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Excitotoxic Storms of Ischemic Stroke: A Non-neuronal Perspective

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Abstract

Numerous neurological disorders share a fatal pathologic process known as glutamate excitotoxicity. Among which, ischemic stroke is the major cause of mortality and disability worldwide. For a long time, the main idea of developing anti-excitotoxic neuroprotective agents was to block glutamate receptors. Despite this, there has been little successful clinical translation to date. After decades of “neuron-centered” views, a growing number of studies have recently revealed the importance of non-neuronal cells. Glial cells, cerebral microvascular endothelial cells, blood cells, and so forth are extensively engaged in glutamate synthesis, release, reuptake, and metabolism. They also express functional glutamate receptors and can listen and respond for fast synaptic transmission. This broadens the thoughts of developing excitotoxicity antagonists. In this review, the critical contribution of non-neuronal cells in glutamate excitotoxicity during ischemic stroke will be emphasized in detail, and the latest research progress as well as corresponding therapeutic strategies will be updated at length, aiming to reconceptualize glutamate excitotoxicity in a non-neuronal perspective.

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Data Availability

No datasets were generated or analyzed during the current study.

Abbreviations

IS:

Ischemic stroke

AIS:

Acute ischemic stroke

FCI:

Focal cerebral ischemia

tPA:

Tissue-type plasminogen activator

Neu2000:

Nelonemdaz

NA-1:

Nerinetide

BBB:

Blood-brain barrier

NMDAR:

NMDA receptor

ROS:

Reactive oxygen species

ECs:

Endothelial cells

BMECs:

Brain microvascular endothelial cells

MBMECs:

Mouse brain microvascular endothelial cells

CNS:

Central nervous system

EAAs:

Excitatory amino acids

EAATs:

Excitatory amino acid transporters

α-KG:

α-Ketoglutarate

MCT-1:

Monocarboxylic acid transport 1

GDH:

Glutamate dehydrogenase

GLS:

Glutaminase

ER:

Endoplasmic reticulum

ICW:

Intracellular Ca2 + waves

mGluRs:

Metabotropic glutamate receptors

IP3:

Inositol 1,4,5-trisphosphate

IP3R:

Inositol 1,4,5-trisphosphate receptor

Gq-linked GPCR:

Gq-linked G protein-coupled receptor

VGLUT:

Vesicular glutamate transporter

VAMP:

Vesicle-associated membrane protein

SNAP:

Synaptosomal-associated protein

TREK-1:

TWIK-related K + channel 1

Best-1:

Bestrophin-1

HI:

Hypoxia-ischemia injury

VRAC:

Volume-regulated anion channel

MCAO:

Middle cerebral artery occlusion

MCAO/R:

Middle cerebral artery occlusion/reperfusion

pMCAO:

Permanent middle cerebral artery occlusion

IClswell:

Swelling-activated Cl- current

P2X7R:

Purinergic P2X7 receptors

NLRP3:

Pyrin structural domain protein 3

OGD:

Oxygen-glucose deprivation

OGD/R:

Oxygen-glucose deprivation/reperfusion

GJs:

Gap junctions

GLAST:

Glutamate/aspartate transporter

GLT-1:

Glutamate transporter-1

rCCAs:

Rat cultured cortical astrocytes

NCX:

Sodium/calcium exchanger

OPCs:

Oligodendrocyte precursor cells

CBX:

Carbenoxolone

CEF:

Ceftriaxone

SDH:

Succinate dehydrogenase

OxAc:

Oxaloacetate

GOT:

Glutamate-oxaloacetate transaminase

hrGOT1:

Human recombinant GOT1

Pyr:

Pyruvate

GPT:

Glutamate-pyruvate transaminases

PD:

Peritoneal dialysis

NPCs:

Neural precursor cells

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Funding

This study was supported by the key projects of Shandong (China) Natural Science Fund [grant number ZR2020KH003] (Sponsor: Bing-bing Han) and the Student Innovation and Entrepreneurship Training Program of Shandong Province [grant number 2022083] (Sponsor: Tian-he Fang).

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Authors and Affiliations

  1. Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, People’s Republic of China

    Xiao-man Yang, Jia-xin Li, Dong-han Xu, Hao Zhang & Pei-yu Yan

  2. College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People’s Republic of China

    Xiao-man Yang, Hao Yu, Na Li, Chong Li, Tian-he Fang, Shi-jun Wang & Bing-bing Han

  3. State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, People’s Republic of China

    Pei-yu Yan

  4. Zhuhai MUST Science and Technology Research Institute, Macau University of Science and Technology, Macau, People’s Republic of China

    Pei-yu Yan

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  1. Xiao-man Yang
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Contributions

All authors contributed to the study conception and design. Literature collection and summarization were performed by Hao Yu, Jia-xin Li, Na Li, Chong Li, Dong-han Xu, Hao Zhang, and Tian-he Fang. The first draft of the manuscript was written by Xiao-man Yang. Review and editing were done by Shi-jun Wang, Pei-yu Yan, and Bing-bing Han. All authors read and approved the final manuscript.

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Correspondence to Shi-jun Wang, Pei-yu Yan or Bing-bing Han.

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Xiao-man Yang and Hao Yu are the co-first authors.

Shi-jun Wang and Pei-yu Yan are the co-corresponding authors; the main corresponding author is Bing-bing Han.

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Yang, Xm., Yu, H., Li, Jx. et al. Excitotoxic Storms of Ischemic Stroke: A Non-neuronal Perspective. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04184-7

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