MicroRNA-126-3p attenuates blood-brain barrier disruption, cerebral edema and neuronal injury following intracerebral hemorrhage by regulating PIK3R2 and Akt.

MiR-126, a microRNA implicated in blood vessel integrity, angiogenesis and vascular inflammation, is markedly decreased in the sera of patients with intracerebral hemorrhage (ICH). The current study aims to evaluate the potential therapeutic effect of miR-126-3p on brain injuries in a rat model of collagenase-induced ICH. Intracerebroventricular administration of a miR-126-3p mimic significantly alleviated behavioral defects 24 h after ICH, as examined by paw placement and corner tests. ICH led to increased blood-brain barrier (BBB) permeability and cerebral edema, both of which were attenuated by miR-126-3p mimic. Treatment with miR-126-3p mimic reduced the numbers of myeloperoxidase (MPO)-positive, OX42-positive, Fluoro Jade B (FJB)-positive and NEUN/TUNEL double-positive cells around the hematoma, implying that miR-126-3p inhibited neutrophil infiltration, microglial activation and neuronal apoptosis following hemorrhage. In addition, miR-126-3p mimic suppressed the upregulation of phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) in the perihematomal area and maintained the activation of Akt. Furthermore, in vitro assays confirmed upregulation of PIK3R2 upon knockdown of miR-126-3p in rat brain microvascular endothelial cells (BMECs), and silencing of miR-126-3p resulted in impaired BMEC barrier permeability and reversed vascular endothelial growth factor (VEGF)- and angiopoietin-1 (Ang-1)-induced activation of Akt and inhibition of BMEC apoptosis. In summary, our results suggest that exogenous miR-126-3p may alleviate BBB disruption, cerebral edema and neuronal injury following ICH by targeting PIK3R2 and the Akt signaling pathway in brain vascular endothelium.

Xi T ，Jin F ，Zhu Y ，Wang J ，Tang L ，Wang Y ，Liebeskind DS ，He Z ... -  《-》

miR-27a-3p protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by targeting endothelial aquaporin-11.

Previous studies have reported that miR-27a-3p is down-regulated in the serum of patients with intracerebral hemorrhage (ICH), but the implication of miR-27a-3p down-regulation in post-ICH complications remains elusive. Here we verified miR-27a-3p levels in the serum of ICH patients by real-time PCR and observed that miR-27a-3p is also significantly reduced in the serum of these patients. We then further investigated the effect of miR-27a-3p on post-ICH complications by intraventricular administration of a miR-27a-3p mimic in rats with collagenase-induced ICH. We found that the hemorrhage markedly reduced miR-27a-3p levels in the hematoma, perihematomal tissue, and serum and that intracerebroventricular administration of the miR-27a-3p mimic alleviated behavioral deficits 24 h after ICH. Moreover, ICH-induced brain edema, vascular leakage, and leukocyte infiltration were also attenuated by this mimic. Of note, miR-27a-3p mimic treatment also inhibited neuronal apoptosis and microglia activation in the perihematomal zone. We further observed that the miR-27a-3p mimic suppressed the up-regulation of aquaporin-11 (AQP11) in the perihematomal area and in rat brain microvascular endothelial cells (BMECs). Moreover, miR-27a-3p down-regulation increased BMEC monolayer permeability and impaired BMEC proliferation and migration. In conclusion, miR-27a-3p down-regulation contributes to brain edema, blood-brain barrier disruption, neuron loss, and neurological deficits following ICH. We conclude that application of exogenous miR-27a-3p may protect against post-ICH complications by targeting AQP11 in the capillary endothelial cells of the brain.

Xi T ，Jin F ，Zhu Y ，Wang J ，Tang L ，Wang Y ，Liebeskind DS ，Scalzo F ，He Z ... -  《-》

MicroRNA-93 regulates the neurological function, cerebral edema and neuronal apoptosis of rats with intracerebral hemorrhage through TLR4/NF-κB signaling pathway.

Shang Y ，Dai S ，Chen X ，Wen W ，Liu X ... -  《-》

MicroRNA-23b alleviates neuroinflammation and brain injury in intracerebral hemorrhage by targeting inositol polyphosphate multikinase.

Neuroinflammation plays a critical role in the pathogenesis of intracerebral hemorrhage (ICH), contributing to detrimental brain injury and neurological function deficits. MicroRNA-23b (miR-23b) exerts anti-inflammatory effects in many diseases and is downregulated in patients with ICH. This study aimed to evaluate the involvement of miR-23b in ICH models in vivo and in vitro, using basal ganglia injection of collagenase type VII in rats and hemin stimulation for cells, respectively. Exogenous overexpression of miR-23b by transfection with lentivirus-miR-23b (LV-miR-23b) or miR-23b mimics was evaluated by RT-qPCR. In this study, we found miR-23b was downregulated in the ICH models and its overexpression effectively alleviated neurological deficits, brain edema, hematoma area, and neuronal apoptosis in ICH rats. Western blotting for neuroinflammation markers and immunofluorescence staining for microglial activation demonstrated that miR-23b could alleviate neuroinflammation in ICH in vivo. We also performed an in vitro mechanism study using BV2 microglial cells and HT22 neuronal cell lines to explore how miR-23b modulates neuroinflammation and neuronal protection after ICH. We found that miR-23b significantly decreased hemin-stimulated inflammation response in BV2 cells and attenuated co-cultured HT22 neuronal cell death. Additionally, we verified that miR-23b suppressed inflammation in BV2 cells by targeting inositol polyphosphate multikinase (IPMK) and that autophagy regulation through the Akt/mTOR pathway was involved in miR-23b-regulated inflammation after ICH. Our study illustrated that miR-23b played a protective role in ICH through inhibiting neuroinflammation by targeting IPMK; this mechanism may be related to the regulation of the Akt/mTOR autophagy pathway, making it a potential target for ICH treatment.

Hu L ，Zhang H ，Wang B ，Ao Q ，Shi J ，He Z ... -  《-》

miR-141-3p protects against blood-brain barrier disruption and brain injury after intracerebral hemorrhage by targeting ZEB2.

MicroRNAs (miRNAs) participate in the diagnosis and treatment of intracerebral hemorrhage (ICH). miR-141-3p has been widely reported to regulate neurological disorders and cerebropathy. However, the specific role of miR-141-3p in ICH has not yet been revealed. The aim of this study was exploration of the biological functions and mechanism of miR-141-3p in ICH by establishing a collagenase-induced ICH mouse model. After ICH induction, miR-141-3p mimics or miR-NC were administered into the right striatum of the model mice followed by the performance of neurological tests. After euthanasia of the mice, the injury volume, brain water content, and injury to the blood-brain barrier (BBB) were evaluated. Evans blue (EB) was used to stain the brain slices, and EB extravasation was detected to evaluate the injury to BBB. miR-141-3p expression in perihematomal edema and hematoma areas after ICH was assessed by RT-qPCR. The levels of tight junction proteins in brain tissues and human brain microvascular endothelial cells (BMECs) were evaluated by western blotting. The FITC-dextran 20 method was used to assess BMEC permeability. The binding between miR-141-3p and zinc finger E-box-binding homeobox 2 (ZEB2) was verified with a luciferase reporter assay. In this study, miR-141-3p overexpression alleviated ICH-induced brain injury and protected BBB integrity in vivo. ZEB2 was a target gene of miR-141-3p. ZEB2 overexpression promoted BBB disruption, and miR-141-3p overexpression attenuated the promoting effect exerted by ZEB2. Overall, miR-141-3p protects against BBB disruption and attenuates brain injuries induced by ICH by targeting ZEB2.

Yu M ，Tian T ，Zhang J ，Hu T ... -  《-》