Cited by 34Intracranial Aneurysms: Treatment and ComplicationsIntracerebral and Subarachnoid Hemorrhage ResearchTakotsubo Cardiomyopathy and Associated Phenomena

Ifenprodil Improves Long-Term Neurologic Deficits Through Antagonizing Glutamate-Induced Excitotoxicity After Experimental Subarachnoid Hemorrhage

Sun, Jing-yi, Zhao, Shi-jun, Wang, Hong-bin, Hou, Ya-jun, Mi, Qiong-jie, Yang, Ming-feng, Yuan, Hui, Ni, Qing-bin +2 more·2021·Translational Stroke Research

Abstract

Excessive glutamate leading to excitotoxicity worsens brain damage after SAH and contributes to long-term neurological deficits. The drug ifenprodil is a non-competitive antagonist of GluN1-GluN2B N-methyl-d-aspartate (NMDA) receptor, which mediates excitotoxic damage in vitro and in vivo. Here, we show that cerebrospinal fluid (CSF) glutamate level within 48 h was significantly elevated in aSAH patients who later developed poor outcome. In rat SAH model, ifenprodil can improve long-term sensorimotor and spatial learning deficits. Ifenprodil attenuates experimental SAH-induced neuronal death of basal cortex and hippocampal CA1 area, cellular and mitochondrial Ca 2+ overload of basal cortex, blood-brain barrier (BBB) damage, and cerebral edema of early brain injury. Using in vitro models, ifenprodil declines the high-concentration glutamate-mediated intracellular Ca 2+ increase and cell apoptosis in primary cortical neurons, reduces the high-concentration glutamate-elevated endothelial permeability in human brain microvascular endothelial cell (HBMEC). Altogether, our results suggest ifenprodil improves long-term neurologic deficits through antagonizing glutamate-induced excitotoxicity.

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Crossref · 10.1007/s12975-021-00906-4

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  • Indirect data on NMDAR-dependent cytosolic Ca2+ rise suggest that glutamate-induced excitotoxicity involves an about 100% increase of glutamatergic transmission.

    “Indirect data on N-methyl-D-aspartate receptor (NMDAR)-dependent cytosolic Ca2+ rise suggest that glutamate-induced excitotoxicity involves an about 100% increase of glutamatergic transmission [58]”

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Authors
Sun, J.-Y., Zhao, S.-J., Wang, H.-B., Hou, Y.-J., Mi, Q.-J., Yang, M.-F., Yuan, H., Ni, Q.-B., Sun, B.-L., & Zhang, Z.-Y.
Affiliations
  • Baotou Central Hospital (CN)
  • Shandong First Medical University (CN)
Venue
Translational Stroke Research
Published
2021-03-12
Volume
12
Issue
6
Pages
1067-1080
ISSN
  • 1868-4483 (ISSN-L)
  • 1868-601X
OpenAlex
W3133506688
Cited by
34
References
45
Citations by year
2026: 5 · 2025: 6 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 2
FWCI
2.75
Type
journal article
Language
en
Open access
closed
Locations
  • Translational Stroke Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Natural Science Foundation of China (81870938, 82071303)
Topics
  • Health Sciences › Medicine › Neurology › Intracranial Aneurysms: Treatment and Complications
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Takotsubo Cardiomyopathy and Associated Phenomena
Keywords
ifenprodil, subarachnoid hemorrhage, excitotoxicity, glutamate, NMDA receptor antagonists, cerebrospinal fluid glutamate, sensorimotor deficits, spatial learning deficits, calcium overload, mitochondrial calcium, blood-brain barrier disruption, cerebral edema, apoptosis, endothelial permeability, hippocampal CA1, cortical neurons, rat model
MeSH terms
Animals, Blood-Brain Barrier, Humans, Piperidines, Subarachnoid Hemorrhage, Receptors, N-Methyl-D-Aspartate, Glutamic Acid, Rats

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