1. Ifenprodil Improves Long-Term Neurologic Deficits Through Antagonizing Glutamate-Induced Excitotoxicity After Experimental Subarachnoid Hemorrhage
- Author
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Hong-Bin Wang, Qingbin Ni, Qiong-Jie Mi, Jing-yi Sun, Shi-jun Zhao, Zong-yong Zhang, Ming-feng Yang, Ya-jun Hou, Hui Yuan, and Baoliang Sun
- Subjects
0301 basic medicine ,Excitotoxicity ,Glutamic Acid ,Brain damage ,medicine.disease_cause ,Receptors, N-Methyl-D-Aspartate ,Cerebral edema ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Ifenprodil ,Animals ,Humans ,Medicine ,business.industry ,General Neuroscience ,Glutamate receptor ,Human brain ,Subarachnoid Hemorrhage ,medicine.disease ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Blood-Brain Barrier ,NMDA receptor ,Neurology (clinical) ,medicine.symptom ,Basal cortex ,Cardiology and Cardiovascular Medicine ,business ,Neuroscience ,030217 neurology & neurosurgery - 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.
- Published
- 2021