Astrocytic p75^NTR 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 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

MicroRNA152-3p Protects Against Ischemia/Reperfusion-Induced Bbb Destruction Possibly Targeting the MAP3K2/JNK/c-Jun Pathway

“…Recently, the beneficial effect of miR-152-3p during brain ischemia has been demonstrated, but its potential impact on ischemia-induced BBB breakdown has remained elusive. BBB disruption following acute ischemic stroke is the primary cause of brain edema and hemorrhagic transformation, which contributes to worse stroke outcome[ 26 , 27 ]. Studies have increasingly suggested that BBB protection is important for ischemic stroke therapy[ 28 ].…”

Chemogenetic activation of astrocytic Gi signaling promotes spinogenesis and motor functional recovery after stroke

“…Sham‐control mice were treated identically except for Rose Bengal administration and cold light illumination. The infarction was assessed using laser speckle contrast imaging (moorFLPI‐2, Moor Instruments, UK) and 2,3,5‐triphenyltetrazolium chloride (TTC) staining (Sigma; 2% in saline) (Qin et al, 2022).…”

Lost in Translation: Neurotrophins Biology and Function in the Neurovascular Unit

“…Moreover, treatment improved brain atrophy and neurodegeneration. It has been reported that treating animals by using LM11A-31 or knocking down p75 NTR mitigates brain injury and BBB disruption via suppressing NF-κB p-65 and HIF-1α signaling following middle cerebral artery occlusion (Qin and others 2022). In another study, administration of 3% ethanol containing drinking water for 5 d following a photothrombotic stroke in mice downregulated the expression of p75 NTR and increased neuronal viability (Khirug and others 2021).…”

“…The astrocytic activation of NF-κB triggered by p75ICD may manifest with enhanced transcription of MMPs and VEGF. This results in tight junction protein degradations, endothelial barrier leakage, and immune cell infiltration (Qin and others 2022). This is aggravated with endothelial p75 NTR -induced activation of RhoA/MAPK (Elshaer and others 2019).…”