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

Publisher: Wolters Kluwer Health, Medknow Country of Publication: India NLM ID: 101316351 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1673-5374 (Print) Linking ISSN: 16735374 NLM ISO Abbreviation: Neural Regen Res Subsets: PubMed not MEDLINE

Publication: 2013 - : Mumbai : Wolters Kluwer Health, Medknow
Original Publication: Shenyang : Editorial Board of Neural Regeneration Research

The involvement of the excitatory amino acids glutamate and aspartate in cerebral 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 excitatory 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 could highlight new therapeutic targets to mitigate brain injury.
(Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

Akins PT, Atkinson RP (2002) Glutamate AMPA receptor antagonist treatment for ischaemic stroke. Curr Med Res Opin 18 Suppl 2:s9-13.
Álvarez-Merz I, Luengo JG, Muñoz MD, Hernández-Guijo JM, Solís JM (2021) Hypoxia-induced depression of synaptic transmission becomes irreversible by intracellular accumulation of non-excitatory amino acids. Neuropharmacology 190:108557.
Álvarez-Merz I, Fomitcheva IV, Sword J, Hernandez-Guijo JM, Solis JM, Kirov SA (2022) Novel mechanism of hypoxic neuronal injury mediated by non-excitatory amino acids and astroglial swelling. Glia 70:2108–2130.
Álvarez-Merz I, Muñoz MD, Hernández-Guijo JM, Solís JM (2023) Identification of non-excitatory amino acids and transporters mediating the irreversible synaptic silencing after hypoxia. Transl Stroke Res doi: 10.1007/s12975-023-01192-y.
Andrew RD, Labron MW, Boehnke SE, Carnduff L, Kirov SA (2007) Physiological evidence that pyramidal neurons lack functional water channels. Cereb Cortex 17:787–802.
Andrew RD, Farkas E, Hartings JA, Brennan KC, Herreras O, Muller M, Kirov SA, Ayata C, Ollen-Bittle N, Reiffurth C, Revah O, Robertson RM, Dawson-Scully KD, Ullah G, Dreier JP (2022a) Questioning glutamate excitotoxicity in acute brain damage: the importance of spreading depolarization. Neurocrit Care 37:11–30.
Andrew RD, Hartings JA, Ayata C, Brennan KC, Dawson-Scully KD, Farkas E, Herreras O, Kirov SA, Muller M, Ollen-Bittle N, Reiffurth C, Revah O, Robertson RM, Shuttleworth CW, Ullah G, Dreier JP (2022b) The critical role of spreading depolarizations in early brain injury: consensus and contention. Neurocrit Care 37:83–101.
Arrigoni E, Crocker AJ, Saper CB, Greene RW, Scammell TE (2005) Deletion of presynaptic adenosine A1 receptors impairs the recovery of synaptic transmission after hypoxia. Neuroscience 132:575–580.
Bak LK, Schousboe A, Waagepetersen HS (2006) The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98:641–653.
Belov Kirdajova D, Kriska J, Tureckova J, Anderova M (2020) Ischemia-triggered glutamate excitotoxicity from the perspective of glial cells. Front Cell Neurosci 14:51.
Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374.
Blaesse P, Airaksinen MS, Rivera C, Kaila K (2009) Cation-chloride cotransporters and neuronal function. Neuron 61:820–838.
Bröer A, Brookes N, Ganapathy V, Dimmer KS, Wagner CA, Lang F, Bröer S (1999) The astroglial ASCT2 amino acid transporter as a mediator of glutamine efflux. J Neurochem 73:2184–2194.
Bröer S (2014) The SLC38 family of sodium-amino acid co-transporters. Pflugers Arch 466:155–172.
Camacho A, Massieu L (2006) Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death. Arch Med Res 37:11–18.
Campos F, Sobrino T, Ramos-Cabrer P, Castillo J (2012) Oxaloacetate: a novel neuroprotective for acute ischemic stroke. Int J Biochem Cell Biol 44:262–265.
Canals S, Larrosa B, Pintor J, Mena MA, Herreras O (2008) Metabolic challenge to glia activates an adenosine-mediated safety mechanism that promotes neuronal survival by delaying the onset of spreading depression waves. J Cereb Blood Flow Metab 28:1835–1844.
Castillo J, Dávalos A, Naveiro J, Noya M (1996) Neuroexcitatory amino acids and their relation to infarct size and neurological deficit in ischemic stroke. Stroke 27:1060–1065.
Castillo J, Loza MI, Mirelman D, Brea J, Blanco M, Sobrino T, Campos F (2016) A novel mechanism of neuroprotection: Blood glutamate grabber. J Cereb Blood Flow Metab 36:292–301.
Chaudhry FA, Reimer RJ, Krizaj D, Barber D, Storm-Mathisen J, Copenhagen DR, Edwards RH (1999) Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Cell 99:769–780.
Chaudhry FA, Schmitz D, Reimer RJ, Larsson P, Gray AT, Nicoll R, Kavanaugh M, Edwards RH (2002) Glutamine uptake by neurons: interaction of protons with system a transporters. J Neurosci 22:62–72.
Chebabo SR, Hester MA, Jing J, Aitken PG, Somjen GG (1995) Interstitial space, electrical resistance and ion concentrations during hypotonia of rat hippocampal slices. J Physiol 487:685–697.
Chen W, Huang J, Hu Y, Khoshnam SE, Sarkaki A (2020) Mitochondrial transfer as a therapeutic strategy against ischemic stroke. Transl Stroke Res 11:1214–1228.
Chen ZH, Han YY, Shang YJ, Zhuang SY, Huang JN, Wu BY, Li CH (2021) Cordycepin ameliorates synaptic dysfunction and dendrite morphology damage of hippocampal CA1 via A1R in cerebral ischemia. Front Cell Neurosci 15:783478.
Cozzolino O, Marchese M, Trovato F, Pracucci E, Ratto GM, Buzzi MG, Sicca F, Santorelli FM (2018) Understanding spreading depression from headache to sudden unexpected death. Front Neurol 9:19.
Dale N, Pearson T, Frenguelli BG (2000) Direct measurement of adenosine release during hypoxia in the CA1 region of the rat hippocampal slice. J Physiol 526:143–155.
Dreier JP, Major S, Foreman B, Winkler MKL, Kang EJ, Milakara D, Lemale CL, DiNapoli V, Hinzman JM, Woitzik J, Andaluz N, Carlson A, Hartings JA (2018) Terminal spreading depolarization and electrical silence in death of human cerebral cortex. Ann Neurol 83:295–310.
Duarte JM, Cunha RA, Carvalho RA (2016) Adenosine A₁ receptors control the metabolic recovery after hypoxia in rat hippocampal slices. J Neurochem 136:947–957.
Ehmsen JT, Liu Y, Wang Y, Paladugu N, Johnson AE, Rothstein JD, du Lac S, Mattson MP, Hoke A (2016) The astrocytic transporter SLC7A10 (Asc-1) mediates glycinergic inhibition of spinal cord motor neurons. Sci Rep 6:35592.
Ennis SR, Kawai N, Ren XD, Abdelkarim GE, Keep RF (1998) Glutamine uptake at the blood-brain barrier is mediated by N-system transport. J Neurochem 71:2565–2573.
Erdemli G, Xu YZ, Krnjević K (1998) Potassium conductance causing hyperpolarization of CA1 hippocampal neurons during hypoxia. J Neurophysiol 80:2378–2390.
Erecińska M, Silver IA (2001) Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol 128:263–276.
Esslinger CS, Cybulski KA, Rhoderick JF (2005) Ngamma-aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site. Bioorg Med Chem 13:1111–1118.
Fedorovich S, Hofmeijer J, van Putten MJ, le Feber J (2017) Reduced synaptic vesicle recycling during hypoxia in cultured cortical neurons. Front Cell Neurosci 11:32.
Ferrari F, Gorini A, Hoyer S, Villa RF (2018) Glutamate metabolism in cerebral mitochondria after ischemia and post-ischemic recovery during aging: relationships with brain energy metabolism. J Neurochem 146:416–428.
Fleidervish IA, Gebhardt C, Astman N, Gutnick MJ, Heinemann U (2001) Enhanced spontaneous transmitter release is the earliest consequence of neocortical hypoxia that can explain the disruption of normal circuit function. J Neurosci 21:4600–4608.
Flores JJ, Zhang Y, Klebe DW, Lekic T, Fu W, Zhang JH (2014) Small molecule inhibitors in the treatment of cerebral ischemia. Expert Opin Pharmacother 15:659–680.
Foster AC, Rangel-Diaz N, Staubli U, Yang JY, Penjwini M, Viswanath V, Li YX (2017) Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices. Neuropharmacology 126:70–83.
Fowler JC (1989) Adenosine antagonists delay hypoxia-induced depression of neuronal activity in hippocampal brain slice. Brain Res 490:378–384.
Fukasawa Y, Segawa H, Kim JY, Chairoungdua A, Kim DK, Matsuo H, Cha SH, Endou H, Kanai Y (2000) Identification and characterization of a Na(+)-independent neutral amino acid transporter that associates with the 4F2 heavy chain and exhibits substrate selectivity for small neutral D- and L-amino acids. J Biol Chem 275:9690–9698.
Gauberti M, Montagne A, Marcos-Contreras OA, Le Behot A, Maubert E, Vivien D (2013) Ultra-sensitive molecular MRI of vascular cell adhesion molecule-1 reveals a dynamic inflammatory penumbra after strokes. Stroke 44:1988–1996.
Gerkau NJ, Rakers C, Petzold GC, Rose CR (2017) Differential effects of energy deprivation on intracellular sodium homeostasis in neurons and astrocytes. J Neurosci Res 95:2275–2285.
Gliddon CM, Shao Z, LeMaistre JL, Anderson CM (2009) Cellular distribution of the neutral amino acid transporter subtype ASCT2 in mouse brain. J Neurochem 108:372–383.
Gundlfinger A, Bischofberger J, Johenning FW, Torvinen M, Schmitz D, Breustedt J (2007) Adenosine modulates transmission at the hippocampal mossy fibre synapse via direct inhibition of presynaptic calcium channels. J Physiol 582:263–277.
Guo C, Ma YY (2021) Calcium permeable-AMPA receptors and excitotoxicity in neurological disorders. Front Neural Circuits 15:711564.
Hardingham G (2019) NMDA receptor C-terminal signaling in development, plasticity, and disease. F1000Res doi: 10.12688/f1000research.19925.1.
Hartings JA, et al. (2017) The continuum of spreading depolarizations in acute cortical lesion development: Examining Leao’s legacy. J Cereb Blood Flow Metab 37:1571–1594.
Helboe L, Egebjerg J, Møller M, Thomsen C (2003) Distribution and pharmacology of alanine-serine-cysteine transporter 1 (asc-1) in rodent brain. Eur J Neurosci 18:2227–2238.
Hong KS, Lee JS (2015) Statins in acute ischemic stroke: a systematic review. J Stroke 17:282–301.
Iglesias-Rey R, da Silva-Candal A, Rodriguez-Yanez M, Estany-Gestal A, Regueiro U, Maqueda E, Avila-Gomez P, Pumar JM, Castillo J, Sobrino T, Campos F, Hervella P (2022) Neurological instability in ischemic stroke: relation with outcome, latency time, and molecular markers. Transl Stroke Res 13:228–237.
Jackson PS, Strange K (1993) Volume-sensitive anion channels mediate swelling-activated inositol and taurine efflux. Am J Physiol 265:C1489–1500.
Jarosch MS, Gebhardt C, Fano S, Huchzermeyer C, Ul Haq R, Behrens CJ, Heinemann U (2015) Early adenosine release contributes to hypoxia-induced disruption of stimulus-induced sharp wave-ripple complexes in rat hippocampal area CA3. Eur J Neurosci 42:1808–1817.
Jayakumar AR, Rao KV, Murthy Ch R, Norenberg MD (2006) Glutamine in the mechanism of ammonia-induced astrocyte swelling. Neurochem Int 48:623–628.
Johnson JW, Ascher P (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531.
Kann O, Papageorgiou IE, Draguhn A (2014) Highly energized inhibitory interneurons are a central element for information processing in cortical networks. J Cereb Blood Flow Metab 34:1270–1282.
Kanthan R, Shuaib A, Griebel R, Miyashita H (1995) Intracerebral human microdialysis. In vivo study of an acute focal ischemic model of the human brain. Stroke 26:870–873.
Kaplan E, Zubedat S, Radzishevsky I, Valenta AC, Rechnitz O, Sason H, Sajrawi C, Bodner O, Konno K, Esaki K, Derdikman D, Yoshikawa T, Watanabe M, Kennedy RT, Billard JM, Avital A, Wolosker H (2018) ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d-serine and neurodevelopment. Proc Natl Acad Sci U S A 115:9628–9633.
Katchman AN, Hershkowitz N (1993) Adenosine antagonists prevent hypoxia-induced depression of excitatory but not inhibitory synaptic currents. Neurosci Lett 159:123–126.
Keep RF, Xiang J (1995) N-system amino acid transport at the blood--CSF barrier. J Neurochem 65:2571–2576.
Kemp JA, McKernan RM (2002) NMDA receptor pathways as drug targets. Nat Neurosci 5 Suppl:1039–1042.
Kirov SA, Fomitcheva IV, Sword J (2020) Rapid neuronal ultrastructure disruption and recovery during spreading depolarization-induced cytotoxic edema. Cereb Cortex 30:5517–5531.
Krnjević K (2008) Electrophysiology of cerebral ischemia. Neuropharmacology 55:319–333.
Lai TW, Zhang S, Wang YT (2014) Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:157–188.
Lau A, Tymianski M (2010) Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch 460:525–542.
Lee SY, Kim JH (2015) Mechanisms underlying presynaptic Ca2+ transient and vesicular glutamate release at a CNS nerve terminal during in vitro ischaemia. J Physiol 593:2793–2806.
Lemale CL, Lückl J, Horst V, Reiffurth C, Major S, Hecht N, Woitzik J, Dreier JP (2022) Migraine aura, transient ischemic attacks, stroke, and dying of the brain share the same key pathophysiological process in neurons driven by gibbs–donnan forces, namely spreading depolarization. Front Cell Neurosci 16:837650.
Lerma J, Herranz AS, Herreras O, Abraira V, Martín del Río R (1986) In vivo determination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis. Brain Res 384:145–155.
Li H, Li C, Yan ZY, Yang J, Chen H (2010) Simultaneous monitoring multiple neurotransmitters and neuromodulators during cerebral ischemia/reperfusion in rats by microdialysis and capillary electrophoresis. J Neurosci Methods 189:162–168.
Liu BH, Pu J, Li ZQ, Zhang XR (2022) The effects of hypothermia on glutamate and gamma-aminobutyric acid metabolism during ischemia in monkeys: a repeated-measures ANOVA study. Sci Rep 12:14470.
Liu F, Lu J, Manaenko A, Tang J, Hu Q (2018) Mitochondria in ischemic stroke: new insight and implications. Aging Dis 9:924–937.
Liu QR, Lopez-Corcuera B, Nelson H, Mandiyan S, Nelson N (1992) Cloning and expression of a cDNA encoding the transporter of taurine and beta-alanine in mouse brain. Proc Natl Acad Sci U S A 89:12145–12149.
Liu QR, López-Corcuera B, Mandiyan S, Nelson H, Nelson N (1993) Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain. J Biol Chem 268:2106–2112.
Luengo JG, Muñoz MD, Álvarez-Merz I, Herranz AS, González JC, Martín Del Río R, Hernández-Guijo JM, Solís JM (2019) Intracellular accumulation of amino acids increases synaptic potentials in rat hippocampal slices. Amino Acids 51:1337–1351.
Lutter D, Ullrich F, Lueck JC, Kempa S, Jentsch TJ (2017) Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels. J Cell Sci 130:1122–1133.
MacAulay N (2021) Molecular mechanisms of brain water transport. Nat Rev Neurosci 22:326–344.
Mackenzie B, Schafer MK, Erickson JD, Hediger MA, Weihe E, Varoqui H (2003) Functional properties and cellular distribution of the system A glutamine transporter SNAT1 support specialized roles in central neurons. J Biol Chem 278:23720–23730.
Matsumoto K, Lo EH, Pierce AR, Halpern EF, Newcomb R (1996) Secondary elevation of extracellular neurotransmitter amino acids in the reperfusion phase following focal cerebral ischemia. J Cereb Blood Flow Metab 16:114–124.
Menyhart A, Frank R, Farkas AE, Sule Z, Varga VE, Nyul-Toth A, Meiller A, Ivankovits-Kiss O, Lemale CL, Szabo I, Toth R, Zolei-Szenasi D, Woitzik J, Marinesco S, Krizbai IA, Bari F, Dreier JP, Farkas E (2022) Malignant astrocyte swelling and impaired glutamate clearance drive the expansion of injurious spreading depolarization foci. J Cereb Blood Flow Metab 42:584–599.
Metzner L, Neubert K, Brandsch M (2006) Substrate specificity of the amino acid transporter PAT1. Amino Acids 31:111–117.
Mitani A, Tanaka K (2003) Functional changes of glial glutamate transporter GLT-1 during ischemia: an in vivo study in the hippocampal CA1 of normal mice and mutant mice lacking GLT-1. J Neurosci 23:7176–7182.
Mongin AA (2016) Volume-regulated anion channel--a frenemy within the brain. Pflugers Arch 468:421–441.
Müller M, Somjen GG (2000) Na(+) and K(+) concentrations, extra- and intracellular voltages, and the effect of TTX in hypoxic rat hippocampal slices. J Neurophysiol 83:735–745.
Mutch WA, Hansen AJ (1984) Extracellular pH changes during spreading depression and cerebral ischemia: mechanisms of brain pH regulation. J Cereb Blood Flow Metab 4:17–27.
Neves D, Salazar IL, Almeida RD, Silva RM (2023) Molecular mechanisms of ischemia and glutamate excitotoxicity. Life Sci 328:121814.
Ni Chroinin D, et al. (2013) Statin therapy and outcome after ischemic stroke: systematic review and meta-analysis of observational studies and randomized trials. Stroke 44:448–456.
Nishimura F, Nishihara M, Mori M, Torii K, Takahashi M (1995) Excitability of neurons in the ventromedial nucleus in rat hypothalamic slices: modulation by amino acids at cerebrospinal fluid levels. Brain Res 691:217–222.
Nissen-Meyer LS, Chaudhry FA (2013) Protein kinase C phosphorylates the system N glutamine transporter SN1 (Slc38a3) and regulates its membrane trafficking and degradation. Front Endocrinol (Lausanne) 4:138.
No authors listed (2000) Phase II Studies of the Glycine Antagonist GV150526 in Acute Stroke: the North American experience. The North American Glycine Antagonist in Neuroprotection (GAIN) Investigators. Stroke 31:358–365.
Pace JR, Martin BM, Paul SM, Rogawski MA (1992) High concentrations of neutral amino acids activate NMDA receptor currents in rat hippocampal neurons. Neurosci Lett 141:97–100.
Payne JA, Rivera C, Voipio J, Kaila K (2003) Cation-chloride co-transporters in neuronal communication, development and trauma. Trends Neurosci 26:199–206.
Pellegrini-Giampietro DE, Zukin RS, Bennett MV, Cho S, Pulsinelli WA (1992) Switch in glutamate receptor subunit gene expression in CA1 subfield of hippocampus following global ischemia in rats. Proc Natl Acad Sci U S A 89:10499–10503.
Pineda M, Fernandez E, Torrents D, Estevez R, Lopez C, Camps M, Lloberas J, Zorzano A, Palacin M (1999) Identification of a membrane protein, LAT–2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J Biol Chem 274:19738–19744.
Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, Reinhardt J, Orth AP, Patapoutian A (2014) SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell 157:447–458.
Raastad M, Shepherd GM (2003) Single-axon action potentials in the rat hippocampal cortex. J Physiol 548:745–752.
Ragni M, Fenaroli F, Ruocco C, Segala A, D’Antona G, Nisoli E, Valerio A (2023) A balanced formula of essential amino acids promotes brain mitochondrial biogenesis and protects neurons from ischemic insult. Front Neurosci 17:1197208.
Revah O, Lasser-Katz E, Fleidervish IA, Gutnick MJ (2016) The earliest neuronal responses to hypoxia in the neocortical circuit are glutamate-dependent. Neurobiol Dis 95:158–167.
Rodriguez-Yanez M, Agulla J, Rodriguez-Gonzalez R, Sobrino T, Castillo J (2008) Statins and stroke. Ther Adv Cardiovasc Dis 2:157–166.
Rodríguez A, Berumen LC, Francisco Z, Giménez C, García-Alcocer MG (2011) Expression of the SNAT2 amino acid transporter during the development of rat cerebral cortex. Int J Dev Neurosci 29:743–748.
Rosenberg D, Artoul S, Segal AC, Kolodney G, Radzishevsky I, Dikopoltsev E, Foltyn VN, Inoue R, Mori H, Billard JM, Wolosker H (2013) Neuronal D-serine and glycine release via the Asc-1 transporter regulates NMDA receptor-dependent synaptic activity. J Neurosci 33:3533–3544.
Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403:316–321.
Scalise M, Pochini L, Galluccio M, Console L, Indiveri C (2020) Glutamine transporters as pharmacological targets: from function to drug design. Asian J Pharm Sci 15:207–219.
Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endou H, Kanai Y (1999) Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem 274:19745–19751.
Seidel JL, Faideau M, Aiba I, Pannasch U, Escartin C, Rouach N, Bonvento G, Shuttleworth CW (2015) Ciliary neurotrophic factor (CNTF) activation of astrocytes decreases spreading depolarization susceptibility and increases potassium clearance. Glia 63:91–103.
Somjen GG (2004) Ions in the brain: normal function, seizures, and stroke. New York, NY: Oxford University Press.
Soria FN, Perez-Samartin A, Martin A, Gona KB, Llop J, Szczupak B, Chara JC, Matute C, Domercq M (2014) Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage. J Clin Invest 124:3645–3655.
Steffensen AB, Sword J, Croom D, Kirov SA, MacAulay N (2015) Chloride cotransporters as a molecular mechanism underlying spreading depolarization-induced dendritic beading. J Neurosci 35:12172–12187.
Suárez LM, Suárez F, Del Olmo N, Ruiz M, González-Escalada JR, Solís JM (2005) Presynaptic NMDA autoreceptors facilitate axon excitability: a new molecular target for the anticonvulsant gabapentin. Eur J Neurosci 21:197–209.
Suárez LM, Solís JM (2006) Taurine potentiates presynaptic NMDA receptors in hippocampal Schaffer collateral axons. Eur J Neurosci 24:405–418.
Swain M, Butterworth RF, Blei AT (1992) Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats. Hepatology 15:449–453.
Szydlowska K, Tymianski M (2010) Calcium, ischemia and excitotoxicity. Cell Calcium 47:122–129.
Takahashi H, Koehler RC, Brusilow SW, Traystman RJ (1991) Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol 261:H825–829.
Tatsumi K, Kinugawa K, Isonishi A, Kitabatake M, Okuda H, Takemura S, Tanaka T, Mori E, Wanaka A (2021) Olig2-astrocytes express neutral amino acid transporter SLC7A10 (Asc-1) in the adult brain. Mol Brain 14:163.
Taylor DL, Obrenovitch TP, Symon L (1996) Changes in extracellular acid-base homeostasis in cerebral ischemia. Neurochem Res 21:1013–1021.
Uchiyama-Tsuyuki Y, Araki H, Yae T, Otomo S (1994) Changes in the extracellular concentrations of amino acids in the rat striatum during transient focal cerebral ischemia. J Neurochem 62:1074–1078.
Utsunomiya-Tate N, Endou H, Kanai Y (1996) Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter. J Biol Chem 271:14883–14890.
Volianskis A, France G, Jensen MS, Bortolotto ZA, Jane DE, Collingridge GL (2015) Long-term potentiation and the role of N-methyl-D-aspartate receptors. Brain Res 1621:5–16.
Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ (2014) Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344:634–638.
Wang F, Xie X, Xing X, Sun X (2022) Excitatory synaptic transmission in ischemic stroke: a new outlet for classical neuroprotective strategies. Int J Mol Sci 23:9381.
Weilinger NL, Wicki-Stordeur LE, Groten CJ, LeDue JM, Kahle KT, MacVicar BA (2022) KCC2 drives chloride microdomain formation in dendritic blebbing. Cell Rep 41:111556.
Wilson CS, Bach MD, Ashkavand Z, Norman KR, Martino N, Adam AP, Mongin AA (2019) Metabolic constraints of swelling-activated glutamate release in astrocytes and their implication for ischemic tissue damage. J Neurochem 151:255–272.
Wu Y, Chen C, Yang Q, Jiao M, Qiu S (2017) Endocytosis of GluN2B-containing NMDA receptors mediates NMDA-induced excitotoxicity. Mol Pain 13:1744806917701921.
Yamakami J, Sakurai E, Sakurada T, Maeda K, Hikichi N (1998) Stereoselective blood-brain barrier transport of histidine in rats. Brain Res 812:105–112.
Yamashita T, Kwak S (2019) Cell death cascade and molecular therapy in ADAR2-deficient motor neurons of ALS. Neurosci Res 144:4–13.
Yang J, Vitery MDC, Chen J, Osei-Owusu J, Chu J, Qiu Z (2019) Glutamate-releasing SWELL1 channel in astrocytes modulates synaptic transmission and promotes brain damage in stroke. Neuron 102:813–827.
Zaghmi A, Dopico-Lopez A, Perez-Mato M, Iglesias-Rey R, Hervella P, Greschner AA, Bugallo-Casal A, da Silva A, Gutierrez-Fernandez M, Castillo J, Perez FC, Gauthier MA (2020) Sustained blood glutamate scavenging enhances protection in ischemic stroke. Commun Biol 3:729.
Zetterling M, Hillered L, Samuelsson C, Karlsson T, Enblad P, Ronne-Engström E (2009) Temporal patterns of interstitial pyruvate and amino acids after subarachnoid haemorrhage are related to the level of consciousness--a clinical microdialysis study. Acta Neurochir (Wien) 151:771–780; discussion 780.
Zeuthen T (2010) Water-transporting proteins. J Membr Biol 234:57–73.
Zeuthen T, Macaulay N (2012) Cotransport of water by Na(+)-K(+)-2Cl(-) cotransporters expressed in Xenopus oocytes: NKCC1 versus NKCC2. J Physiol 590:1139–1154.
Zhang S, Zhou J, Zhang Y, Liu T, Friedel P, Zhuo W, Somasekharan S, Roy K, Zhang L, Liu Y, Meng X, Deng H, Zeng W, Li G, Forbush B, Yang M (2021) The structural basis of function and regulation of neuronal cotransporters NKCC1 and KCC2. Commun Biol 4:226.
Zhang X, Peng K, Zhang X (2020) The function of the NMDA receptor in hypoxic-ischemic encephalopathy. Front Neurosci 14:567665.
Zhou Y, Holmseth S, Guo C, Hassel B, Hofner G, Huitfeldt HS, Wanner KT, Danbolt NC (2012) Deletion of the gamma-aminobutyric acid transporter 2 (GAT2 and SLC6A13) gene in mice leads to changes in liver and brain taurine contents. J Biol Chem 287:35733–35746.
Zielinska M, Popek M, Albrecht J (2014) Roles of changes in active glutamine transport in brain edema development during hepatic encephalopathy: an emerging concept. Neurochem Res 39:599–604.

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