The disruption of the blood-brain barrier (BBB) plays a critical role in the pathology of ischemic stroke. p75 neurotrophin receptor (p75 NTR ) contributes to the disruption of the blood-retinal barrier in retinal ischemia. However, whether p75 NTR influences the BBB permeability after acute cerebral ischemia remains unknown. The present study investigated the role and underlying mechanism of p75 NTR on BBB integrity in an ischemic stroke mouse model, middle cerebral artery occlusion (MCAO). After 24 h of MCAO, astrocytes and endothelial cells in the infarct-affected brain area upregulated p75 NTR . Genetic p75 NTR knockdown (p75 NTR+/À ) or pharmacological inhibition of p75 NTR using LM11A-31, a selective inhibitor of p75 NTR , both attenuated brain damage and BBB leakage in MCAO mice. Astrocyte-specific conditional knockdown of p75 NTR mediated with an adeno-associated virus significantly ameliorated BBB disruption and brain tissue damage, as well as the neurological functions after stroke. Further molecular biological examinations indicated that astrocytic p75 NTR activated NF-κB and HIF-1α signals, which upregulated the expression of MMP-9 and vascular endothelial growth factor (VEGF), subsequently leading to tight junction degradation after ischemia. As a result, increased leukocyte infiltration and microglia activation exacerbated brain injury after stroke. Overall, our results provide novel insight into the role of astrocytic p75 NTR in BBB disruption after acute cerebral ischemia. The p75 NTR may therefore be a potential therapeutic target for the treatment of ischemic stroke.astrocyte, blood-brain barrier, ischemic stroke, p75 NTR , tight junction proteins | INTRODUCTIONIschemic stroke is a leading cause of mortality and long-term disability worldwide (Matsumoto et al., 2020). It constitutes a major public health burden, yet current therapeutic interventions are limited (Pirson et al., 2020). Thus, there is an urgent need for investigating the mechanism of stroke-induced ischemic injury to find potential pharmacological targets of the disease.Blood-brain barrier (BBB) breakdown is a hallmark of ischemic stroke, which contributes to the brain pathology (Abdullahi et al., 2018;Kassner & Merali, 2015).Therefore, protecting the BBB may be a therapeutic strategy for alleviating brain ischemia injury. The BBB is composed of endothelial cells lining the cerebral vasculature, pericytes, and astrocytic end-feet. The static barrier function of the BBB mainly dependents on endothelial cells and the tight junctions, which restricts paracellular permeability. BBB disruption leads to