Astrocytic <scp>p75^NTR</scp> expression provoked by ischemic stroke exacerbates the blood–brain barrier disruption

Abstract

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-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.