The disruption of the blood–brain barrier (BBB) plays a critical role in the pathology of
ischemic stroke. p75 neurotrophin receptor (p75NTR) contributes to the disruption of
the blood-retinal barrier in retinal ischemia. However, whether p75NTR influences the
BBB permeability after acute cerebral ischemia remains unknown. The present study
investigated the role and underlying mechanism of p75NTR 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 up-regulated
p75NTR. Genetic p75NTR knockdown (p75NTR+/ ) or pharmacological inhibition of
p75NTR using LM11A-31, a selective inhibitor of p75NTR, both attenuated brain damage and BBB leakage in MCAO mice. Astrocyte-specific conditional knockdown of
p75NTR 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 p75NTR 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 p75NTR in BBB disruption after acute cerebral ischemia. The p75NTR may
therefore be a potential therapeutic target for the treatment of ischemic stroke