Glutamate Efflux at the Blood–Brain Barrier: Cellular Mechanisms and Potential Clinical Relevance

2014 ◽  
Vol 45 (8) ◽  
pp. 639-645 ◽  
Author(s):  
Helms Hans Christian Cederberg ◽  
Nielsen Carsten Uhd ◽  
Birger Brodin
Keyword(s):  
Blood Brain Barrier ◽  
Clinical Relevance ◽  
Brain Barrier ◽  
Cellular Mechanisms ◽  
Blood Brain ◽  
Glutamate Efflux

scholarly journals Blood-Brain Barrier: From Physiology to Disease and Back

2019 ◽  
Vol 99 (1) ◽  
pp. 21-78 ◽  
Author(s):  
Melanie D. Sweeney ◽  
Zhen Zhao ◽  
Axel Montagne ◽  
Amy R. Nelson ◽  
Berislav V. Zlokovic
Keyword(s):  
Blood Brain Barrier ◽  
Genetic Defect ◽  
Cellular Level ◽  
Lessons Learned ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Cellular Mechanisms ◽  
Blood Brain ◽  
Technological Advances ◽  
Cord Injury

The blood-brain barrier (BBB) prevents neurotoxic plasma components, blood cells, and pathogens from entering the brain. At the same time, the BBB regulates transport of molecules into and out of the central nervous system (CNS), which maintains tightly controlled chemical composition of the neuronal milieu that is required for proper neuronal functioning. In this review, we first examine molecular and cellular mechanisms underlying the establishment of the BBB. Then, we focus on BBB transport physiology, endothelial and pericyte transporters, and perivascular and paravascular transport. Next, we discuss rare human monogenic neurological disorders with the primary genetic defect in BBB-associated cells demonstrating the link between BBB breakdown and neurodegeneration. Then, we review the effects of genes underlying inheritance and/or increased susceptibility for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, and amyotrophic lateral sclerosis (ALS) on BBB in relation to other pathologies and neurological deficits. We next examine how BBB dysfunction relates to neurological deficits and other pathologies in the majority of sporadic AD, PD, and ALS cases, multiple sclerosis, other neurodegenerative disorders, and acute CNS disorders such as stroke, traumatic brain injury, spinal cord injury, and epilepsy. Lastly, we discuss BBB-based therapeutic opportunities. We conclude with lessons learned and future directions, with emphasis on technological advances to investigate the BBB functions in the living human brain, and at the molecular and cellular level, and address key unanswered questions.

Cellular mechanisms of IL‐17‐induced blood‐brain barrier disruption

2009 ◽  
Vol 24 (4) ◽  
pp. 1023-1034 ◽  
Author(s):  
Jula Huppert ◽  
Dorothea Closhen ◽  
Andrew Croxford ◽  
Robin White ◽  
Paulina Kulig ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Cellular Mechanisms ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

scholarly journals The Effects of Propofol on the Human Blood Brain Barrier

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Kirsten A. Lewis ◽  
Jason M. Hughes ◽  
Scott G. Canfield
Keyword(s):  
Blood Brain Barrier ◽  
Induced Pluripotent Stem Cell ◽  
Barrier Properties ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Activity Levels ◽  
Cellular Mechanisms ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Human Ipscs

Background and Hypothesis: Recently, the safety of repeated and lengthy anesthesia in young children has been called into question. Previous studies have shown propofol, an anesthetic, can diminish blood-brain barrier (BBB) properties. However, the underlying cellular mechanisms are relatively unknown. The BBB is critical in ensuring that potentially harmful circulating factors are impermeable to the brain. Previous animal studies models have shown that propofol increases the levels of matrix metalloproteinases (MMPs), which have independently been shown to degrade the extracellular matrix and breakdown tight junctions, a critical component of the BBB. Hypothesis: Propofol exposure to a human induced pluripotent stem cell (iPSC)-derived BBB model increases MMP activity ultimately contributing to a leaky barrier phenotype. Experimental Design or Project Methods: This study utilized human iPSCs differentiated into brain microvascular endothelial cells (BMECs), the barrier forming cell type of the BBB. iPSC-derived BMECS were exposed to propofol (50μM) for three hours and barrier properties were monitored. Barrier tightness was monitored using trans-endothelial electrical resistance (TEER) and sodium fluorescein permeability assays. Tight junction localization was determined with immunocytochemistry. MMP activity was determined with SensoLyte assay kits. To determine the role of MMPs, a broad spectrum MMP inhibitor, GM6001, was utilized and barrier properties were monitored. Results: Propofol treatment significantly reduced TEER and increased sodium fluorescein permeability, indicative of a leaky barrier. Propofol treatment increased levels of MMP-2 activity but not MMP-9 when compared to non-treated BMECs. Inhibition of MMPs by GM6001 prior to propofol treatment appeared to partially restore barrier integrity as monitored by sodium fluorescein permeability. Conclusion and Potential Impact: These results indicate that increased MMP-2 activity levels could be in part responsible for diminished BBB properties. Inhibition of MMPs protected barrier integrity from propofol treatment. A further understanding of the underlying mechanisms of anesthetic-induced damage can potentially improve anesthesia safety.  

scholarly journals Hydralazine is a Suitable Mimetic Agent of Hypoxia to Study the Impact of Hypoxic Stress on In Vitro Blood-Brain Barrier Model

2017 ◽  
Vol 42 (4) ◽  
pp. 1592-1602 ◽  
Author(s):  
Morgane Chatard ◽  
Clémentine Puech ◽  
Nathalie Perek ◽  
Frédéric Roche
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Hypoxic Stress ◽  
Cellular Mechanisms ◽  
Blood Brain ◽  
Junction Protein ◽  
Set Up ◽  
In Vitro Bbb Model ◽  
The Impact

Background/Aims: Understanding cellular mechanisms induced by hypoxia is fundamental to reduce blood-brain barrier (BBB) disruption. Nevertheless, the investigation of hypoxia on cellular pathways is complex with true hypoxia because HIF-1α has a short lifetime and rapidly reverts back to a normoxic state. To overcome this difficulty, mimetic agents of the hypoxia pathway have been developed, including the gold standard CoCl2. In this study, we proposed to compare CoCl2 and hydralazine in order to determine a suitable mimetic agent of hypoxia for the study on the BBB. Methods: We studied the cytotoxicity and the impact of these molecules on the integrity of an in vitro BBB model by comparing them to hypoxia controls. Results: We showed that the impact of hypoxic stress in our in vitro BBB model is rather similar between hydralazine and CoCl2. Chemical hypoxic stress led to an increase of BBB permeability either with CoCl2 or hydralazine. Tight junction protein expressions showed that this chemical hypoxic stress decreased ZO-1 but not occluding expressions, and cells had set up a defence mechanism by increasing expression and activity of their efflux transporters. Conclusion: Our results demonstrated that hydralazine is a better mimetic agent and more suitable than CoCl2 because it had the same effect but without the cytotoxic effect on in vitro BBB cells.

scholarly journals VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway

1999 ◽  
Vol 276 (5) ◽  
pp. C1148-C1153 ◽  
Author(s):  
William G. Mayhan
Keyword(s):  
Nitric Oxide ◽  
Blood Brain Barrier ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Brain Barrier ◽  
Cellular Mechanisms ◽  
Blood Brain ◽  
Cerebrovascular Trauma ◽  
Pial Arterioles

It appears that the expression of vascular endothelial growth factor (VEGF) is increased during brain injury and thus may contribute to disruption of the blood-brain barrier (BBB) during cerebrovascular trauma. The first goal of this study was to determine the effect of VEGF on permeability of the BBB in vivo. The second goal was to determine possible cellular mechanisms by which VEGF increases permeability of the BBB. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the BBB [clearance of FITC-labeled dextran of molecular mass 10,000 Da (FITC-dextran-10K)] and diameter of pial arterioles were measured in absence and presence of VEGF (0.01 and 0.1 nM). During superfusion with vehicle (saline), clearance of FITC-dextran-10K from pial vessels was minimal and diameter of pial arterioles remained constant. Topical application of VEGF (0.01 nM) did not alter permeability of the BBB to FITC-dextran-10K or arteriolar diameter. However, superfusion with VEGF (0.1 nM) produced a marked increase in clearance of FITC-dextran-10K and a modest dilatation of pial arterioles. To determine a potential role for nitric oxide and stimulation of soluble guanylate cyclase in VEGF-induced increases in permeability of the BBB and arteriolar dilatation, we examined the effects of N G-monomethyl-l-arginine (l-NMMA; 10 μM) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1.0 μM), respectively.l-NMMA and ODQ inhibited VEGF-induced increases in permeability of the BBB and arteriolar dilatation. The findings of the present study suggest that VEGF, which appears to be increased in brain tissue during cerebrovascular trauma, increases the permeability of the BBB via the synthesis/release of nitric oxide and subsequent activation of soluble guanylate cyclase.

The Blood-Brain Barrier

2016 ◽  
Vol 23 (2) ◽  
pp. 124-136 ◽  
Author(s):  
Weihong Pan ◽  
Abba J. Kastin
Keyword(s):  
Blood Brain Barrier ◽  
Relevant Literature ◽  
The Body ◽  
Brain Barrier ◽  
Structural Basis ◽  
Sleep Disruption ◽  
Cellular Mechanisms ◽  
Blood Brain ◽  
Junction Protein ◽  
The Impact

Sleep and its disorders are known to affect the functions of essential organs and systems in the body. However, very little is known about how the blood-brain barrier (BBB) is regulated. A few years ago, we launched a project to determine the impact of sleep fragmentation and chronic sleep restriction on BBB functions, including permeability to fluorescent tracers, tight junction protein expression and distribution, glucose and other solute transporter activities, and mediation of cellular mechanisms. Recent publications and relevant literature allow us to summarize here the sleep-BBB interactions in five sections: (1) the structural basis enabling the BBB to serve as a huge regulatory interface; (2) BBB transport and permeation of substances participating in sleep-wake regulation; (3) the circadian rhythm of BBB function; (4) the effect of experimental sleep disruption maneuvers on BBB activities, including regional heterogeneity, possible threshold effect, and reversibility; and (5) implications of sleep disruption-induced BBB dysfunction in neurodegeneration and CNS autoimmune diseases. After reading the review, the general audience should be convinced that the BBB is an important mediating interface for sleep-wake regulation and a crucial relay station of mind-body crosstalk. The pharmaceutical industry should take into consideration that sleep disruption alters the pharmacokinetics of BBB permeation and CNS drug delivery, being attentive to the chrono timing and activation of co-transporters in subjects with sleep disorders.

Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles

2004 ◽  
Vol 30 (7) ◽  
pp. 979-989 ◽  
Author(s):  
Nickolai Sheikov ◽  
Nathan McDannold ◽  
Natalia Vykhodtseva ◽  
Ferenc Jolesz ◽  
Kullervo Hynynen
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Cellular Mechanisms ◽  
Blood Brain ◽  
Barrier Opening ◽  
Blood Brain Barrier Opening

scholarly journals Nitric oxide mediates hypoxia-induced changes in paracellular permeability of cerebral microvasculature

2004 ◽  
Vol 286 (1) ◽  
pp. H174-H180 ◽  
Author(s):  
Karen S. Mark ◽  
Amanda R. Burroughs ◽  
Rachel C. Brown ◽  
Jason D. Huber ◽  
Thomas P. Davis
Keyword(s):  
Nitric Oxide ◽  
Blood Brain Barrier ◽  
Tissue Injury ◽  
Paracellular Permeability ◽  
Bovine Brain ◽  
Brain Barrier ◽  
Hypoxic Exposure ◽  
Cellular Mechanisms ◽  
No Donor ◽  
Blood Brain

Ischemic stroke from a reduction in blood flow to the brain microvasculature results in a subsequent decreased delivery of oxygen (i.e., hypoxia) and vital nutrients to endothelial, neuronal, and glial cells. Hypoxia associated with stroke has been shown to increase paracellular permeability of the blood-brain barrier, leading to the release of cellular mediators and brain tissue injury. Whereas reperfusion does not occur in all ischemic strokes, increased permeability has been seen in posthypoxic reoxygenation. Currently, it is unknown whether these deleterious effects result from cellular mechanisms stimulated by decreased oxygen during stroke or posthypoxic reoxygenation stress. This study used primary bovine brain microvessel endothelial cells (BBMECs) to examine the involvement of nitric oxide (NO) as a mediator in hypoxia-induced permeability changes. Hypoxia-induced increased transport of [14C]sucrose across BBMEC monolayers compared with normoxia was attenuated by either posthypoxic reoxygenation or inhibition of NO synthase (NOS). The hypoxia-induced permeability effect was further reduced when NOS inhibition was combined with posthypoxic reoxygenation. Additionally, a significant increase in total NO was seen in BBMECs after hypoxic exposure. This correlation was supported by the increased [14C]sucrose permeability observed when BBMECs were exposed to the NO donor diethylenetriaamine NONOate. Western blot analyses of NOS isoforms showed a significant increase in the inducible isoform after hypoxic exposure with a subsequent reduction in expression on reoxygenation. Results from this study suggest that hypoxia-induced blood-brain barrier breakdown can be diminished by inhibition of NO synthesis, decreased concentration of NO metabolites, and/or reoxygenation.

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