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. 2021 Dec;12(6):1067-1080.
doi: 10.1007/s12975-021-00906-4. Epub 2021 Mar 12.

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

Jing-Yi Sun  1   2 , Shi-Jun Zhao  3 , Hong-Bin Wang  2 , Ya-Jun Hou  2 , Qiong-Jie Mi  2 , Ming-Feng Yang  2 , Hui Yuan  2 , Qing-Bin Ni  4 , Bao-Liang Sun  5 , Zong-Yong Zhang  6
Affiliations

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

Jing-Yi Sun et al. Transl Stroke Res. 2021 Dec.

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 Ca2+ 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 Ca2+ 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.

Keywords: Excitotoxicity; Glutamate; Ifenprodil; Subarachnoid hemorrhage.

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