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.

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 Endothelium-targeted deletion of the miR-15a/16-1 cluster ameliorates blood-brain barrier dysfunction in ischemic stroke

2020 ◽  
Vol 13 (626) ◽  
pp. eaay5686 ◽  
Author(s):  
Feifei Ma ◽  
Ping Sun ◽  
Xuejing Zhang ◽  
Milton H. Hamblin ◽  
Ke-Jie Yin
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Neuronal Loss ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Protein Abundance ◽  
Barrier Dysfunction ◽  
Small Noncoding Rnas ◽  
Blood Brain

The blood-brain barrier (BBB) maintains a stable brain microenvironment. Breakdown of BBB integrity during cerebral ischemia initiates a devastating cascade of events that eventually leads to neuronal loss. MicroRNAs are small noncoding RNAs that suppress protein expression, and we previously showed that the miR-15a/16-1 cluster is involved in the pathogenesis of ischemic brain injury. Here, we demonstrated that when subjected to experimentally induced stroke, mice with an endothelial cell (EC)–selective deletion of miR-15a/16-1 had smaller brain infarcts, reduced BBB leakage, and decreased infiltration of peripheral immune cells. These mice also showed reduced infiltration of proinflammatory M1-type microglia/macrophage in the peri-infarct area without changes in the number of resolving M2-type cells. Stroke decreases claudin-5 abundance, and we found that EC-selective miR-15a/16-1 deletion enhanced claudin-5 mRNA and protein abundance in ischemic mouse brains. In cultured mouse brain microvascular ECs (mBMECs), the miR-15a/16-1 cluster directly bound to the 3′ untranslated region (3′UTR) of Claudin-5, and lentivirus-mediated ablation of miR-15a/16-1 diminished oxygen-glucose deprivation (OGD)–induced down-regulation of claudin-5 mRNA and protein abundance and endothelial barrier dysfunction. These findings suggest that genetic deletion of endothelial miR-15a/16-1 suppresses BBB pathologies after ischemic stroke. Elucidating the molecular mechanisms of miR-15a/16-1–mediated BBB dysfunction may enable the discovery of new therapies for ischemic stroke.

scholarly journals Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Zi-xian Chen ◽  
Qing-qing Xu ◽  
Chun-shuo Shan ◽  
Yi-hua Shi ◽  
Yong Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Ischemic Injury ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Glycoprotein P ◽  
Blood Brain ◽  
Cerebral Ischemic Injury ◽  
Bbb Permeability ◽  
Cerebral Ischemic

Borneol, a natural product in the Asteraceae family, is widely used as an upper ushering drug for various brain diseases in many Chinese herbal formulae. The blood-brain barrier (BBB) plays an essential role in maintaining a stable homeostatic environment, while BBB destruction and the increasing BBB permeability are common pathological processes in many serious central nervous system (CNS) diseases, which is especially an essential pathological basis of cerebral ischemic injury. Here, we aimed to conduct a systematic review to assess preclinical evidence of borneol for experimental ischemic stroke as well as investigate in the possible neuroprotective mechanisms, which mainly focused on regulating the permeability of BBB. Seven databases were searched from their inception to July 2018. The studies of borneol for ischemic stroke in animal models were included. RevMan 5.3 was applied for data analysis. Fifteen studies investigated the effects of borneol in experimental ischemic stroke involving 308 animals were ultimately identified. The present study showed that the administration of borneol exerted a significant decrease of BBB permeability during cerebral ischemic injury according to brain Evans blue content and brain water content compared with controls (P<0.01). In addition, borneol could improve neurological function scores (NFS) and cerebral infarction area. Thus, borneol may be a promising neuroprotective agent for cerebral ischemic injury, largely through alleviating the BBB disruption, reducing oxidative reactions, inhibiting the occurrence of inflammation, inhibiting apoptosis, and improving the activity of lactate dehydrogenase (LDH) as well as P-glycoprotein (P-GP) and NO signaling pathway.

Abstract WP137: Time-Course Characterization of Blood-Brain Barrier Disruption in Secondary Thalamic Injury After Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Zhijuan Cao ◽  
Sean Harvey ◽  
Arjun Pendharkar ◽  
Terrance Chiang ◽  
Michelle Cheng ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Stroke Recovery ◽  
Brain Barrier ◽  
Tube Length ◽  
Left Middle Cerebral Artery ◽  
Vessel Morphology ◽  
Blood Brain ◽  
Branching Points ◽  
Bbb Permeability

Introduction: A secondary degenerative injury occurs in the thalamus after primary cortical ischemic stroke. This secondary thalamic injury progresses long-term and is associated with somatosensory dysfunctions. Blood-brain barrier (BBB) disruption is one of the feature pathological changes in primary ischemic stroke, but whether BBB disruption happens in the secondary thalamic injury is unclear. In this study, we aim to investigate the BBB changes during the development of secondary thalamic injury after stroke. Methods: Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery on male C57BL6J mice (12-15 weeks). BBB permeability was assessed by Biocytin-TMR (869 Da, 1mg/mL) at post-stroke days (PD) 1, 3, 7, 14, 28, 56, and 84. Immunostainings of CD68 (inflammation) and CD31 (vascular morphology) were performed. Brain sections were imaged with Confocal LSM800 and quantified by NIH ImageJ and Wimasis Image Analysis. BBB permeability related genes were quantified by real-time PCR among naïve, PD7 and PD28. Results: In ipsilesional thalamus (iTH), the Biocytin-TMR was detected as early as PD3 in the secondary thalamic injury area and persisted until at least PD84. The fluorescence intensity of Biocytin-TMR significantly increased during PD28-84 and peaked at PD56, suggesting the BBB is chronically disrupted in iTH. Compared to naïve animals, stroke animals exhibited significant increase in tube length, total number of tubes and total number of branching points at PD56 and PD84. mRNA expression of ZO-2 significantly down-regulated at PD7 and returned to baseline levels by PD28. mRNA of Angiopoietin-1 ( Ang-1 ), VEGFa and Adam10 were significantly increased at PD28. Conclusion: Our data demonstrate that the BBB disruption begins early at PD3 and continues to progress until PD84 in the secondary degenerative thalamus. This BBB disruption is accompanied by changes in blood vessel morphology and permeability related genes. Current studies are examining the expression of key genes at PD56 using qPCR and immunohistochemistry. Our results will elucidate the cellular and molecular changes of BBB disruption involved in thalamic injury, which will provide potential targets for enhancing stroke recovery.

scholarly journals Caveolae-Mediated Endothelial Transcytosis across the Blood-Brain Barrier in Acute Ischemic Stroke

2021 ◽  
Vol 10 (17) ◽  
pp. 3795
Author(s):  
Min Zhou ◽  
Samuel X. Shi ◽  
Ning Liu ◽  
Yinghua Jiang ◽  
Mardeen S. Karim ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Hemorrhagic Transformation ◽  
Brain Barrier ◽  
Blood Brain ◽  
Entry Points

Blood-brain barrier (BBB) disruption following ischemic stroke (IS) contributes to hemorrhagic transformation, brain edema, increased neural dysfunction, secondary injury, and mortality. Brain endothelial cells form a para and transcellular barrier to most blood-borne solutes via tight junctions (TJs) and rare transcytotic vesicles. The prevailing view attributes the destruction of TJs to the resulting BBB damage following IS. Recent studies define a stepwise impairment of the transcellular barrier followed by the paracellular barrier which accounts for the BBB leakage in IS. The increased endothelial transcytosis that has been proven to be caveolae-mediated, precedes and is independent of TJs disintegration. Thus, our understanding of post stroke BBB deficits needs to be revised. These recent findings could provide a conceptual basis for the development of alternative treatment strategies. Presently, our concept of how BBB endothelial transcytosis develops is incomplete, and treatment options remain limited. This review summarizes the cellular structure and biological classification of endothelial transcytosis at the BBB and reviews related molecular mechanisms. Meanwhile, relevant transcytosis-targeted therapeutic strategies for IS and research entry points are prospected.

scholarly journals Temporal analysis of blood–brain barrier disruption and cerebrospinal fluid matrix metalloproteinases in rhesus monkeys subjected to transient ischemic stroke

2016 ◽  
Vol 37 (8) ◽  
pp. 2963-2974 ◽  
Author(s):  
Yingqian Zhang ◽  
Feng Fan ◽  
Guojun Zeng ◽  
Linlin Zhou ◽  
Yinbing Zhang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Dynamic Change ◽  
Fold Increase ◽  
Temporal Analysis ◽  
Brain Barrier ◽  
Infarction Size ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Bbb Permeability

Blood–brain barrier (BBB) disruption plays an important role in pathophysiological progress of ischemic stroke. However, our knowledge of the dynamic change of BBB permeability and its mechanism remains limited. In the current study, we used a non-human primate (NHP) MCAO model and a serial CSF sampling method that allowed us to determine the dynamic change of BBB permeability by calculating the CSF/serum albumin ratio (AR). We showed that AR increased rapidly and significantly after ischemia, and the fold increase of AR is highly correlated with the infarction size during the subacute phase. Moreover, we determined the temporal change of MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, MMP-13, TIMP-1, and TIMP-2 in CSF and serum. Each MMP and TIMP showed different change patterns when comparing their values in CSF and serum. Based on the longitudinal dataset, we showed that the fold increase of MMP-9 in serum and CSF are both correlated to infarction size. Among the measured MMPs and TIMPs, only MMP-2, MMP-13, and TIMP-2 in CSF correlated with AR to some extent. Our data suggest there is no single MMP or TIMP fully responsible for BBB breakdown, which is regulated by a much more complicated signal network and further investigations of the mechanisms are needed.

DCE-MRI blood–brain barrier assessment in acute ischemic stroke

Neurology ◽  
2016 ◽  
Vol 88 (5) ◽  
pp. 433-440 ◽  
Author(s):  
Kersten Villringer ◽  
Borja E. Sanz Cuesta ◽  
Ann-Christin Ostwaldt ◽  
Ulrike Grittner ◽  
Peter Brunecker ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Symptom Onset ◽  
Brain Barrier ◽  
Stroke Patients ◽  
Dce Mri ◽  
Link Type ◽  
Blood Brain ◽  
Bbb Permeability

Objective:To quantitatively evaluate blood–brain barrier changes in ischemic stroke patients using dynamic contrast-enhanced (DCE) MRI.Methods:We examined 54 stroke patients (clinicaltrials.govNCT00715533, NCT02077582) in a 3T MRI scanner within 48 hours after symptom onset. Twenty-eight patients had a follow-up examination on day 5–7. DCE T1 mapping and Patlak analysis were employed to assess BBB permeability changes.Results:Median stroke Ktrans values (0.7 × 10−3 min−1 [interquartile range (IQR) 0.4–1.8] × 10−3 min−1) were more than 3-fold higher compared to median mirror Ktrans values (0.2 × 10−3 min−1, IQR 0.1–0.7 × 10−3 min−1, p < 0.001) and further increased at follow-up (n = 28, 2.3 × 10−3 min−1, IQR 0.8–4.6 × 10−3 min−1, p < 0.001). By contrast, mirror Ktrans values decreased over time with a clear interaction of timepoint and stroke/mirror side (p < 0.001). Median stroke Ktrans values were 2.5 times lower than in hemorrhagic transformed regions (0.7 vs 1.8 × 10−3 min−1; p = 0.055). There was no association between stroke Ktrans values and the delay from symptom onset to baseline examination, age, and presence of hyperintense acute reperfusion marker.Conclusion:BBB in acute stroke patients can be successfully assessed quantitatively. The decrease of BBB permeability in unaffected regions at follow-up may be an indicator of global BBB leakage even in vessel territories remote from the index infarct.

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.

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.

scholarly journals Increase in Blood-Brain Barrier (BBB) Permeability Is Regulated by MMP3 via the ERK Signaling Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Qin Zhang ◽  
Mei Zheng ◽  
Cristian E. Betancourt ◽  
Lifeng Liu ◽  
Albert Sitikov ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Erk Signaling ◽  
Anesthesia Induction ◽  
Matrix Metalloproteinase 3 ◽  
Blood Brain ◽  
Bbb Permeability

Background. The blood-brain barrier (BBB) regulates the exchange of molecules between the brain and peripheral blood and is composed primarily of microvascular endothelial cells (BMVECs), which form the lining of cerebral blood vessels and are linked via tight junctions (TJs). The BBB is regulated by components of the extracellular matrix (ECM), and matrix metalloproteinase 3 (MMP3) remodels the ECM’s basal lamina, which forms part of the BBB. Oxidative stress is implicated in activation of MMPs and impaired BBB. Thus, we investigated whether MMP3 modulates BBB permeability. Methods. Experiments included in vivo assessments of isoflurane anesthesia and dye extravasation from brain in wild-type (WT) and MMP3-deficient (MMP3-KO) mice, as well as in vitro assessments of the integrity of monolayers of WT and MMP3-KO BMVECs and the expression of junction proteins. Results. Compared to WT mice, measurements of isoflurane usage and anesthesia induction time were higher in MMP3-KO mice and lower in WT that had been treated with MMP3 (WT+MMP3), while anesthesia emergence times were shorter in MMP3-KO mice and longer in WT+MMP3 mice than in WT. Extravasation of systemically administered dyes was also lower in MMP3-KO mouse brains and higher in WT+MMP3 mouse brains, than in the brains of WT mice. The results from both TEER and Transwell assays indicated that MMP3 deficiency (or inhibition) increased, while MMP3 upregulation reduced barrier integrity in either BMVEC or the coculture. MMP3 deficiency also increased the abundance of TJs and VE-cadherin proteins in BMVECs, and the protein abundance declined when MMP3 activity was upregulated in BMVECs, but not when the cells were treated with an inhibitor of extracellular signal related-kinase (ERK). Conclusion. MMP3 increases BBB permeability following the administration of isoflurane by upregulating the ERK signaling pathway, which subsequently reduces TJ and VE-cadherin proteins in BMVECs.

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