A combined extract of Salvia miltiorrhiza and Panax notoginseng enhances collateral flow and protects the neurovascular unit after ischemic stroke.

BACKGROUND: Ischemic stroke remains a major cause of mortality and disability, with few therapeutic options outside the narrow time window for reperfusion. Collateral circulation critically sustains penumbral viability, yet no pharmacological agent is approved to enhance collateral flow. Salvia (S.) miltiorrhiza and Panax (P.) notoginseng possess complementary vascular, anti-inflammatory, and neuroprotective actions, suggesting potential synergy in acute ischemia. METHODS: A combined extract of S. miltiorrhiza and P. notoginseng (SM/PN) was tested in a permanent middle cerebral artery occlusion (pMCAO) mouse model and in vitro systems. Endpoints included infarct volume, anterior cerebral artery (ACA) perfusion, vascular endothelial growth factor (VEGF) expression, microglial activation, inflammatory mediators, and endothelial barrier integrity. RESULTS: Pre-ischemic SM/PN (15-60 mg/kg) significantly reduced cortical infarct volume and sustained ACA perfusion during the first 15 min after occlusion without increasing VEGF in brain or endothelial cells. SM/PN decreased Iba-1 immunoreactivity in peri-infarct regions and suppressed inducible nitric oxide synthase, interleukin-6, and tumor necrosis factor-α in lipopolysaccharide-stimulated BV2 microglia. It also reduced endothelial PECAM-1 upregulation while restoring occludin and partially recovering claudin-5, accompanied by reduced phosphorylation of STAT3 and p38. CONCLUSIONS: SM/PN provides early neurovascular protection through non-angiogenic collateral enhancement, microglial modulation, and blood-brain barrier stabilization. This integrated mechanism distinguishes SM/PN from conventional pro-collateral or angiogenic strategies and supports its potential as an adjunctive therapy for acute ischemic stroke, especially for patients who cannot undergo reperfusion.