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Recombinant human prourokinase (rhPro-UK) is an emerging thrombolytic agent, but its impact on BBB integrity compared to alteplase (recombinant tissue plasminogen activator, rt-PA) and its potential additive effect with adjuvant neuroprotectants like Total Salvianolic Acid Injection (TSI) remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A mouse thromboembolic stroke model was established, and treatments were administered intravenously 4.5\u00a0h post-occlusion. Mice were randomized into groups including sham, thrombus, rt-PA, rhPro-UK, TSI, and rhPro-UK\u2009+\u2009TSI. Cerebral blood flow, thrombus area, infarct volume, neurological scores, and BBB integrity (Evans blue leakage, cerebral edema, hemorrhage) were assessed. In vitro, human brain microvascular endothelial cells (HBMECs) underwent oxygen-glucose deprivation\/reoxygenation (OGD\/R) with or without rhPro-UK and TSI. Transendothelial electrical resistance, permeability, junctional proteins, matrix metalloproteinase (MMP)-2\/9 activity, and oxidative stress markers were evaluated. Data were analyzed by ANOVA (Analysis of Variance) with Bonferroni post-hoc tests.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>rhPro-UK induced less Evans blue leakage and hemorrhagic transformation than rt-PA. Combined rhPro-UK and TSI treatment, but not monotherapies, significantly reduced cerebral infarction and improved neurological function. This combination preserved BBB integrity by preventing the degradation of junctional proteins (occludin, VE-cadherin) and basement membrane components (collagen IV). In HBMECs, TSI co-treatment attenuated OGD\/R+rhPro-UK-induced barrier dysfunction, suppressed reactive oxygen species (ROS) production, and reduced MMP\u20112\u2011related gelatinolytic activity without altering MMP-2\/9 expression. TSI also mitigated membrane translocation of the NADPH oxidase (NOX) subunits gp91phox and p47phox.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>rhPro-UK exhibits a superior safety profile over rt-PA regarding BBB disruption. TSI potentiates rhPro-UK-mediated protection to improve BBB integrity during late-phase thrombolysis by suppressing NOX-2-derived oxidative stress and subsequent MMP-2 activation. This combinatory strategy represents a promising therapeutic approach to enhance the safety and efficacy of delayed thrombolysis within the standard 4.5\u2011hour window for ischemic stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08583-3","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:03:56Z","timestamp":1784034236000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adjuvant therapy with total salvianolic acid injection enhances the safety and efficacy of recombinant prourokinase in ischemic stroke by mitigating blood\u2013brain barrier disruption"],"prefix":"10.1186","volume":"24","author":[{"given":"Xiao-Yi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Shui","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Yu","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Zhong","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2286-8076","authenticated-orcid":false,"given":"Jing-Yan","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"8583_CR1","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/S1474-4422(24)00369-7","volume":"23","author":"GBDSRF Collaborators","year":"2024","unstructured":"Collaborators GBDSRF. 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