Targeting harmful effects of non-excitatory amino acids as an alternative therapeutic strategy to reduce ischemic damage  

作　　者：Victoria Jiménez Carretero IrisÁlvarez-Merz Jorge Hernández-Campano Sergei A.Kirov Jesús M.Hernández-Guijo 

机构地区：[1]Department of Pharmacology and Therapeutic,School of Medicine,Univ.Autónoma de Madrid,Madrid,Spain [2]Ramón y Cajal Institute for Health Research(IRYCIS),Neurobiology-Research Service,Hospital Ramón y Cajal,Madrid,Spain [3]Institute of Neurobiology,Faculty of Mathematics and Natural Sciences,Heinrich Heine University Düsseldorf,Düsseldorf,Germany [4]Department of Neuroscience and Regenerative Medicine&Department of Neurosurgery,Medical College of Georgia at Augusta University,Augusta,GA,USA

出　　处：《Neural Regeneration Research》2025年第9期2454-2463,共10页中国神经再生研究（英文版）

基　　金：supported by MICIU(grant number PID2021-128133NB-100/AEI/FEDER10.13039/501100011033 to JMHG);by the National Institutes of Health(grant number R01 NS083858 to SAK);the Intramural Grants Program IGPP00057(to SAK);VIC enjoys a FPU contract from the Comunidad de Madrid(PIPF-2022/SAL-GL-25948)。

摘　　要：The involvement of the excitatory amino acids glutamate and aspartate in ce rebral ischemia and excitotoxicity is well-documented.Nevertheless,the role of non-excitatory amino acids in brain damage following a stroke or brain trauma remains largely understudied.The release of amino acids by necrotic cells in the ischemic core may contribute to the expansion of the penumbra.Our findings indicated that the reversible loss of field excitato ry postsynaptic potentials caused by transient hypoxia became irreversible when exposed to a mixture of just four non-excitatory amino acids(L-alanine,glycine,L-glutamine,and L-serine)at their plasma concentrations.These amino acids induce swelling in the somas of neurons and astrocytes during hypoxia,along with permanent dendritic damage mediated by N-methyl-D-aspartate receptors.Blocking N-methyl-D-aspartate receptors prevented neuronal damage in the presence of these amino acids during hypoxia.It is likely that astroglial swelling caused by the accumulation of these amino acids via the alanine-serine-cysteine transporter 2 exchanger and system N transporters activates volume-regulated anion channels,leading to the release of excitotoxins and subsequent neuronal damage through N-methyl-D-aspartate receptor activation.Thus,previously unrecognized mechanisms involving non-excitatory amino acids may contribute to the progression and expansion of brain injury in neurological emergencies such as stroke and traumatic brain injury.Understanding these pathways co uld highlight new therapeutic targets to mitigate brain injury.

关 键 词：cell swelling N-methyl-D-aspartate receptor non-excitatory amino acids STROKE synaptic transmission 

分 类 号：R743.3[医药卫生—神经病学与精神病学]