{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:54:56Z","timestamp":1793105696821,"version":"4.5.0"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"},{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurol Ther"],"published-print":{"date-parts":[[2025,12]]},"DOI":"10.1007\/s40120-025-00825-8","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T08:45:22Z","timestamp":1758271522000},"page":"2277-2293","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Microglial Polarization and Therapeutic Strategies in Post-stroke Neuroinflammation"],"prefix":"10.1007","volume":"14","author":[{"given":"Travis Yui Hei","family":"Chan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian De Yu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy Keith","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny Sum Yee","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin Wai Yue","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,19]]},"reference":[{"key":"825_CR1","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1177\/17474930241308142","volume":"20","author":"VL Feigin","year":"2024","unstructured":"Feigin VL, Brainin M, Norrving B, et al. World Stroke Organization (WSO): global stroke fact sheet 2025. Int J Stroke. 2024;20:132\u201344.","journal-title":"Int J Stroke"},{"issue":"1","key":"825_CR2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/s40256-013-0007-6","volume":"13","author":"S Bansal","year":"2013","unstructured":"Bansal S, Sangha KS, Khatri P. Drug treatment of acute ischemic stroke. Am J Cardiovasc Drugs. 2013;13(1):57\u201369.","journal-title":"Am J Cardiovasc Drugs"},{"issue":"1","key":"825_CR3","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s12974-019-1516-2","volume":"16","author":"RL Jayaraj","year":"2019","unstructured":"Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflamm. 2019;16(1):142.","journal-title":"J Neuroinflamm"},{"issue":"2\u20133","key":"825_CR4","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.ijcard.2003.02.007","volume":"95","author":"R Pujadas Capmany","year":"2004","unstructured":"Pujadas Capmany R, Arboix A, Casa\u00f1as-Mu\u00f1oz R, Anguera-Ferrando N. Specific cardiac disorders in 402 consecutive patients with ischaemic cardioembolic stroke. Int J Cardiol. 2004;95(2\u20133):129\u201334.","journal-title":"Int J Cardiol"},{"issue":"142","key":"825_CR5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.pneurobio.2016.05.001","volume":"1","author":"XY Xiong","year":"2016","unstructured":"Xiong XY, Liu L, Yang QW. Functions and mechanisms of microglia\/macrophages in neuroinflammation and neurogenesis after stroke. Progr Neurobiol. 2016;1(142):23\u201344.","journal-title":"Progr Neurobiol"},{"issue":"11","key":"825_CR6","doi-asserted-by":"publisher","first-page":"3063","DOI":"10.1161\/STROKEAHA.112.659656","volume":"43","author":"X Hu","year":"2012","unstructured":"Hu X, Li P, Guo Y, et al. Microglia\/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke. 2012;43(11):3063\u201370.","journal-title":"Stroke"},{"issue":"1","key":"825_CR7","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1186\/s12883-021-02097-9","volume":"21","author":"D Hou","year":"2021","unstructured":"Hou D, Wang C, Ye X, Zhong P, Wu D. Persistent inflammation worsens short-term outcomes in massive stroke patients. BMC Neurol. 2021;21(1):62.","journal-title":"BMC Neurol"},{"issue":"2","key":"825_CR8","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1161\/STROKEAHA.115.012079","volume":"47","author":"X Liu","year":"2016","unstructured":"Liu X, Liu J, Zhao S, et al. Interleukin-4 is essential for microglia\/macrophage M2 polarization and long-term recovery after cerebral ischemia. Stroke. 2016;47(2):498\u2013504.","journal-title":"Stroke"},{"issue":"1\u20132","key":"825_CR9","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.jneuroim.2009.02.003","volume":"210","author":"A Michelucci","year":"2009","unstructured":"Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: effects of oligomeric and fibrillar amyloid-\u03b2. J Neuroimmunol. 2009;210(1\u20132):3\u201312.","journal-title":"J Neuroimmunol"},{"issue":"1","key":"825_CR10","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1111\/j.1471-4159.2009.06098.x","volume":"110","author":"F de Bilbao","year":"2009","unstructured":"de Bilbao F, Arsenijevic D, Moll T, et al. In vivo over-expression of interleukin-10 increases resistance to focal brain ischemia in mice. J Neurochem. 2009;110(1):12\u201322.","journal-title":"J Neurochem"},{"issue":"12","key":"825_CR11","doi-asserted-by":"publisher","first-page":"e8101","DOI":"10.1371\/journal.pone.0008101","volume":"4","author":"A Madinier","year":"2009","unstructured":"Madinier A, Bertrand N, Mossiat C, et al. Microglial involvement in neuroplastic changes following focal brain ischemia in rats. PLoS ONE. 2009;4(12):e8101.","journal-title":"PLoS ONE"},{"issue":"1","key":"825_CR12","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1186\/s13041-020-00582-9","volume":"13","author":"R Rauti","year":"2020","unstructured":"Rauti R, Cellot G, D\u2019Andrea P, et al. BDNF impact on synaptic dynamics: extra or intracellular long-term release differently regulates cultured hippocampal synapses. Mol Brain. 2020;13(1):43.","journal-title":"Mol Brain"},{"key":"825_CR13","doi-asserted-by":"publisher","first-page":"100270","DOI":"10.1016\/j.bbih.2021.100270","volume":"15","author":"MK Schuhmann","year":"2021","unstructured":"Schuhmann MK, Kollikowski AM, M\u00e4rz AG, Bieber M, Pham M, Stoll G. Danger-associated molecular patterns are locally released during occlusion in hyper-acute stroke. Brain Behav Immunity Health. 2021;15:100270.","journal-title":"Brain Behav Immunity Health"},{"issue":"6","key":"825_CR14","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1007\/s10072-012-1131-9","volume":"34","author":"W Li","year":"2012","unstructured":"Li W, Ling HP, You WC, et al. Recombinant high-mobility group box 1 protein (HMGB-1) promotes myeloid differentiation primary response protein 88 (Myd88) upregulation in mouse primary cortical neurons. Neurol Sci. 2012;34(6):847\u201353.","journal-title":"Neurol Sci"},{"issue":"117","key":"825_CR15","doi-asserted-by":"publisher","first-page":"109102","DOI":"10.1016\/j.biopha.2019.109102","volume":"1","author":"S Yang","year":"2019","unstructured":"Yang S, Wang H, Yang Y, et al. Baicalein administered in the subacute phase ameliorates ischemia-reperfusion-induced brain injury by reducing neuroinflammation and neuronal damage. Biomed Pharmacother. 2019;1(117):109102\u201312.","journal-title":"Biomed Pharmacother"},{"issue":"2","key":"825_CR16","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1161\/01.STR.0000254477.34231.cb","volume":"38","author":"GJ del Zoppo","year":"2007","unstructured":"del Zoppo GJ, Milner R, Mabuchi T, et al. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke. 2007;38(2):646\u201351.","journal-title":"Stroke"},{"key":"825_CR17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2022\/4335272","volume":"2022","author":"W Liu","year":"2022","unstructured":"Liu W, Qi Z, Li W, Liang J, Zhao L, Shi Y. M1 microglia induced neuronal injury on ischemic stroke via mitochondrial crosstalk between microglia and neurons. Oxid Med Cell Longev. 2022;2022:1\u201316.","journal-title":"Oxid Med Cell Longev"},{"key":"825_CR18","first-page":"12","volume":"30","author":"EN Goddery","year":"2021","unstructured":"Goddery EN, Fain CE, Lipovsky CG, et al. Microglia and perivascular macrophages act as antigen presenting cells to promote CD8 T\u00a0cell infiltration of the brain. Front Immunol. 2021;30:12.","journal-title":"Front Immunol"},{"issue":"6","key":"825_CR19","doi-asserted-by":"publisher","first-page":"1399","DOI":"10.1161\/01.STR.0000223001.06264.af","volume":"37","author":"A Rosell","year":"2006","unstructured":"Rosell A, Ortega-Aznar A, Alvarez-Sab\u00edn J, et al. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke. 2006;37(6):1399\u2013406.","journal-title":"Stroke"},{"issue":"5","key":"825_CR20","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1038\/jcbfm.2012.11","volume":"32","author":"GJ del Zoppo","year":"2012","unstructured":"del Zoppo GJ, Frankowski H, Gu YH, et al. Microglial cell activation is a source of metalloproteinase generation during hemorrhagic transformation. J Cereb Blood Flow Metab. 2012;32(5):919\u201332.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"2","key":"825_CR21","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.hest.2021.01.002","volume":"2","author":"R Pan","year":"2021","unstructured":"Pan R, Liu W, Liu KJ. MMP-2\/9-cleaved occludin promotes endothelia cell death in ischemic stroke. Brain Hemorrhages. 2021;2(2):63\u201370.","journal-title":"Brain Hemorrhages"},{"issue":"4","key":"825_CR22","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1161\/STROKEAHA.107.500868","volume":"39","author":"A Rosell","year":"2008","unstructured":"Rosell A, Cuadrado E, Ortega-Aznar A, Hern\u00e1ndez-GuillamonM M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type\u00a0IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke. 2008;39(4):1121\u20136.","journal-title":"Stroke"},{"key":"825_CR23","first-page":"12","volume":"23","author":"Y Qiu","year":"2021","unstructured":"Qiu Y, Zhang C, Chen A, et al. Immune cells in the BBB disruption after acute ischemic stroke: targets for immune therapy? Front Immunol. 2021;23:12.","journal-title":"Front Immunol"},{"issue":"1","key":"825_CR24","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1172\/JCI118392","volume":"97","author":"ES Connolly","year":"1996","unstructured":"Connolly ES, Winfree CJ, Springer TA, et al. Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke. J Clin Investig. 1996;97(1):209\u201316.","journal-title":"J Clin Investig"},{"issue":"1","key":"825_CR25","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1186\/s12974-022-02551-6","volume":"19","author":"Y Ye","year":"2022","unstructured":"Ye Y, Jian Z, Jin T, et al. NOX2-mediated reactive oxygen species are double-edged swords in focal cerebral ischemia in mice. J Neuroinflamm. 2022;19(1):184.","journal-title":"J Neuroinflamm"},{"issue":"12","key":"825_CR26","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1097\/01.WCB.0000090680.07515.C8","volume":"23","author":"C Justicia","year":"2003","unstructured":"Justicia C, Pan\u00e9s J, Sol\u00e9 S, et al. Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion\/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab. 2003;23(12):1430\u201340.","journal-title":"J Cereb Blood Flow Metab"},{"issue":"10","key":"825_CR27","doi-asserted-by":"publisher","first-page":"e154225","DOI":"10.1172\/JCI154225","volume":"132","author":"D Frederik","year":"2022","unstructured":"Frederik D, Portier I, Rustad JL, et al. Neutrophil extracellular traps regulate ischemic stroke brain injury. J Clin Investig. 2022;132(10):e154225.","journal-title":"J Clin Investig"},{"issue":"3","key":"825_CR28","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1016\/j.surneu.2005.12.028","volume":"66","author":"J Huang","year":"2006","unstructured":"Huang J, Upadhyay UM, Tamargo RJ. Inflammation in stroke and focal cerebral ischemia. Surg Neurol. 2006;66(3):232\u201345.","journal-title":"Surg Neurol"},{"issue":"6","key":"825_CR29","doi-asserted-by":"publisher","first-page":"3916","DOI":"10.4049\/jimmunol.173.6.3916","volume":"173","author":"JK Olson","year":"2004","unstructured":"Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173(6):3916\u201324.","journal-title":"J Immunol"},{"key":"825_CR30","first-page":"9","volume":"4","author":"F Xia","year":"2018","unstructured":"Xia F, Qian CR, Xun Z, et al. TCR and CD28 concomitant stimulation elicits a distinctive calcium response in naive T\u00a0cells. Front Immunol. 2018;4:9.","journal-title":"Front Immunol"},{"issue":"1","key":"825_CR31","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1186\/s12974-017-1017-0","volume":"14","author":"Y Feng","year":"2017","unstructured":"Feng Y, Liao S, Wei C, et al. Infiltration and persistence of lymphocytes during late-stage cerebral ischemia in middle cerebral artery occlusion and photothrombotic stroke models. J Neuroinflamm. 2017;14(1):248.","journal-title":"J Neuroinflamm"},{"key":"825_CR32","doi-asserted-by":"publisher","DOI":"10.1111\/cns.70061","author":"H He","year":"2024","unstructured":"He H, Zhang X, He H, et al. Microglial priming by IFN-\u03b3 involves STAT1-mediated activation of the NLRP3 inflammasome. CNS Neurosci Ther. 2024. https:\/\/doi.org\/10.1111\/cns.70061.","journal-title":"CNS Neurosci Ther"},{"issue":"4","key":"825_CR33","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.1007\/s12035-023-03723-y","volume":"61","author":"J Wang","year":"2023","unstructured":"Wang J, Gao Y, Yuan Y, Wang H, Wang Z, Zhang X. Th17 cells and IL-17A in ischemic stroke. Mol Neurobiol. 2023;61(4):2411\u201329.","journal-title":"Mol Neurobiol"},{"issue":"4","key":"825_CR34","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1179\/1743132812Y.0000000021","volume":"34","author":"XN Tang","year":"2012","unstructured":"Tang XN, Cairns B, Kim JY, Yenari MA. NADPH oxidase in stroke and cerebrovascular disease. Neurol Res. 2012;34(4):338\u201345.","journal-title":"Neurol Res"},{"issue":"1","key":"825_CR35","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1186\/s13550-015-0115-1","volume":"5","author":"K Abe","year":"2015","unstructured":"Abe K, Tonomura M, Ito M, et al. Imaging of reactive oxygen species in focal ischemic mouse brain using a radical trapping tracer [3H]hydromethidine. EJNMMI Res. 2015;5(1):115.","journal-title":"EJNMMI Res"},{"issue":"1","key":"825_CR36","doi-asserted-by":"publisher","first-page":"20","DOI":"10.3164\/jcbn.17-62","volume":"62","author":"K Watanabe","year":"2018","unstructured":"Watanabe K, Tanaka M, Yuki S, Hirai M, Yamamoto Y. How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis? J Clin Biochem Nutr. 2018;62(1):20\u201338.","journal-title":"J Clin Biochem Nutr"},{"issue":"5","key":"825_CR37","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1021\/jp110400t","volume":"115","author":"A P\u00e9rez-Gonz\u00e1lez","year":"2010","unstructured":"P\u00e9rez-Gonz\u00e1lez A, Galano A. OH radical scavenging activity of edaravone: mechanism and kinetics. J Phys Chem B. 2010;115(5):1306\u201314.","journal-title":"J Phys Chem B"},{"issue":"10","key":"825_CR38","doi-asserted-by":"publisher","first-page":"2220","DOI":"10.1161\/01.STR.0000182241.07096.06","volume":"36","author":"N Zhang","year":"2005","unstructured":"Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y, Urabe T. Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke. 2005;36(10):2220\u20135.","journal-title":"Stroke"},{"issue":"4","key":"825_CR39","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1001\/jamaneurol.2023.5716","volume":"81","author":"Y Fu","year":"2024","unstructured":"Fu Y, Wang A, Tang R, et al. Sublingual edaravone dexborneol for the treatment of acute ischemic stroke. JAMA Neurol. 2024;81(4):319\u201326.","journal-title":"JAMA Neurol"},{"issue":"6","key":"825_CR40","doi-asserted-by":"publisher","first-page":"e3","DOI":"10.1136\/svn-2023-002998","volume":"8","author":"L Liu","year":"2023","unstructured":"Liu L, Li Z, Zhou H, et al. Chinese Stroke Association guidelines for clinical management of ischaemic cerebrovascular diseases: executive summary and 2023 update. Stroke Vasc Neurol. 2023;8(6):e3-3.","journal-title":"Stroke Vasc Neurol"},{"key":"825_CR41","first-page":"1","volume":"18","author":"X Jiang","year":"2024","unstructured":"Jiang X, Chen L, Wang J, et al. Combined selective endovascular brain hypothermia with edaravone dexborneol versus edaravone dexborneol alone for endovascular treatment in acute ischemic stroke (SHE): protocol for a multicenter, single-blind, randomized controlled study. Cerebrovasc Dis. 2024;18:1\u201310.","journal-title":"Cerebrovasc Dis"},{"issue":"4","key":"825_CR42","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1007\/s10072-021-05089-2","volume":"42","author":"B Fiani","year":"2021","unstructured":"Fiani B, Covarrubias C, Wong A, et al. Cerebrolysin for stroke, neurodegeneration, and traumatic brain injury: review of the literature and outcomes. Neurol Sci. 2021;42(4):1345\u201353.","journal-title":"Neurol Sci"},{"key":"825_CR43","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.568813","author":"DH Kang","year":"2020","unstructured":"Kang DH, Choi BY, Lee SH, et al. Effects of cerebrolysin on hippocampal neuronal death after pilocarpine-induced seizure. Front Neurosci. 2020. https:\/\/doi.org\/10.3389\/fnins.2020.568813.","journal-title":"Front Neurosci"},{"issue":"3","key":"825_CR44","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1177\/1747493015625645","volume":"11","author":"L Zhang","year":"2016","unstructured":"Zhang L, Chopp M, Lu M, et al. Cerebrolysin dose-dependently improves neurological outcome in rats after acute stroke: a prospective, randomized, blinded, and placebo-controlled study. Int J Stroke. 2016;11(3):347\u201355.","journal-title":"Int J Stroke"},{"issue":"206","key":"825_CR45","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107300","volume":"9","author":"N Guo","year":"2024","unstructured":"Guo N, Wang X, Xu M, Bai J, Yu H. PI3K\/AKT signaling pathway: molecular mechanisms and therapeutic potential in depression. Pharmacol Res. 2024;9(206):107300.","journal-title":"Pharmacol Res"},{"issue":"5","key":"825_CR46","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.3390\/jcm11051273","volume":"11","author":"DF Mure\u0219anu","year":"2022","unstructured":"Mure\u0219anu DF, Livin\u021b Popa L, Chira D, et al. Role and impact of cerebrolysin for ischemic stroke care. J Clin Med. 2022;11(5):1273.","journal-title":"J Clin Med"},{"key":"825_CR47","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-025-01355-z","author":"J Staszewski","year":"2025","unstructured":"Staszewski J, D\u0119biec A, Strilciuc S, et al. Efficacy of cerebrolysin treatment as an add-on therapy to mechanical thrombectomy in patients with acute ischemic stroke due to large vessel occlusion in anterior circulation: results of a 3-month follow-up of a prospective, open label, single-center study. Transl Stroke Res. 2025. https:\/\/doi.org\/10.1007\/s12975-025-01355-z.","journal-title":"Transl Stroke Res"},{"issue":"1","key":"825_CR48","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s12883-023-03159-w","volume":"23","author":"DR Khasanova","year":"2023","unstructured":"Khasanova DR, Kalinin MN. Cerebrolysin as an early add-on to reperfusion therapy: risk of hemorrhagic transformation after ischemic stroke (CEREHETIS), a prospective, randomized, multicenter pilot study. BMC Neurol. 2023;23(1):121.","journal-title":"BMC Neurol"},{"key":"825_CR49","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1161\/STROKEAHA.124.049834","volume":"56","author":"V Homberg","year":"2025","unstructured":"Homberg V, Jianu DC, Stan A, et al. Speech therapy combined with cerebrolysin in enhancing nonfluent aphasia recovery after acute ischemic stroke: ESCAS randomized pilot study. Stroke. 2025;56:937\u201347.","journal-title":"Stroke"},{"issue":"9","key":"825_CR50","doi-asserted-by":"publisher","first-page":"2831","DOI":"10.1111\/ene.14936","volume":"28","author":"E Beghi","year":"2021","unstructured":"Beghi E, Binder H, Birle C, et al. European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke. Eur J Neurol. 2021;28(9):2831\u201345.","journal-title":"Eur J Neurol"},{"issue":"3","key":"825_CR51","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/s40263-014-0144-8","volume":"28","author":"P Grieb","year":"2014","unstructured":"Grieb P. Neuroprotective properties of citicoline: facts, doubts and unresolved issues. CNS Drugs. 2014;28(3):185\u201393.","journal-title":"CNS Drugs"},{"issue":"4","key":"825_CR52","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.3390\/brainsci3031395","volume":"3","author":"J \u00c1lvarez-Sab\u00edn","year":"2013","unstructured":"\u00c1lvarez-Sab\u00edn J, Rom\u00e1n G. The role of citicoline in neuroprotection and neurorepair in ischemic stroke. Brain Sci. 2013;3(4):1395\u2013414.","journal-title":"Brain Sci"},{"issue":"17","key":"825_CR53","doi-asserted-by":"publisher","first-page":"e70030","DOI":"10.1096\/fj.202400823R","volume":"38","author":"S Cavalu","year":"2024","unstructured":"Cavalu S, Saber S, Ramadan A, et al. Unveiling citicoline\u2019s mechanisms and clinical relevance in the treatment of neuroinflammatory disorders. FASEB J. 2024;38(17):e70030.","journal-title":"FASEB J"},{"issue":"9839","key":"825_CR54","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/S0140-6736(12)60813-7","volume":"380","author":"A D\u00e1valos","year":"2012","unstructured":"D\u00e1valos A, Alvarez-Sab\u00edn J, Castillo J, et al. Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet. 2012;380(9839):349\u201357.","journal-title":"Lancet"},{"issue":"7","key":"825_CR55","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.1016\/j.jstrokecerebrovasdis.2014.01.020","volume":"23","author":"K Overgaard","year":"2014","unstructured":"Overgaard K. The effects of citicoline on acute ischemic stroke: a review. J Stroke Cerebrovasc Dis. 2014;23(7):1764\u20139.","journal-title":"J Stroke Cerebrovasc Dis"},{"issue":"6","key":"825_CR56","doi-asserted-by":"publisher","first-page":"2659","DOI":"10.1038\/s41380-022-01511-z","volume":"27","author":"EG Knox","year":"2022","unstructured":"Knox EG, Aburto MR, Clarke G, Cryan JF, O'Driscoll CM. The blood\u2013brain barrier in aging and neurodegeneration. Mol Psychiatry. 2022;27(6):2659\u201373.","journal-title":"Mol Psychiatry"},{"issue":"5594","key":"825_CR57","doi-asserted-by":"publisher","first-page":"846","DOI":"10.1126\/science.1072873","volume":"298","author":"M Aarts","year":"2002","unstructured":"Aarts M. Treatment of ischemic brain damage by perturbing NMDA receptor\u2014PSD-95 protein interactions. Science. 2002;298(5594):846\u201350.","journal-title":"Science"},{"issue":"5","key":"825_CR58","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1038\/aps.2018.5","volume":"39","author":"B Ballarin","year":"2018","unstructured":"Ballarin B, Tymianski M. Discovery and development of NA-1 for the treatment of acute ischemic stroke. Acta Pharmacol Sin. 2018;39(5):661\u20138 (Mar 22).","journal-title":"Acta Pharmacol Sin"},{"key":"825_CR59","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30258-0","author":"MD Hill","year":"2020","unstructured":"Hill MD, Goyal M, Menon BK, et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet. 2020. https:\/\/doi.org\/10.1016\/S0140-6736(20)30258-0.","journal-title":"Lancet"},{"key":"825_CR60","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1007\/s12264-020-00627-y","volume":"37","author":"XF Zhou","year":"2021","unstructured":"Zhou XF. ESCAPE-NA1 trial brings hope of neuroprotective drugs for acute ischemic stroke: highlights of the phase\u00a03 clinical trial on nerinetide. Neurosci Bull. 2021;37:579\u201381.","journal-title":"Neurosci Bull"},{"issue":"10","key":"825_CR61","doi-asserted-by":"publisher","first-page":"2500","DOI":"10.1161\/STROKEAHA.123.043159","volume":"54","author":"J Hofmeijer","year":"2023","unstructured":"Hofmeijer J, Ham F, Kwakkel G. Evidence of rTMS for motor or cognitive stroke recovery: hype or hope? Stroke. 2023;54(10):2500\u201311.","journal-title":"Stroke"},{"issue":"1","key":"825_CR62","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/s41398-022-02297-y","volume":"13","author":"B Guo","year":"2023","unstructured":"Guo B, Zhang M, Hao W, Wang Y, Zhang T, Liu C. Neuroinflammation mechanisms of neuromodulation therapies for anxiety and depression. Transl Psychiatry. 2023;13(1):5.","journal-title":"Transl Psychiatry"},{"issue":"554","key":"825_CR63","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.neuroscience.2024.07.004","volume":"10","author":"Y Yang","year":"2024","unstructured":"Yang Y, Xia C, Xu Z, et al. rTMS applied to the PFC relieves neuropathic pain and modulates neuroinflammation in CCI rats. Neuroscience. 2024;10(554):137\u201345.","journal-title":"Neuroscience"},{"issue":"11","key":"825_CR64","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1016\/j.clinph.2014.05.021","volume":"125","author":"JP Lefaucheur","year":"2014","unstructured":"Lefaucheur JP, Andr\u00e9-Obadia N, Antal A, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014;125(11):2150\u2013206.","journal-title":"Clin Neurophysiol"},{"issue":"8","key":"825_CR65","first-page":"20230005","volume":"1","author":"T Chino","year":"2023","unstructured":"Chino T, Kinoshita S, Abo M. Repetitive transcranial magnetic stimulation and rehabilitation therapy for upper limb hemiparesis in stroke patients: a narrative review. Prog Rehabil Med. 2023;1(8):20230005.","journal-title":"Prog Rehabil Med"},{"issue":"10","key":"825_CR66","doi-asserted-by":"publisher","first-page":"e109305","DOI":"10.1371\/journal.pone.0109305","volume":"9","author":"B Mead","year":"2014","unstructured":"Mead B, Logan A, Berry M, Leadbeater W, Scheven BA. Paracrine-mediated neuroprotection and neuritogenesis of axotomised retinal ganglion cells by human dental pulp stem cells: comparison with human bone marrow and adipose-derived mesenchymal stem cells. PLoS ONE. 2014;9(10):e109305.","journal-title":"PLoS ONE"},{"key":"825_CR67","volume":"16","author":"K Houkin","year":"2024","unstructured":"Houkin K, Osanai T, Uchiyama S, et al. Allogeneic stem cell therapy for acute ischemic stroke: the phase\u00a02\/3 TREASURE randomized clinical trial. JAMA Neurol. 2024;16:e235200.","journal-title":"JAMA Neurol"},{"issue":"7","key":"825_CR68","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1161\/STROKEAHA.116.012995","volume":"47","author":"GK Steinberg","year":"2016","unstructured":"Steinberg GK, Kondziolka D, Wechsler LR, et al. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke. Stroke. 2016;47(7):1817\u201324.","journal-title":"Stroke"},{"key":"825_CR69","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.ymthe.2024.12.006","volume":"33","author":"B Klein","year":"2025","unstructured":"Klein B, Ciesielska A, Losada PM, et al. Modified human mesenchymal stromal\/stem cells restore cortical excitability after focal ischemic stroke in rats. Mol Ther. 2025;33:375\u2013400.","journal-title":"Mol Ther"},{"key":"825_CR70","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2021.121111","volume":"277","author":"W He","year":"2021","unstructured":"He W, Zhang Z, Sha X. Nanoparticles-mediated emerging approaches for effective treatment of ischemic stroke. Biomaterials. 2021;277:121111.","journal-title":"Biomaterials"},{"issue":"1554","key":"825_CR71","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.brainres.2014.01.038","volume":"30","author":"D Shimbo","year":"2014","unstructured":"Shimbo D, Abumiya T, Shichinohe H, Nakayama N, Kazumata K, Houkin K. Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin can reduce ischemia reperfusion injury. Brain Res. 2014;30(1554):59\u201366.","journal-title":"Brain Res"},{"issue":"1","key":"825_CR72","doi-asserted-by":"publisher","first-page":"12651","DOI":"10.1038\/srep12651","volume":"5","author":"Z Wang","year":"2015","unstructured":"Wang Z, Zhao Y, Jiang Y, et al. Enhanced anti-ischemic stroke of ZL006 by T7-conjugated PEGylated liposomes drug delivery system. Sci Rep. 2015;5(1):12651.","journal-title":"Sci Rep"},{"issue":"5","key":"825_CR73","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1007\/s00401-018-1930-z","volume":"137","author":"KL Lambertsen","year":"2018","unstructured":"Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation\u2014target or tool for therapy? Acta Neuropathol. 2018;137(5):693\u2013714.","journal-title":"Acta Neuropathol"},{"issue":"5","key":"825_CR74","doi-asserted-by":"publisher","first-page":"e2987","DOI":"10.1002\/brb3.2987","volume":"13","author":"B Gao","year":"2023","unstructured":"Gao B, Wang S, Li J, et al. HMGB1, angel or devil, in ischemic stroke. Brain Behav. 2023;13(5):e2987.","journal-title":"Brain Behav"},{"issue":"6","key":"825_CR75","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1136\/svn-2023-002938","volume":"9","author":"C Wang","year":"2024","unstructured":"Wang C, Gu HQ, Dong Q, et al. Rationale and design of treatment of acute ischaemic stroke with edaravone dexborneol II (TASTE-2): a multicentre randomised controlled trial. Stroke Vasc Neurol. 2024;9(6):730\u20137. https:\/\/doi.org\/10.1136\/svn-2023-002938.","journal-title":"Stroke Vasc Neurol"},{"issue":"1","key":"825_CR76","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1161\/STROKEAHA.115.009416","volume":"47","author":"DF Muresanu","year":"2016","unstructured":"Muresanu DF, Heiss WD, Hoemberg V, et al. Cerebrolysin and recovery after stroke (CARS). Stroke. 2016;47(1):151\u20139.","journal-title":"Stroke"},{"issue":"5","key":"825_CR77","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1016\/S1474-4422(17)30046-7","volume":"16","author":"DC Hess","year":"2017","unstructured":"Hess DC, Wechsler LR, Clark WM, et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): a randomised, double-blind, placebo-controlled, phase\u00a02 trial. Lancet Neurol. 2017;16(5):360\u20138.","journal-title":"Lancet Neurol"},{"key":"825_CR78","first-page":"10","volume":"21","author":"Y Li","year":"2022","unstructured":"Li Y, Wang H, Jin J, Yang C, Hu J, Li J. Advances in the research of nano delivery systems in ischemic stroke. Front Bioeng Biotechnol. 2022;21:10.","journal-title":"Front Bioeng Biotechnol"},{"issue":"Nov 1","key":"825_CR79","doi-asserted-by":"publisher","first-page":"394","DOI":"10.25259\/SNI_703_2024","volume":"15","author":"BDY Ma","year":"2024","unstructured":"Ma BDY, Chan TYH, Lo BWY. Unveiling the hidden culprit: how the brain-gut axis fuels neuroinflammation in ischemic stroke. Surg Neurol Int. 2024;15(Nov 1):394.","journal-title":"Surg Neurol Int"},{"key":"825_CR80","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2024.1400808","author":"L Xie","year":"2024","unstructured":"Xie L, He M, Ying C, Chu H. Mechanisms of inflammation after ischemic stroke in brain-peripheral crosstalk. Front Mol Neurosci. 2024. https:\/\/doi.org\/10.3389\/fnmol.2024.1400808.","journal-title":"Front Mol Neurosci"}],"container-title":["Neurology and Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40120-025-00825-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40120-025-00825-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40120-025-00825-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T12:04:19Z","timestamp":1763381059000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40120-025-00825-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,19]]},"references-count":80,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["825"],"URL":"https:\/\/doi.org\/10.1007\/s40120-025-00825-8","relation":{},"ISSN":["2193-8253","2193-6536"],"issn-type":[{"value":"2193-8253","type":"print"},{"value":"2193-6536","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,19]]},"assertion":[{"value":"29 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"The authors, Travis Yui Hei Chan, Brian De Yu Ma, Timothy Keith Hung, Jenny Sum Yee Wong, and Benjamin Wai Yue Lo, have nothing to disclose.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}