44 , 45 , 46 ]. The Bax proteins, inactive monomers, undergo mitochondrial translocation and form active Bax oligomers on the outer mitochondrial membrane, which prompts mitochondrial outer membrane permeabilization because of Ca 2+ overload and cytochrome c release [ 47 , 48 , 49 ].…”

Section: Quercetinmentioning

confidence: 99%

Quercetin’s Effects on Glutamate Cytotoxicity

Riche

Lenard

2022

Molecules

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The potentially therapeutic effects of the naturally abundant plant flavonoid quercetin have been extensively studied. An extensive body of literature suggests that quercetin’s powerful antioxidant effects may relate to its ability to treat disease. Glutamate excitotoxicity occurs when a neuron is overstimulated by the neurotransmitter glutamate and causes dysregulation of intracellular calcium concentrations. Quercetin has been shown to be preventative against many forms of neuronal cell death resulting from glutamate excitotoxicity, such as oncosis, intrinsic apoptosis, mitochondrial permeability transition, ferroptosis, phagoptosis, lysosomal cell death, parthanatos, and death by reactive oxygen species (ROS)/reactive nitrogen species (RNS) generation. The clinical importance for the attenuation of glutamate excitotoxicity arises from the need to deter the continuous formation of tissue infarction caused by various neurological diseases, such as ischemic stroke, seizures, neurodegenerative diseases, and trauma. This review aims to summarize what is known concerning glutamate physiology and glutamate excitotoxic pathophysiology and provide further insight into quercetin’s potential to hinder neuronal death caused by cell death pathways activated by glutamate excitotoxicity. Quercetin’s bioavailability may limit its use clinically, however. Thus, future research into ways to increase its bioavailability are warranted.

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Targeting glutamate metabolism in chronic lung diseases

Guo,

Yan

2024

Clinical and Translational Dis

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Amino acids are necessary for all life forms, which play various roles. Disorder of amino acid metabolism is now considered an important driving mechanism in diverse pulmonary conditions, particularly chronic lung diseases like chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and lung cancer. Glutamate actively participates in multiple vital biological processes, while the intricate glutamate metabolism, glutamate receptors and glutamate transporters assume crucial regulatory functions in the development of chronic lung diseases. This review aims to discuss the relationship between glutamate dysfunction and chronic lung diseases. By discussing the physiological and pathological function of glutamate, we probe the potential drug targets for chronic lung diseases in the glutamate pathway.

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Glutamate excitotoxicity: Potential therapeutic target for ischemic stroke

Cited by 102 publications

References 391 publications

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Quercetin’s Effects on Glutamate Cytotoxicity

Targeting glutamate metabolism in chronic lung diseases

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