Astrocytic p75(NTR) expression provoked by ischemic stroke exacerbates the blood-brain barrier disruption

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 up-regulated p75(NTR). Genetic p75(NTR) knockdown (p75(NTR+/-)) 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-kappa B and HIF-1 alpha 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.