scholarly journals Blood-Brain Barrier Damage in Ischemic Stroke and Its Regulation by Endothelial Mechanotransduction

2020 ◽  
Vol 11 ◽  
Author(s):  
Keqing Nian ◽  
Ian C. Harding ◽  
Ira M. Herman ◽  
Eno E. Ebong
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
The United States ◽  
Brain Barrier ◽  
Endothelial Glycocalyx ◽  
Altered Expression ◽  
Blood Brain

Ischemic stroke, a major cause of mortality in the United States, often contributes to disruption of the blood-brain barrier (BBB). The BBB along with its supportive cells, collectively referred to as the “neurovascular unit,” is the brain’s multicellular microvasculature that bi-directionally regulates the transport of blood, ions, oxygen, and cells from the circulation into the brain. It is thus vital for the maintenance of central nervous system homeostasis. BBB disruption, which is associated with the altered expression of tight junction proteins and BBB transporters, is believed to exacerbate brain injury caused by ischemic stroke and limits the therapeutic potential of current clinical therapies, such as recombinant tissue plasminogen activator. Accumulating evidence suggests that endothelial mechanobiology, the conversion of mechanical forces into biochemical signals, helps regulate function of the peripheral vasculature and may similarly maintain BBB integrity. For example, the endothelial glycocalyx (GCX), a glycoprotein-proteoglycan layer extending into the lumen of bloods vessel, is abundantly expressed on endothelial cells of the BBB and has been shown to regulate BBB permeability. In this review, we will focus on our understanding of the mechanisms underlying BBB damage after ischemic stroke, highlighting current and potential future novel pharmacological strategies for BBB protection and recovery. Finally, we will address the current knowledge of endothelial mechanotransduction in BBB maintenance, specifically focusing on a potential role of the endothelial GCX.

scholarly journals Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke

2019 ◽  
Vol 316 (2) ◽  
pp. C135-C153 ◽  
Author(s):  
Changjun Yang ◽  
Kimberly E. Hawkins ◽  
Sylvain Doré ◽  
Eduardo Candelario-Jalil
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
Neurological Dysfunction ◽  
Brain Barrier ◽  
Blood Brain

As part of the neurovascular unit, the blood-brain barrier (BBB) is a unique, dynamic regulatory boundary that limits and regulates the exchange of molecules, ions, and cells between the blood and the central nervous system. Disruption of the BBB plays an important role in the development of neurological dysfunction in ischemic stroke. Blood-borne substances and cells have restricted access to the brain due to the presence of tight junctions between the endothelial cells of the BBB. Following stroke, there is loss of BBB tight junction integrity, leading to increased paracellular permeability, which results in vasogenic edema, hemorrhagic transformation, and increased mortality. Thus, understanding principal mediators and molecular mechanisms involved in BBB disruption is critical for the development of novel therapeutics to treat ischemic stroke. This review discusses the current knowledge of how neuroinflammation contributes to BBB damage in ischemic stroke. Specifically, we provide an updated overview of the role of cytokines, chemokines, oxidative and nitrosative stress, adhesion molecules, matrix metalloproteinases, and vascular endothelial growth factor as well as the role of different cell types in the regulation of BBB permeability in ischemic stroke.

scholarly journals The Effects and Underlying Mechanisms of Cell Therapy on Blood-Brain Barrier Integrity After Ischemic Stroke

2020 ◽  
Vol 18 (12) ◽  
pp. 1213-1226
Author(s):  
Li Gao ◽  
Zhenghong Song ◽  
Jianhua Mi ◽  
Pinpin Hou ◽  
Chong Xie ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cell Therapy ◽  
Blood Brain Barrier ◽  
Current Knowledge ◽  
Brain Barrier ◽  
Neural Cells ◽  
Promising Tool ◽  
Cell Based Therapy ◽  
Blood Brain ◽  
Underlying Mechanisms

Ischemic stroke is one of the main causes of mortality and disability worldwide. However, efficient therapeutic strategies are still lacking. Stem/progenitor cell-based therapy, with its vigorous advantages, has emerged as a promising tool for the treatment of ischemic stroke. The mechanisms involve new neural cells and neuronal circuitry formation, antioxidation, inflammation alleviation, angiogenesis, and neurogenesis promotion. In the past decades, in-depth studies have suggested that cell therapy could promote vascular stabilization and decrease blood-brain barrier (BBB) leakage after ischemic stroke. However, the effects and underlying mechanisms on BBB integrity induced by the engrafted cells in ischemic stroke have not been reviewed yet. Herein, we will update the progress in research on the effects of cell therapy on BBB integrity after ischemic stroke and review the underlying mechanisms. First, we will present an overview of BBB dysfunction under the ischemic condition and cells engraftment for ischemic treatment. Then, we will summarize and discuss the current knowledge about the effects and underlying mechanisms of cell therapy on BBB integrity after ischemic stroke. In particular, we will review the most recent studies in regard to the relationship between cell therapy and BBB in tissue plasminogen activator (t-PA)-mediated therapy and diabetic stroke.

Abstract TP86: The Ischemic Blood-brain Barrier In A Dish: Use Of Patient-derived Stem Cells To Model The Response Of The Neurovascular Unit To Oxygen-glucose Deprivation Stress

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Shyanne Page ◽  
Ronak Patel ◽  
Abraham Alahmad
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Neurovascular Unit ◽  
Barrier Properties ◽  
Cell Types ◽  
Brain Barrier ◽  
Blood Brain

The blood-brain barrier (BBB) constitutes a component of the neurovascular unit formed by specialized brain microvascular endothelial cells (BMECs) surrounded by astrocytes, pericytes and neurons. During ischemic stroke injury, the BBB constitutes the first responding element resulting in the opening of the BBB and eventually neural cell death by excitotoxicity. A better understanding of the cellular mechanisms underlying the opening of the BBB during ischemic stroke is essential to identify targets to restore such barrier function after injury. Current in vitro models of the human BBB, based on primary or immortalized BMECs monocultures, display poor barrier properties but also lack one or two cellular components of the neurovascular unit.In this study, we designed an integrative in vitro model of the BBB by generating BMECs, astrocytes and neurons using patient-derived BMECs from two iPSC lines (IMR90-c4 and CTR66M). We were able to obtain all three cell types from these two cell lines. iPSC-derived BMECs showed barrier properties similar or better barrier function than hCMEC/D3 monolayer (an immortalized adult somatic BMEC). Furthermore, iPSC—derived astrocytes were capable to induce barrier properties in BMECs upon co-cultures. whereas iPSC-derived neurons were capable to form extensive and branched neurites. Upon OGD stress, iPSC-derived BMECs showed a disruption of their barrier function as early as 6 hours of OGD stress and showed a complete disruption by 24 hours. Such disruption was reversed by reoxygenation. Interestingly such barrier disruption occurs through a VEGF-independent mechanism. In the other hand, iPSC-derived neurons showed a significant decrease in cell metabolic activity preceding neurites pruning. Finally, astrocytes showed the most robust phenotype, as we noted no cell death by 24 hours OGD.In this study, we demonstrated the ability to differentiate three cell types from the same patient in two iPSC lines. We also demonstrated the ability of these cells to respond to OGD/reoxygenation stress in agreement with the current literature. We are currently investigating the molecular mechanisms by which OGD/reoxygenation drive the cellular response in these cell types.

scholarly journals Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 192 ◽  
Author(s):  
Junzhi Yang ◽  
Bianca Reilly ◽  
Thomas Davis ◽  
Patrick Ronaldson
Keyword(s):  
Blood Brain Barrier ◽  
Abc Transporters ◽  
Adverse Drug Events ◽  
Current Knowledge ◽  
Opioid Analgesic ◽  
The United States ◽  
Brain Barrier ◽  
Atp Binding ◽  
Blood Brain ◽  
Atp Binding Cassette

Opioids are highly effective analgesics that have a serious potential for adverse drug reactions and for development of addiction and tolerance. Since the use of opioids has escalated in recent years, it is increasingly important to understand biological mechanisms that can increase the probability of opioid-associated adverse events occurring in patient populations. This is emphasized by the current opioid epidemic in the United States where opioid analgesics are frequently abused and misused. It has been established that the effectiveness of opioids is maximized when these drugs readily access opioid receptors in the central nervous system (CNS). Indeed, opioid delivery to the brain is significantly influenced by the blood-brain barrier (BBB). In particular, ATP-binding cassette (ABC) transporters that are endogenously expressed at the BBB are critical determinants of CNS opioid penetration. In this review, we will discuss current knowledge on the transport of opioid analgesic drugs by ABC transporters at the BBB. We will also examine how expression and trafficking of ABC transporters can be modified by pain and/or opioid pharmacotherapy, a novel mechanism that can promote opioid-associated adverse drug events and development of addiction and tolerance.

scholarly journals Sphenopalatine Ganglion Stimulation Upregulates Transport of Temozolomide across the Blood-Brain Barrier

2020 ◽  
Vol 88 (3) ◽  
pp. 40
Author(s):  
Thana N. Theofanis ◽  
Ankit K. Rochani ◽  
Richard F. Schmidt ◽  
Michael J. Lang ◽  
Geoffrey P. Stricsek ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Therapeutic Potential ◽  
Low Frequency ◽  
The United States ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Target Tissue ◽  
Sphenopalatine Ganglion ◽  
Blood Brain ◽  
Treatment Paradigm

Sphenopalatine ganglion (SPG) stimulation has been shown to reversibly alter blood-brain barrier (BBB) permeability. It is widely used for the treatment of cluster headaches in Europe and is well tolerated in humans. The therapeutic potential for SPG stimulation in other central nervous system (CNS) diseases has yet to be explored. Glioblastoma Multiforme (GBM) remains one of the most difficult primary CNS neoplasms to treat, with an average survival of approximately 18 months at the time of diagnosis. Since 2004, the gold standard of treatment for GBM in the United States includes surgery followed by treatment with temozolomide (TMZ) and radiation. We sought to determine if SPG stimulation could increase chemotherapy concentrations in rodent brains with an intact BBB. Here, we show a statistically significant (p = 0.0006), five-fold upregulation of TMZ crossing the BBB and reaching brain parenchyma in rats receiving low-frequency (LF, 10 Hz) SPG stimulation. All the measurements were performed using a highly sensitive liquid chromatography mass spectrometry (LCMS) method that was developed for quantitation of TMZ in plasma and brain tissue. Our treatment paradigm shows novel delivery route by which we could more effectively and safely deliver TMZ in a targeted manner, to minimize systemic toxicity and maximize action at the target tissue.

scholarly journals The Blood–Brain Barrier, an Evolving Concept Based on Technological Advances and Cell–Cell Communications

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 133
Author(s):  
Camille Menaceur ◽  
Fabien Gosselet ◽  
Laurence Fenart ◽  
Julien Saint-Pol
Keyword(s):  
Blood Brain Barrier ◽  
Current Knowledge ◽  
Neurovascular Unit ◽  
Cell Communication ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Pericytes ◽  
History Of ◽  
The Brain ◽  
Cell Cell

The construction of the blood–brain barrier (BBB), which is a natural barrier for maintaining brain homeostasis, is the result of a meticulous organisation in space and time of cell–cell communication processes between the endothelial cells that carry the BBB phenotype, the brain pericytes, the glial cells (mainly the astrocytes), and the neurons. The importance of these communications for the establishment, maturation and maintenance of this unique phenotype had already been suggested in the pioneering work to identify and demonstrate the BBB. As for the history of the BBB, the evolution of analytical techniques has allowed knowledge to evolve on the cell–cell communication pathways involved, as well as on the role played by the cells constituting the neurovascular unit in the maintenance of the BBB phenotype, and more particularly the brain pericytes. This review summarises the key points of the history of the BBB, from its origin to the current knowledge of its physiology, as well as the cell–cell communication pathways identified so far during its development, maintenance, and pathophysiological alteration.

scholarly journals Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

2017 ◽  
Vol 9 ◽  
pp. 117957351769380 ◽  
Author(s):  
Hrvoje Brzica ◽  
Wazir Abdullahi ◽  
Kathryn Ibbotson ◽  
Patrick T Ronaldson
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
The United States ◽  
Brain Barrier ◽  
Therapeutic Window ◽  
Multidrug Resistance Proteins ◽  
Stroke Treatment ◽  
Blood Brain

Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity) greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB) provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion–transporting polypeptides (Oatps) and organic cation transporters (Octs). In addition, multidrug resistance proteins (Mrps) are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.

scholarly journals Age-Associated mRNA and miRNA Expression Changes in the Blood-Brain Barrier

2019 ◽  
Vol 20 (12) ◽  
pp. 3097 ◽  
Author(s):  
Emily F. Goodall ◽  
Vicki Leach ◽  
Chunfang Wang ◽  
Johnathan Cooper-Knock ◽  
Paul R. Heath ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Vascular Dysfunction ◽  
Neurovascular Unit ◽  
Enrichment Analysis ◽  
Brain Barrier ◽  
Pathway Enrichment Analysis ◽  
Altered Expression ◽  
Blood Brain ◽  
Junction Protein ◽  
Laser Capture

Functional and structural age-associated changes in the blood-brain barrier (BBB) may affect the neurovascular unit and contribute to the onset and progression of age-associated neurodegenerative pathologies, including Alzheimer’s disease. The current study interrogated the RNA profile of the BBB in an ageing human autopsy brain cohort and an ageing mouse model using combined laser capture microdissection and expression profiling. Only 12 overlapping genes were altered in the same direction in the BBB of both ageing human and mouse cohorts. These included genes with roles in regulating vascular tone, tight junction protein expression and cell adhesion, all processes prone to dysregulation with advancing age. Integrated mRNA and miRNA network and pathway enrichment analysis of the datasets identified 15 overlapping miRNAs that showed altered expression. In addition to targeting genes related to DNA binding and/or autophagy, many of the miRNAs identified play a role in age-relevant processes, including BBB dysfunction and regulating the neuroinflammatory response. Future studies have the potential to develop targeted therapeutic approaches against these candidates to prevent vascular dysfunction in the ageing brain.

scholarly journals Sustained Opening of the Blood-Brain Barrier with Progressive Accumulation of White Matter Hyperintensities Following Ischemic Stroke

2019 ◽  
Vol 9 (1) ◽  
pp. 16 ◽  
Author(s):  
Imama Naqvi ◽  
Emi Hitomi ◽  
Richard Leigh
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Acute Stroke ◽  
Blood Brain Barrier ◽  
White Matter Hyperintensities ◽  
Brain Barrier ◽  
Common Finding ◽  
Blood Brain ◽  
History Of ◽  
Iv Tpa

Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding in patients with vascular risk factors such as a history of stroke. The pathophysiology of WMH is not fully understood; however, there is growing evidence to suggest that the development of WMH may be preceded by the BBB disruption in the NAWM. Methods: We studied a patient enrolled in the National Institutes of Health Natural History of Stroke Study who was scanned with magnetic resonance imaging (MRI) after presenting to the emergency room with an acute stroke. After a treatment with IV tPA, she underwent further MRI scanning at 2 h, 24 h, 5 days, 30 days, 90 days, 6 months, and 1-year post stroke. BBB permeability images were generated from the perfusion weighted imaging (PWI) source images. MRIs from each time point were co-registered to track changes in BBB disruption and WMH over time. Results: An 84-year-old woman presented after acute onset right hemiparesis, right-sided numbness and aphasia with an initial NIHSS of 13. MRI showed diffusion restriction in the left frontal lobe and decreased blood flow on perfusion imaging. Fluid attenuated inversion recovery (FLAIR) imaging showed bilateral confluent WMH involving the deep white matter and periventricular regions. She was treated with IV tPA without complication and her NIHSS improved initially to 3 and ultimately to 0. Permeability maps identified multiple regions of chronic BBB disruption remote from the acute stroke, predominantly spanning the junction of WMH and NAWM. The severity of BBB disruption was greatest at 24 h after the stroke but persisted on subsequent MRI scans. Progression of WMH into NAWM over the year of observation was detected bilaterally but was most dramatic in the regions adjacent to the initial stroke. Conclusions: WMH-associated BBB disruption may be exacerbated by an acute stroke, even in the contralateral hemisphere, and can persist for months after the initial event. Transformation of NAWM to WMH may be evident in areas of BBB disruption within a year after the stroke. Further studies are needed to investigate the relationship between chronic BBB disruption and progressive WMH in patients with a history of cerebrovascular disease and the potential for acute stroke to trigger or exacerbate the process leading to the development of WMH.

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