{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:33:32Z","timestamp":1785450812566,"version":"3.56.0"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T00:00:00Z","timestamp":1744848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Taipei Veterans General Hospital in Taiwan","award":["V101D-002-1"],"award-info":[{"award-number":["V101D-002-1"]}]},{"name":"Taipei Veterans General Hospital in Taiwan","award":["V102D-002-1"],"award-info":[{"award-number":["V102D-002-1"]}]},{"name":"Taipei Veterans General Hospital in Taiwan","award":["V104E6-001"],"award-info":[{"award-number":["V104E6-001"]}]},{"name":"Taipei Veterans General Hospital in Taiwan","award":["CY10724"],"award-info":[{"award-number":["CY10724"]}]},{"name":"Taipei Veterans General Hospital in Taiwan","award":["CY10836"],"award-info":[{"award-number":["CY10836"]}]},{"name":"Cheng Hsin General Hospital Joint National Yang Ming Chiao Tung University Research Program in Taiwan","award":["V101D-002-1"],"award-info":[{"award-number":["V101D-002-1"]}]},{"name":"Cheng Hsin General Hospital Joint National Yang Ming Chiao Tung University Research Program in Taiwan","award":["V102D-002-1"],"award-info":[{"award-number":["V102D-002-1"]}]},{"name":"Cheng Hsin General Hospital Joint National Yang Ming Chiao Tung University Research Program in Taiwan","award":["V104E6-001"],"award-info":[{"award-number":["V104E6-001"]}]},{"name":"Cheng Hsin General Hospital Joint National Yang Ming Chiao Tung University Research Program in Taiwan","award":["CY10724"],"award-info":[{"award-number":["CY10724"]}]},{"name":"Cheng Hsin General Hospital Joint National Yang Ming Chiao Tung University Research Program in Taiwan","award":["CY10836"],"award-info":[{"award-number":["CY10836"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ischemic stroke leads to cerebral ionic imbalance, increases acidosis, oxidative stress and release of glutamate and inflammatory mediators. Removing solute or stimulants from the ischemic core may block cell-damaging events and confer neuroprotection. In this study, we developed a minimally invasive therapeutic microdialysis (tMD) method, choosing to include serum albumin in the buffer because it is a multifunctional protein with osmotic properties. Aiming at the ischemic core, continuous perfusion of buffer supplemented with osmotic agents removes mediators of inflammation\/cell damage\/death from the lesion. This tMD treatment significantly removed the glutamate and zinc ions from the core, thereby reducing infarct volumes and affording high-grade neurobehavioral protection against ischemic stroke. The tMD treatment effectively protected neurons and reduced microglial activation. Furthermore, this tMD approach extended the therapeutic window to protect beyond 6 h after stroke onset. These findings support the potential clinical feasibility of applying tMD to patients with ischemic stroke, potentially without adverse effects.<\/jats:p>","DOI":"10.3390\/ijms26083821","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T20:50:46Z","timestamp":1744923046000},"page":"3821","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting the Ischemic Core: A Therapeutic Microdialytic Approach to Prevent Neuronal Death and Restore Functional Behaviors"],"prefix":"10.3390","volume":"26","author":[{"given":"May-Jywan","family":"Tsai","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dann-Ying","family":"Liou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Yu","family":"Fay","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Department of Medicine, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Ling","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Cheng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Department of Medicine, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Ming","family":"Chern","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan"},{"name":"Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Department of Neurology, En Chu Kong Hospital, New Taipei City 23702, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen-Kou","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Cheng Hsin General Hospital, Taipei 11283, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrich","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Neural Regeneration and Repair, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Department of Medicine, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan"},{"name":"Department and Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei 11230, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiang-Suo","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s00401-009-0496-1","article-title":"Inflammation, plasticity and real-time imaging after cerebral ischemia","volume":"117","author":"Kriz","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/S1474-4422(23)00277-6","article-title":"Pragmatic solutions to reduce the global burden of stroke: A World Stroke Organization-Lancet Neurology Commission","volume":"22","author":"Feigin","year":"2023","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41582-023-00921-z","article-title":"Addressing disparities in the global epidemiology of stroke","volume":"20","author":"Prust","year":"2024","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1001\/jama.2020.26867","article-title":"Diagnosis and Management of Transient Ischemic Attack and Acute Ischemic Stroke: A Review","volume":"325","author":"Mendelson","year":"2021","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kong, J., and Zhang, D. (2023). Current status and quality of radiomics studies for predicting outcome in acute ischemic stroke patients: A systematic review and meta-analysis. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1335851"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.drudis.2020.01.007","article-title":"Novel approaches for the delivery of therapeutics in ischemic stroke","volume":"25","author":"Nozohouri","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e34121","DOI":"10.1016\/j.heliyon.2024.e34121","article-title":"A comprehensive review on the neuroprotective potential of resveratrol in ischemic stroke","volume":"10","author":"Owjfard","year":"2024","journal-title":"Heliyon"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"108721","DOI":"10.1016\/j.pharmthera.2024.108721","article-title":"Potential application of natural compounds in ischaemic stroke: Focusing on the mechanisms underlying \u201clysosomocentric\u201d dysfunction of the autophagy-lysosomal pathway","volume":"263","author":"Liu","year":"2024","journal-title":"Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Pawluk, H., Tafelska-Kaczmarek, A., Soponska, M., Porzych, M., Modrzejewska, M., Pawluk, M., Kurhaluk, N., Tkaczenko, H., and Kolodziejska, R. (2024). The Influence of Oxidative Stress Markers in Patients with Ischemic Stroke. Biomolecules, 14.","DOI":"10.3390\/biom14091130"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1136\/svn-2022-002154","article-title":"Treatment with intravenous alteplase in ischaemic stroke patients with onset time between 4.5 and 24 hours (HOPE): Protocol for a randomised, controlled, multicentre study","volume":"9","author":"Luo","year":"2024","journal-title":"Stroke Vasc. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/S0140-6736(16)00163-X","article-title":"Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials","volume":"387","author":"Goyal","year":"2016","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e344","DOI":"10.1161\/STR.0000000000000211","article-title":"Guidelines for the Early Management of Patients with Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals from the American Heart Association\/American Stroke Association","volume":"50","author":"Powers","year":"2019","journal-title":"Stroke"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1212\/WNL.0000000000012781","article-title":"Global Epidemiology of Stroke and Access to Acute Ischemic Stroke Interventions","volume":"97","author":"Saini","year":"2021","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1161\/STROKEAHA.109.571935","article-title":"Oxidative stress after thrombolysis-induced reperfusion in human stroke","volume":"41","author":"Dominguez","year":"2010","journal-title":"Stroke"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e14634","DOI":"10.1111\/cns.14634","article-title":"Advancing stroke therapy: A deep dive into early phase of ischemic stroke and recanalization","volume":"30","author":"He","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/s41392-022-01064-1","article-title":"Signaling pathways involved in ischemic stroke: Molecular mechanisms and therapeutic interventions","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1161\/01.STR.32.2.553","article-title":"Human albumin therapy of acute ischemic stroke: Marked neuroprotective efficacy at moderate doses and with a broad therapeutic window","volume":"32","author":"Belayev","year":"2001","journal-title":"Stroke"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0014-2999(01)01255-9","article-title":"Neuroprotective effect of treatment with human albumin in permanent focal cerebral ischemia: Histopathology and cortical perfusion studies","volume":"428","author":"Liu","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s12028-017-0400-0","article-title":"Albumin-Induced Neuroprotection in Focal Cerebral Ischemia in the ALIAS Trial: Does Severity, Mechanism, and Time of Infusion Matter?","volume":"28","author":"Khatri","year":"2018","journal-title":"Neurocrit Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1007\/s10072-021-05244-9","article-title":"Albumin therapy for acute ischemic stroke: A meta-analysis","volume":"42","author":"Huang","year":"2021","journal-title":"Neurol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1161\/STROKEAHA.116.012825","article-title":"ALIAS (Albumin in Acute Ischemic Stroke) Trials: Analysis of the Combined Data from Parts 1 and 2","volume":"47","author":"Martin","year":"2016","journal-title":"Stroke"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5525","DOI":"10.1039\/D3AN01117H","article-title":"Influence of bovine and human serum albumin on the binding kinetics of biomolecular interactions","volume":"148","author":"Charron","year":"2023","journal-title":"Analyst"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Rahman, N., and Khalil, N. (2023). Characterization of sulfasalazine-bovine serum albumin and human serum albumin interaction by spectroscopic and theoretical approach. Spectrochim. Acta A Mol. Biomol. Spectrosc., 300.","DOI":"10.1016\/j.saa.2023.122865"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.neuron.2010.07.002","article-title":"The science of stroke: Mechanisms in search of treatments","volume":"67","author":"Moskowitz","year":"2010","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuroscience.2023.12.010","article-title":"Acute Ischemic Stroke Thrombus Composition","volume":"550","author":"Vandelanotte","year":"2024","journal-title":"Neuroscience"},{"key":"ref_26","first-page":"45","article-title":"The acute ischemic penumbra: Topography, life span, and therapeutic response","volume":"73","author":"Ginsberg","year":"1999","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1002\/neu.480230915","article-title":"Excitotoxic cell death","volume":"23","author":"Choi","year":"1992","journal-title":"J. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.neuint.2007.04.026","article-title":"Excitotoxic mechanisms in stroke: An update of concepts and treatment strategies","volume":"50","author":"Hazell","year":"2007","journal-title":"Neurochem. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1089\/neu.1997.14.677","article-title":"Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury?","volume":"14","author":"Obrenovitch","year":"1997","journal-title":"J. Neurotrauma"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"121814","DOI":"10.1016\/j.lfs.2023.121814","article-title":"Molecular mechanisms of ischemia and glutamate excitotoxicity","volume":"328","author":"Neves","year":"2023","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Kaplan-Arabaci, O., Acari, A., Ciftci, P., and Gozuacik, D. (2022). Glutamate Scavenging as a Neuroreparative Strategy in Ischemic Stroke. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.866738"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jneumeth.2005.11.014","article-title":"Synaptic release of zinc from brain slices: Factors governing release, imaging, and accurate calculation of concentration","volume":"154","author":"Frederickson","year":"2006","journal-title":"J. Neurosci. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/S0306-4522(02)00513-4","article-title":"Zinc translocation accelerates infarction after mild transient focal ischemia","volume":"115","author":"Lee","year":"2002","journal-title":"Neuroscience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1097\/WCO.0000000000000047","article-title":"The ischemic penumbra: The location rather than the volume of recovery determines outcome","volume":"27","author":"Rosso","year":"2014","journal-title":"Curr. Opin. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1002\/jps.10410","article-title":"Use of osmotic agents in microdialysis studies to improve the recovery of macromolecules","volume":"92","author":"Trickler","year":"2003","journal-title":"J. Pharm. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.brainres.2004.10.067","article-title":"The neuroprotective effect of glial cell line-derived neurotrophic factor in fibrin glue against chronic focal cerebral ischemia in conscious rats","volume":"1033","author":"Cheng","year":"2005","journal-title":"Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.neuroscience.2015.07.074","article-title":"Acidic FGF promotes neurite outgrowth of cortical neurons and improves neuroprotective effect in a cerebral ischemic rat model","volume":"305","author":"Tsai","year":"2015","journal-title":"Neuroscience"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1002\/jnr.21395","article-title":"Dual effect of adenovirus-mediated transfer of BMP7 in mixed neuron-glial cultures: Neuroprotection and cellular differentiation","volume":"85","author":"Tsai","year":"2007","journal-title":"J. Neurosci. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jvs.2007.04.044","article-title":"Resveratrol neuroprotective effects during focal cerebral ischemia injury via nitric oxide mechanism in rats","volume":"46","author":"Tsai","year":"2007","journal-title":"J. Vasc. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.expneurol.2013.03.004","article-title":"Anti-oxidative, anti-apoptotic, and pro-angiogenic effects mediate functional improvement by sonic hedgehog against focal cerebral ischemia in rats","volume":"247","author":"Huang","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_41","first-page":"100","article-title":"Middle cerebral artery occlusion in rats: A neurological and pathological evaluation of a reproducible model","volume":"31","author":"Menzies","year":"1992","journal-title":"Neurosurgery"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Tsai, M.J., Tsai, S.K., Hu, B.R., Liou, D.Y., Huang, S.L., Huang, M.C., Huang, W.C., Cheng, H., and Huang, S.S. (2014). Recovery of neurological function of ischemic stroke by application of conditioned medium of bone marrow mesenchymal stem cells derived from normal and cerebral ischemia rats. J. Biomed. Sci., 21.","DOI":"10.1186\/1423-0127-21-5"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"649809","DOI":"10.1155\/2013\/649809","article-title":"Enhanced prostacyclin synthesis by adenoviral gene transfer reduced glial activation and ameliorated dopaminergic dysfunction in hemiparkinsonian rats","volume":"2013","author":"Tsai","year":"2013","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.neuint.2010.09.005","article-title":"Silymarin protects spinal cord and cortical cells against oxidative stress and lipopolysaccharide stimulation","volume":"57","author":"Tsai","year":"2010","journal-title":"Neurochem. Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1196\/annals.1338.031","article-title":"Effect of enhanced prostacyclin synthesis by adenovirus-mediated transfer on lipopolysaccharide stimulation in neuron-glia cultures","volume":"1042","author":"Tsai","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3821\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:16:52Z","timestamp":1760030212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/8\/3821"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,17]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26083821"],"URL":"https:\/\/doi.org\/10.3390\/ijms26083821","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,17]]}}}