Hemorrhagic transformation after late-window thrombolysis remains one of the most feared complications in acute ischemic stroke care — a problem that grows more acute as treatment windows expand to 4.5 hours. Evidence that combining a newer thrombolytic agent with a plant-derived neuroprotective compound could simultaneously preserve clot-clearing efficacy while protecting the blood-brain barrier would meaningfully shift how adjuvant stroke therapy is designed.
Using a mouse thromboembolic stroke model treated intravenously at the 4.5-hour mark, this study compared recombinant human prourokinase (rhPro-UK) against the standard alteplase (rt-PA), and then evaluated the additive effect of Total Salvianolic Acid Injection (TSI) — a polyphenolic extract from Danshen (Salvia miltiorrhiza). rhPro-UK alone produced measurably less Evans blue dye leakage and hemorrhagic transformation than rt-PA, suggesting a relatively more BBB-sparing thrombolytic profile. Critically, only the combination of rhPro-UK and TSI — not either monotherapy — significantly reduced cerebral infarct volume and improved neurological scores. In parallel human brain microvascular endothelial cell (HBMEC) experiments under oxygen-glucose deprivation, the combination preserved transendothelial electrical resistance, reduced paracellular permeability, maintained tight-junction protein expression, and suppressed matrix metalloproteinase-2/9 activity along with oxidative stress markers.
Salvianolic acids, particularly salvianolic acid B, have a documented literature history as antioxidants and MMP inhibitors in cerebrovascular contexts, so the mechanistic story here is biologically coherent rather than surprising. What elevates this work is the specific pairing with rhPro-UK — a fibrin-selective thrombolytic with a distinct activation mechanism compared to rt-PA — and the demonstration of synergy rather than mere additive protection. The principal limitations are significant, however: this is entirely preclinical, relying on a mouse model that incompletely recapitulates human stroke pathophysiology, with no pharmacokinetic harmonization data for the combination in humans. TSI is currently used clinically in China but lacks regulatory approval in Western markets. Whether these BBB-protective effects translate to reduced clinical hemorrhage rates in human trials remains unestablished. This finding is mechanistically interesting and provides a rational preclinical basis for a combination trial, but should be considered hypothesis-generating rather than practice-informing at this stage.