Ifenprodil Improves Long-Term Neurologic Deficits Through Antagonizing Glutamate-Induced Excitotoxicity After Experimental Subarachnoid Hemorrhage
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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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]”
From Fibromyalgia pathogenesis explained by a neuroendocrine multistable model (2024) · cites this paper as [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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