总丹酚酸注射液的辅助治疗通过减轻血脑屏障的破坏，提高了重组尿激酶原治疗缺血性卒中的安全性和有效性
Adjuvant therapy with total salvianolic acid injection enhances the safety and efficacy of recombinant prourokinase in ischemic stroke by mitigating blood-brain barrier disruption.
摘要(中文译文)
急性缺血性卒中4.5小时时间窗内的晚期溶栓会加剧血脑屏障（BBB）破坏，增加出血转化风险。重组人尿激酶原（rhPro-UK）是一种新兴溶栓药物，但其与阿替普酶（重组组织型纤溶酶原激活剂，rt-PA）相比对BBB完整性的影响，以及其与辅助神经保护剂如总丹酚酸注射液（TSI）的潜在叠加效应尚不明确。建立小鼠血栓栓塞性卒中模型，于闭塞后4.5小时静脉给药。小鼠随机分为假手术组、血栓组、rt-PA组、rhPro-UK组、TSI组及rhPro-UK+TSI组。评估脑血流量、血栓面积、梗死体积、神经功能评分及BBB完整性（伊文思蓝渗漏、脑水肿、出血）。体外实验中，人脑微血管内皮细胞（HBMECs）接受氧糖剥夺/复氧（OGD/R）处理，并给予或不给予rhPro-UK及TSI。评估跨内皮电阻、通透性、连接蛋白、基质金属蛋白酶（MMP）-2/9活性及氧化应激标志物。数据采用方差分析（ANOVA）及Bonferroni事后检验分析。rhPro-UK所致伊文思蓝渗漏及出血转化均少于rt-PA。rhPro-UK联合TSI治疗（而非单药治疗）显著减小脑梗死体积并改善神经功能。该联合方案通过防止连接蛋白（occludin、VE-cadherin）及基底膜成分（IV型胶原）降解而保护BBB完整性。在HBMECs中，TSI共处理可减轻OGD/R+rhPro-UK诱导的屏障功能障碍，抑制活性氧（ROS）产生，并降低MMP-2相关明胶酶活性，而不改变MMP-2/9表达。TSI还可减轻NADPH氧化酶（NOX）亚基gp91phox和p47phox的膜转位。rhPro-UK在BBB破坏方面较rt-PA具有更优的安全性。TSI通过抑制NOX-2源性氧化应激及随后的MMP-2激活，增强rhPro-UK介导的保护作用，从而在晚期溶栓过程中改善BBB完整性。该联合策略是提高缺血性卒中标准4.5小时时间窗内延迟溶栓安全性和有效性的一种有前景的治疗方法。
Abstract
Late-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. A 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. 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‑2‑related gelatinolytic activity without altering MMP-2/9 expression. TSI also mitigated membrane translocation of the NADPH oxidase (NOX) subunits gp91phox and p47phox. 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‑hour window for ischemic stroke.
如何引用
AMA
Xiao-Yi Wang, Quan Li, Li Yan, Di Wang, Chun-Shui Pan, Jing-Yu Fan, et al. Adjuvant therapy with total salvianolic acid injection enhances the safety and efficacy of recombinant prourokinase in ischemic stroke by mitigating blood-brain barrier disruption.. Journal of translational medicine. 2026; doi:10.1186/s12967-026-08583-3.
APA
Xiao-Yi Wang, Quan Li, Li Yan, Di Wang, Chun-Shui Pan, Jing-Yu Fan, et al (2026). Adjuvant therapy with total salvianolic acid injection enhances the safety and efficacy of recombinant prourokinase in ischemic stroke by mitigating blood-brain barrier disruption.. Journal of translational medicine. https://doi.org/10.1186/s12967-026-08583-3
GB/T 7714
Xiao-Yi Wang, Quan Li, Li Yan, Di Wang, Chun-Shui Pan, Jing-Yu Fan, et al. Adjuvant therapy with total salvianolic acid injection enhances the safety and efficacy of recombinant prourokinase in ischemic stroke by mitigating blood-brain barrier disruption.[J]. Journal of translational medicine, 2026 doi:10.1186/s12967-026-08583-3.
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