Astragaloside IV confers vascular protection after traumatic brain injury through an Nrf2-dependent mechanism involving VWF.

Traumatic brain injury (TBI) is a major cause of neurological disability worldwide, yet effective pharmacological therapies remain limited. Astragaloside IV (AS-IV), a major active component derived from Astragalus membranaceus, exhibits neuroprotective properties, but the mechanisms underlying its effects after TBI remain unclear. In this study, we investigated the role of nuclear factor erythroid 2 related factor 2 (Nrf2) signaling in AS-IV mediated neuroprotection using a mouse TBI model. AS-IV significantly improved neurological function and attenuated neuronal injury after TBI, accompanied by enhanced Nrf2 nuclear translocation. The anti-inflammatory and antioxidant effects of AS-IV were partially attenuated in Nrf2-deficient mice, whereas its protective effects on brain edema, blood-brain barrier integrity, and cerebral blood flow were nearly completely abolished. Further analyses identified von Willebrand factor (VWF) as a vascular related gene associated with Nrf2 dependent vascular protection following TBI. These findings indicate that the vascular protective effects of AS-IV after TBI rely on Nrf2 signaling, with VWF potentially contributing to this process.