Crossing the blood–brain barrier: clinical interactions between neurologists and hematologists in pediatrics – advances in childhood arterial ischemic stroke and cerebral venous thrombosis

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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AIM2 deletion enhances blood‐brain barrier integrity in experimental ischemic stroke

CNS Neuroscience & Therapeutics ◽

10.1111/cns.13699 ◽

2021 ◽

Author(s):

Si‐yi Xu ◽

Hui‐jie Bian ◽

Shu Shu ◽

Sheng‐nan Xia ◽

Yue Gu ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Integrity ◽

Blood Brain ◽

Blood Brain Barrier Integrity

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Could Lipoxins Represent a New Standard in Ischemic Stroke Treatment?

International Journal of Molecular Sciences ◽

10.3390/ijms22084207 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4207

Author(s):

Nikola Tułowiecka ◽

Dariusz Kotlęga ◽

Andrzej Bohatyrewicz ◽

Małgorzata Szczuko

Keyword(s):

Ischemic Stroke ◽

Cardiovascular Diseases ◽

Blood Brain Barrier ◽

Inflammatory Cytokines ◽

The Body ◽

Brain Barrier ◽

Lipoxin A4 ◽

Stroke Treatment ◽

Blood Brain ◽

Anti Inflammatory

Introduction: Cardiovascular diseases including stroke are one of the most common causes of death. Their main cause is atherosclerosis and chronic inflammation in the body. An ischemic stroke may occur as a result of the rupture of unstable atherosclerotic plaque. Cardiovascular diseases are associated with uncontrolled inflammation. The inflammatory reaction produces chemical mediators that stimulate the resolution of inflammation. One of these mediators is lipoxins—pro-resolving mediators that are derived from the omega-6 fatty acid family, promoting inflammation relief and supporting tissue regeneration. Aim: The aim of the study was to review the available literature on the therapeutic potential of lipoxins in the context of ischemic stroke. Material and Methods: Articles published up to 31 January 2021 were included in the review. The literature was searched on the basis of PubMed and Embase in terms of the entries: ‘stroke and lipoxin’ and ‘stroke and atherosclerosis’, resulting in over 110 articles in total. Studies that were not in full-text English, letters to the editor, and conference abstracts were excluded. Results: In animal studies, the injection/administration of lipoxin A4 improved the integrity of the blood–brain barrier (BBB), decreased the volume of damage caused by ischemic stroke, and decreased brain edema. In addition, lipoxin A4 inhibited the infiltration of neutrophils and the production of cytokines and pro-inflammatory chemokines, such as interleukin (Il-1β, Il-6, Il-8) and tumor necrosis factor-α (TNF-α). The beneficial effects were also observed after introducing the administration of lipoxin A4 analog—BML-111. BML-111 significantly reduces the size of a stroke and protects the cerebral cortex, possibly by reducing the permeability of the blood–brain barrier. Moreover, more potent than lipoxin A4, it has an anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines and increasing the amount of anti-inflammatory cytokines. Conclusions: Lipoxins and their analogues may find application in reducing damage caused by stroke and improving the prognosis of patients after ischemic stroke.

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Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

Frontiers in Neurology ◽

10.3389/fneur.2013.00032 ◽

2013 ◽

Vol 4 ◽

Cited By ~ 137

Author(s):

Shaheen E. Lakhan ◽

Annette Kirchgessner ◽

Deborah Tepper ◽

Aidan Leonard

Keyword(s):

Ischemic Stroke ◽

Matrix Metalloproteinases ◽

Acute Ischemic Stroke ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Disruption ◽

Blood Brain Barrier Disruption ◽

Blood Brain ◽

Brain Barrier Disruption

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

Current Neuropharmacology ◽

10.2174/1570159x18666200914162013 ◽

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.

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Effects of fasudil on blood-brain barrier integrity

10.21203/rs.3.rs-1116440/v1 ◽

2021 ◽

Author(s):

Kei Sato ◽

Shinsuke Nakagawa ◽

Yoichi Morofuji ◽

Yuki Matsunaga ◽

Takashi Fujimoto ◽

...

Keyword(s):

Endothelial Cells ◽

Ischemic Stroke ◽

Tight Junction ◽

Acute Ischemic Stroke ◽

Blood Brain Barrier ◽

Tight Junction Protein ◽

Brain Barrier ◽

Blood Brain ◽

Junction Protein ◽

Culture Models

Abstract Background Cerebral infarction accounts for 85% of all stroke cases. Even in an era of rapid and effective recanalization using an intravascular approach, the majority of patients have poor functional outcomes. Thus, there is an urgent need for the development of therapeutic agents to treat acute ischemic stroke. We evaluated the effect of fasudil, a Rho kinase inhibitor, on blood brain barrier (BBB) functions under normoxia or oxygen-glucose deprivation (OGD) conditions using a primary cell-based in vitro BBB model. Medhods: BBB models from rat primary cultures (brain capillary endothelial cells, astrocytes, and pericytes) were subjected to either normoxia or 6-hour OGD/24-hour reoxygenation. To assess the effects of fasudil on BBB functions, we evaluated real time impedance, transendothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction protein expression using immunohistochemistry and western blotting. Lastly, to understand the observed protective mechanism on BBB functions by fasudil we examined the role of cyclooxygenase-2 and thromboxane A2 receptor agonist U-46619 in BBB-forming cells. Results We found that treatment with 0.3–30 µM of fasudil increased cellular impedance. Fasudil enhanced barrier properties in a concentration-dependent manner, as measured by an increased (TEER) and decreased permeability. Fasudil also increased the expression of tight junction protein claudin-5. Reductions in TEER and increased permeability were observed after OGD/reoxygenation exposure in mono- and co-culture models. The improvement in BBB integrity by fasudil was confirmed in both of the models, but was significantly higher in the co-culture than in the monoculture model. Treatment with U-46619 did not show significant changes in TEER in the monoculture model, whereas it showed a significant reduction in TEER in the co-culture model. Fasudil significantly improved the U-46619-induced TEER reduction in the co-culture models. Pericytes and astrocytes have opposite effects on endothelial cells and may contribute to endothelial injury in hyperacute ischemic stroke. Overall, fasudil protects the integrity of BBB both by a direct protective effect on endothelial cells and by a pathway mediated via pericytes and astrocytes. Conclusions Our findings suggest that fasudil is a BBB-protective agent against acute ischemic stroke.

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