{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:28:58Z","timestamp":1760243338189,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2014,10,27]],"date-time":"2014-10-27T00:00:00Z","timestamp":1414368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST)","award":["2012R1A2A2A01040132"],"award-info":[{"award-number":["2012R1A2A2A01040132"]}]},{"DOI":"10.13039\/501100002632","name":"Hallym University","doi-asserted-by":"publisher","award":["HRF-201402-011"],"award-info":[{"award-number":["HRF-201402-011"]}],"id":[{"id":"10.13039\/501100002632","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1\u2212\/\u2212 female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood\u2013brain barrier (BBB) disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1\u2212\/\u2212 female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under  ischemic conditions.<\/jats:p>","DOI":"10.3390\/ijms151119444","type":"journal-article","created":{"date-parts":[[2014,10,27]],"date-time":"2014-10-27T11:38:09Z","timestamp":1414409889000},"page":"19444-19457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["EAAC1 Gene Deletion Increases Neuronal Death and Blood Brain Barrier Disruption after Transient Cerebral Ischemia  in Female Mice"],"prefix":"10.3390","volume":"15","author":[{"given":"Bo","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Physiology, Hallym University, College of Medicine, Chuncheon 200-702, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, Hallym University, College of Medicine, Chuncheon 200-702, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, Hallym University, College of Medicine, Chuncheon 200-702, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Physiology, Hallym University, College of Medicine, Chuncheon 200-702, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology, Hallym University, College of Medicine, Chuncheon 200-702, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Sohn","sequence":"additional","affiliation":[{"name":"Department of Nursing, Inha University, Incheon 402-751, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang","family":"Suh","sequence":"additional","affiliation":[{"name":"Department of Physiology, Hallym University, College of Medicine, Chuncheon 200-702, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2014,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4289","DOI":"10.2174\/138161212802481200","article-title":"Inflammation in ischemic stroke subtypes","volume":"18","author":"Tuttolomondo","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4266","DOI":"10.2174\/138161212802481237","article-title":"Atherosclerosis as an inflammatory disease","volume":"18","author":"Tuttolomondo","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.cyto.2012.02.012","article-title":"Single nucleotide polymorphisms (SNPs) of pro-inflammatory\/anti-inflammatory and thrombotic\/fibrinolytic genes in patients with acute ischemic stroke in relation to TOAST subtype","volume":"58","author":"Tuttolomondo","year":"2012","journal-title":"Cytokine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s00018-003-3319-x","article-title":"Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury","volume":"61","author":"Arundine","year":"2004","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.freeradbiomed.2004.11.032","article-title":"The powerhouse takes control of the cell: Is the mitochondrial permeability transition a viable therapeutic target against neuronal dysfunction and death?","volume":"38","author":"Stavrovskaya","year":"2005","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5260","DOI":"10.1523\/JNEUROSCI.1067-09.2009","article-title":"Neuroprotection by the NR3A subunit of the NMDA receptor","volume":"29","author":"Nakanishi","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/360467a0","article-title":"Primary structure and functional characterization of a high-affinity glutamate transporter","volume":"360","author":"Kanai","year":"1992","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1126\/science.276.5319.1699","article-title":"Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1","volume":"276","author":"Tanaka","year":"1997","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1046\/j.1460-9568.1998.00108.x","article-title":"Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice","volume":"10","author":"Watase","year":"1998","journal-title":"Eur. J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1113\/jphysiol.1996.sp021393","article-title":"Interaction of l-cysteine with a human excitatory amino acid transporter","volume":"493","author":"Zerangue","year":"1996","journal-title":"J. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1007\/s00702-003-0049-z","article-title":"Role of neuronal glutamate transporter in the cysteine uptake and intracellular glutathione levels in cultured cortical neurons","volume":"110","author":"Himi","year":"2003","journal-title":"J. Neural Transm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1046\/j.1471-4159.2003.01630.x","article-title":"The glutamate transporters EAAT2 and EAAT3 mediate cysteine uptake in cortical neuron cultures","volume":"84","author":"Chen","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9404","DOI":"10.1523\/JNEUROSCI.3351-08.2008","article-title":"A dominant role of GTRAP3\u201318 in neuronal glutathione synthesis","volume":"28","author":"Watabe","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1254\/jphs.08R01CR","article-title":"Regulation of neuronal glutathione synthesis","volume":"108","author":"Aoyama","year":"2008","journal-title":"J. Pharmacol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/S0165-0173(97)00045-3","article-title":"Neurodegenerative disorders in humans: The role of glutathione in oxidative stress-mediated neuronal death","volume":"25","author":"Bains","year":"1997","journal-title":"Brain Res. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4904","DOI":"10.1046\/j.1432-1327.2000.01595.x","article-title":"Glutathione, oxidative stress and neurodegeneration","volume":"267","author":"Schulz","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0301-0082(99)00060-X","article-title":"Metabolism and functions of glutathione in brain","volume":"62","author":"Dringen","year":"2000","journal-title":"Prog. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/nn1609","article-title":"Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse","volume":"9","author":"Aoyama","year":"2006","journal-title":"Nat. Neurosci"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15409","DOI":"10.1523\/JNEUROSCI.2084-10.2010","article-title":"EAAC1 gene deletion alters zinc homeostasis and exacerbates neuronal injury after transient cerebral ischemia","volume":"30","author":"Won","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jtemb.2012.04.010","article-title":"EAAC1 gene deletion alters zinc homeostasis and enhances cortical neuronal injury after transient cerebral ischemia in mice","volume":"26","author":"Jang","year":"2012","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1038\/jcbfm.2010.222","article-title":"Glutamate transporter type 3 knockout reduces brain tolerance to focal brain ischemia in mice","volume":"31","author":"Li","year":"2011","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1002\/ana.21511","article-title":"Glucose and NADPH oxidase drive neuronal superoxide formation in stroke","volume":"64","author":"Suh","year":"2008","journal-title":"Ann. Neurol."},{"key":"ref_23","first-page":"270","article-title":"N-Acetyl-l-cysteine","volume":"17F","year":"1993","journal-title":"J. Cell. Biochem. Suppl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1600-0609.1996.tb01370.x","article-title":"Red blood cell permeability to thiol compounds following oxidative stress","volume":"57","author":"Mazor","year":"1996","journal-title":"Eur. J. Haematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1056\/NEJMoa044397","article-title":"A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis","volume":"354","author":"Polman","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.1073\/pnas.93.7.3031","article-title":"Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis","volume":"93","author":"Liblau","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/BF00686975","article-title":"Foreign and endogenous serum protein extravasation during harmaline tremors or kainic acid seizures in the rat: A comparison","volume":"76","author":"Ruth","year":"1988","journal-title":"Acta Neuropathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1213\/ANE.0b013e3181b6709a","article-title":"Volatile anesthetics attenuate oxidative stress-reduced activity of glutamate transporter type 3","volume":"109","author":"Lee","year":"2009","journal-title":"Anesth. Analg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1093\/emboj\/16.13.3822","article-title":"Glutamate transporter EAAC1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration","volume":"16","author":"Peghini","year":"1997","journal-title":"EMBO J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/S0896-6273(00)80958-7","article-title":"Mutant mice and neuroscience: Recommendations concerning genetic background. Banbury Conference on genetic background in mice","volume":"19","author":"Silva","year":"1997","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0006-8993(00)02513-0","article-title":"Fluoro-Jade B: A high affinity fluorescent marker for the localization of neuronal degeneration","volume":"874","author":"Schmued","year":"2000","journal-title":"Brain Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10681","DOI":"10.1523\/JNEUROSCI.23-33-10681.2003","article-title":"Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia","volume":"23","author":"Suh","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e81523","DOI":"10.1371\/journal.pone.0081523","article-title":"Pyruvate administration reduces recurrent\/moderate hypoglycemia-induced cortical neuron death in diabetic rats","volume":"8","author":"Choi","year":"2013","journal-title":"PLoS One"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.brainres.2012.08.032","article-title":"Prevention of traumatic brain injury-induced neuronal death by inhibition of NADPH oxidase activation","volume":"1481","author":"Choi","year":"2012","journal-title":"Brain Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.brainres.2013.01.007","article-title":"Post-treatment of an NADPH oxidase inhibitor prevents seizure-induced neuronal death","volume":"1499","author":"Kim","year":"2013","journal-title":"Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1177\/29.4.6166661","article-title":"Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures","volume":"29","author":"Hsu","year":"1981","journal-title":"J. Histochem. Cytochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.jneumeth.2010.05.004","article-title":"Digitally quantifying cerebral hemorrhage using Photoshop and Image J","volume":"190","author":"Tang","year":"2010","journal-title":"J. Neurosci. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/11\/19444\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:17:26Z","timestamp":1760217446000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/15\/11\/19444"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,27]]},"references-count":37,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2014,11]]}},"alternative-id":["ijms151119444"],"URL":"https:\/\/doi.org\/10.3390\/ijms151119444","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2014,10,27]]}}}