scholarly journals Valproate Sodium Protects Blood Brain Barrier Integrity in Intracerebral Hemorrhage Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Wei Zhao ◽  
Lianhua Zhao ◽  
Zaiyu Guo ◽  
Yanwei Hou ◽  
Jiafeng Jiang ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Brain Barrier ◽  
Valproate Sodium ◽  
Therapeutic Method ◽  
Neurological Outcomes ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Matrix Metalloproteinases 9

Valproate sodium (VPA) is a traditional antiepileptic drug with a neuroprotective role in cerebrovascular disease. After intracerebral hemorrhage (ICH), mechanical compression by hematoma, neuroinflammation, oxidative stress, and cytotoxicity of hematoma lysates caused the destruction of the blood brain barrier (BBB). Targeting BBB is a major therapeutic method for patients with ICH. The purpose of the present study was to explore the role of VPA in preserving BBB integrity in the ICH model and investigate the underlying molecular mechanisms. One hundred and thirty-six adult male CD1 mice were randomly divided into five groups in the study. Mice subjected to ICH were administered intraperitoneally with VPA at 3, 24, and 48 h post-ICH, respectively. Neurobehavioral assessments, BBB permeability, Evans blue fluorescence, hematoma volume, and protein expression were evaluated. The administration of VPA reduced BBB permeability and improved the neurobehavior significantly post-ICH. VPA administration significantly decreased the expression of phosphorylated nuclear factor-kappa B (p-NFκB), matrix metalloproteinases 9 (MMP9), tumor necrosis factorα (TNFα), and interleukin-6 (IL-6), while it enhanced the expression of claudin 5 and occludin in the brain. In conclusion, VPA administration maintained the integrity of BBB after experimental ICH, thus reducing brain edema and improving the neurological outcomes. Therefore, VPA administration might be a new therapeutic method to protect BBB integrity for patients with ICH.

scholarly journals Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qianshuo Liu ◽  
Xiaobai Liu ◽  
Defeng Zhao ◽  
Xuelei Ruan ◽  
Rui Su ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Vital Role ◽  
Brain Barrier ◽  
Blood Brain ◽  
Bbb Permeability ◽  
Novel Target ◽  
And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

scholarly journals Nicotinamide Mononucleotide Adenylyltransferase 1 Regulates Cerebral Ischemia-Induced Blood–Brain Barrier Disruption Through NAD+/SIRT1 Signaling Pathway

2021 ◽  
Author(s):  
Yang Zhang ◽  
Xun Guo ◽  
Zhifeng Peng ◽  
Chang Liu ◽  
Lili Ren ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Sirtuin 1 ◽  
Brain Barrier ◽  
Blood Brain ◽  
Nicotinamide Mononucleotide ◽  
Nicotinamide Mononucleotide Adenylyltransferase ◽  
Bbb Permeability

Abstract The molecular mechanisms of blood–brain barrier (BBB) disruption in the early stage after ischemic stroke are poorly understood. In the present study, we investigated the potential role of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) in ischemia-induced BBB damage using an animal middle cerebral artery occlusion (MCAO) model of ischemic stroke. Recombinant human NMNAT1 (rh-NMNAT1) was administered intranasally and Sirtuin 1 (SIRT1) siRNA was administered by intracerebroventricular injection. Our results indicated that rh-NMNAT1 reduced infarct volume, improved functional outcome and decreased BBB permeability in mice after ischemic stroke. Furthermore, rh-NMNAT1 prevented the loss of tight junction proteins (occludin and claudin-5) and reduced cell apoptosis in ischemic microvessels. NMNAT1-mediated BBB permeability was correlated with the elevation of nicotinamide adenine dinucleotide (NAD+)/NADH and SIRT1 level in ischemic microvessels. In addition, rh-NMNAT1 treatment significantly decreased the levels of acetylated nuclear factor-κB, acetylated p53 and matrix metalloproteinase-9 in ischemic microvessels. Moreover, the protective effects of rh-NMNAT1 were reversed by SIRT1 siRNA. In conclusion, these findings indicate that NMNAT1 protects BBB after ischemic stroke in mice which was in part via the NAD+/SIRT1 signaling pathway in brain microvascular endothelial cells. NMNAT1 may be a novel potential therapeutic target for reducing BBB disruption after ischemic stroke.

Gliotransmitters and cytokines in the control of blood-brain barrier permeability

2018 ◽  
Vol 29 (5) ◽  
pp. 567-591 ◽  
Author(s):  
Elena D. Osipova ◽  
Oxana V. Semyachkina-Glushkovskaya ◽  
Andrey V. Morgun ◽  
Natalia V. Pisareva ◽  
Natalia A. Malinovskaya ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Neurovascular Unit ◽  
Glutamate Transporters ◽  
Brain Barrier ◽  
Functional Coupling ◽  
Blood Brain ◽  
Substantial Progress ◽  
Bbb Permeability ◽  
Brain Microvessel

AbstractThe contribution of astrocytes and microglia to the regulation of neuroplasticity or neurovascular unit (NVU) is based on the coordinated secretion of gliotransmitters and cytokines and the release and uptake of metabolites. Blood-brain barrier (BBB) integrity and angiogenesis are influenced by perivascular cells contacting with the abluminal side of brain microvessel endothelial cells (pericytes, astrocytes) or by immune cells existing (microglia) or invading the NVU (macrophages) under pathologic conditions. The release of gliotransmitters or cytokines by activated astroglial and microglial cells is provided by distinct mechanisms, affects intercellular communication, and results in the establishment of microenvironment controlling BBB permeability and neuroinflammation. Glial glutamate transporters and connexin and pannexin hemichannels working in the tight functional coupling with the purinergic system serve as promising molecular targets for manipulating the intercellular communications that control BBB permeability in brain pathologies associated with excessive angiogenesis, cerebrovascular remodeling, and BBB-mediated neuroinflammation. Substantial progress in deciphering the molecular mechanisms underlying the (patho)physiology of perivascular glia provides promising approaches to novel clinically relevant therapies for brain disorders. The present review summarizes the current understandings on the secretory machinery expressed in glial cells (glutamate transporters, connexin and pannexin hemichannels, exocytosis mechanisms, membrane-derived microvesicles, and inflammasomes) and the role of secreted gliotransmitters and cytokines in the regulation of NVU and BBB permeability in (patho)physiologic conditions.

Abstract 2618: Blood Brain Barrier Permeability Increases in Intracerebral Hemorrhage do not Predict Perihematoma Edema Growth

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Sana Vahidy ◽  
Rebecca McCourt ◽  
E B Gould ◽  
Deepak Gupta ◽  
Umair Mushtaq ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Blood Brain Barrier ◽  
Symptom Onset ◽  
Volume Growth ◽  
Brain Barrier ◽  
Hematoma Expansion ◽  
Hematoma Volume ◽  
Edema Volume ◽  
Blood Brain ◽  
Bbb Permeability

Background: The etiology of edema in intracerebral hemorrhage (ICH) is controversial. Most studies are consistent with a vasogenic rather than cytotoxic pathophysiology. It is unknown, however, if the blood brain barrier (BBB) is compromised in ICH and to what extent this is related to either hematoma expansion or edema development. BBB permeability was measured with CT perfusion (CTP) in ICH patients. We hypothesized that perihematoma edema volume and growth would be associated with elevated permeability. We also tested the hypothesis that elevated PS would be associated with hematoma growth. Methods: Patients with ICH were assessed with CTP within 24 hours of symptom onset. Maps of BBB permeability-surface area product (PS), a measure of extravascular contrast leakage rate, were calculated from CTP source images. Mean PS was measured in regions of interest (ROI) defining the hematoma, a 1cm radial peri-hematoma region, and ipsilateral and contralateral hemispheres. The total perihematoma edema volume was also measured objectively, based on Hounsfield unit thresholds of ≤24 at the time of the CTP and 24 h later. Results: PS maps were generated in 50 patients (13 female). The median (IQR) time from symptom onset to CTP was 8.2 (12.4) h. Median hematoma volume at baseline was 16.4 (28.2) mL. Mean PS was higher in the hematoma (3.24±1.34 ml/100g/min), relative to contralateral regions (1.82±0.84 ml/100g/min, P<0.0001). PS was also elevated in the perihematoma region (2.50±1.13 ml/100g/min vs. 1.78±0.81 ml/100g/min, P<0.0001). Ipsilateral hemispheric PS was higher (2.08±1.00 ml/100g/min) than in the contralateral hemisphere (1.82±0.82 ml/100g/min, P=0.002). Acute hematoma volume did not predict PS elevations in the hematoma itself (R=0.004 [-0.01, 0.02], P=0.07) or perihematoma region (R=0.002 [-0.01, 0.01], P=0.74). Linear regression indicated that acute edema volume was not predicted by perihematoma PS (R=-0.68 [-2.15, 0.79], P=0.36). Follow-up CT scans at a median of 22.5 (IQR=2.4) h after the baseline CTP were obtained in 43 patients. Median perihematoma edema volume increased from 1.9 (2.6) mL to 3.2 (5.0) mL (P=<0.0001). This edema volume growth was not predicted by the acute perihematoma PS (R=0.03 [-1.62, 1.68], P=0.98). Significant hematoma expansion (>6 ml) was seen in 5 patients. There was a non-significant trend to higher median hematoma PS values in these 5 patients (3.7 (1.9) vs. 2.7 (1.7) in those with stable hematoma volumes, P=0.09). Conclusions: Small elevations in BBB permeability in and around the hematoma are common in ICH and do not appear to be related to hematoma volume. Neither acute perihematoma edema volume or edema growth is explained by BBB compromise. A relationship between elevated intra-hematoma permeability and significant hematoma expansion cannot be excluded and should be explored in a larger ICH population.

scholarly journals Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wei He ◽  
Qin Lu ◽  
Prativa Sherchan ◽  
Lei Huang ◽  
Xin Hu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Intracerebral Hemorrhage ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Neurological Function ◽  
Brain Barrier ◽  
Secondary Brain Injury ◽  
Blood Brain ◽  
Bbb Permeability

Abstract Background Destruction of blood–brain barrier (BBB) ​​is one of the main mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Frizzled-7 is a key protein expressed on the surface of endothelial cells that controls vascular permeability through the Wnt-canonical pathway involving WNT1-inducible signaling pathway protein 1 (WISPI). This study aimed to investigate the role of Frizzled-7 signaling in BBB preservation after ICH in mice. Methods Adult CD1 mice were subjected to sham surgery or collagenase-induced ICH. Frizzled-7 activation or knockdown was performed by administration of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) by intracerebroventricular injection at 48 h before ICH induction. WISP1 activation or WISP1 knockdown was performed to evaluate the underlying signaling pathway. Post-ICH assessments included neurobehavior, brain edema, BBB permeability, hemoglobin level, western blot and immunofluorescence. Results The brain expressions of Frizzled-7 and WISP1 significantly increased post-ICH. Frizzled-7 was expressed in endothelial cells, astrocytes, and neurons after ICH. Activation of Frizzled-7 significantly improved neurological function, reduced brain water content and attenuated BBB permeability to large molecular weight substances after ICH. Whereas, knockdown of Frizzled-7 worsened neurological function and brain edema after ICH. Activation of Frizzled-7 significantly increased the expressions of Dvl, β-Catenin, WISP1, VE-Cadherin, Claudin-5, ZO-1 and reduced the expression of phospho-β-Catenin. WISP1 knockdown abolished the effects of Frizzled-7 activation on the expressions of VE-Cadherin, Claudin-5 and ZO-1 at 24 h after ICH. Conclusions Frizzled-7 activation potentially attenuated BBB permeability and improved neurological deficits after ICH through Dvl​​/β-Catenin/WISP1 pathway. Frizzled-7 may be a potential target for the development of ICH therapeutic drugs.

scholarly journals Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

2019 ◽  
Vol 20 (3) ◽  
pp. 571 ◽  
Author(s):  
Shotaro Michinaga ◽  
Yutaka Koyama
Keyword(s):  
Brain Damage ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Secondary Damage ◽  
The Central Nervous System ◽  
Bbb Permeability ◽  
Novel Therapeutic Strategies ◽  
Glial Derived Neurotrophic Factor ◽  
Endothelial Growth Factors

The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.

scholarly journals Early Appearance of Activated Matrix Metalloproteinase-9 after Focal Cerebral Ischemia in Mice: A Possible Role in Blood—Brain Barrier Dysfunction

1999 ◽  
Vol 19 (9) ◽  
pp. 1020-1028 ◽  
Author(s):  
Yvan Gasche ◽  
Miki Fujimura ◽  
Yuiko Morita-Fujimura ◽  
Jean-Christophe Copin ◽  
Makoto Kawase ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Blood Brain Barrier ◽  
Focal Cerebral Ischemia ◽  
Vasogenic Edema ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Brain Barrier ◽  
Critical Event ◽  
Secondary Brain Injury ◽  
Blood Brain ◽  
Bbb Permeability

During cerebral ischemia blood–brain barrier (BBB) disruption is a critical event leading to vasogenic edema and secondary brain injury. Gelatinases A and B are matrix metalloproteinases (MMP) able to open the BBB. The current study analyzes by zymography the early gelatinases expression and activation during permanent ischemia in mice (n = 15). ProMMP-9 expression was significantly ( P < 0.001) increased in ischemic regions compared with corresponding contralateral regions after 2 hours of ischemia (mean 694.7 arbitrary units [AU], SD ± 238.4 versus mean 107.6 AU, SD ± 15.6) and remained elevated until 24 hours (mean 745,7 AU, SD ± 157.4). Moreover, activated MMP-9 was observed 4 hours after the initiation of ischemia. At the same time as the appearance of activated MMP-9, we detected by the Evan's blue extravasation method a clear increase of BBB permeability, Tissue inhibitor of metalloproteinase-1 was not modified during permanent ischemia at any time. The ProMMP-2 was significantly ( P < 0.05) increased only after 24 hours of permanent ischemia (mean 213.2 AU, SD ± 60.6 versus mean 94.6 AU, SD ± 13.3), and no activated form was observed. The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that MMP-9 may play an active role in early vasogenic edema development after stroke.

scholarly journals Glycocalyx degradation leads to blood–brain barrier dysfunction and brain edema after asphyxia cardiac arrest in rats

2017 ◽  
Vol 38 (11) ◽  
pp. 1979-1992 ◽  
Author(s):  
Jiajia Zhu ◽  
Xing Li ◽  
Jia Yin ◽  
Yafang Hu ◽  
Yong Gu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Survival Rate ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Neurologic Outcome ◽  
Endothelial Glycocalyx ◽  
Inflammatory Factors ◽  
Blood Brain ◽  
Bbb Permeability

The role of glycocalyx in blood–brain barrier (BBB) integrity and brain damage is poorly understood. Our study aimed to investigate the impacts of endothelial glycocalyx on BBB function in a rat model of cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Male Sprague-Dawley rats subjected to 8-min asphyxia CA/CPR. Compared to controls, glycocalyx was mildly injured by CA, severely disrupted by hyaluronidase (HAase) with CA, and mitigated by hydrocortisone (HC) with CA. More importantly, the disruption of glycocalyx caused by HAase treatment was associated with higher BBB permeability and aggravated brain edema at 24 h after return of spontaneous circulation, as well as lower survival rate and poorer neurologic outcome at seventh day. Reversely, less degradation of glycocalyx by HC treatment was accompanied by higher seven-day survival rate and better neurologic outcome. Mechanistically, HAase treatment further increased CA/CPR-induced activation of glia cells and expression of inflammatory factors, whereas HC decreased them in the brain cortex and hippocampus. Glycocalyx degradation results in BBB leakage, brain edema, and deteriorates neurologic outcome after asphyxia CA/CPR in rats. Preservation of glycocalyx by HC could improve neurologic outcome and reduce BBB permeability, apparently through reduced gene transcription-protein synthesis and inflammation.

scholarly journals Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects

2021 ◽  
Vol 22 (18) ◽  
pp. 10045
Author(s):  
Phuong Thao Do ◽  
Chung-Che Wu ◽  
Yung-Hsiao Chiang ◽  
Chaur-Jong Hu ◽  
Kai-Yun Chen
Keyword(s):  
Stem Cells ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Time Window ◽  
Brain Regions ◽  
Brain Barrier ◽  
Therapeutic Effects ◽  
Pathophysiological Mechanism ◽  
Cell Based Therapy ◽  
Blood Brain

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood–brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

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