ArticleJournal of translational medicine2026
Adjuvant therapy with total salvianolic acid injection enhances the safety and efficacy of recombinant prourokinase in ischemic stroke by mitigating blood-brain barrier disruption.
Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundLate-phase thrombolysis within the 4.5-hour window for acute ischemic stroke exacerbates blood-brain barrier (BBB) disruption, increasing the risk of hemorrhagic transformation. 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.
methodsA mouse thromboembolic stroke model was established, and treatments were administered intravenously 4.5 h post-occlusion. Mice were randomized into groups including sham, thrombus, rt-PA, rhPro-UK, TSI, and rhPro-UK + TSI. 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.
resultsrhPro-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‑2‑related gelatinolytic activity without altering MMP-2/9 expression. TSI also mitigated membrane translocation of the NADPH oxidase (NOX) subunits gp91phox and p47phox.
conclusionsrhPro-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‑hour window for ischemic stroke.
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