The dynamic blood–brain barrier

Keaney, James; Campbell, Matthew

doi:10.1111/febs.13412

Cited by 500 publications

(379 citation statements)

References 112 publications

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“…In the lymphoid organs, multiple perivascular cellular components maintain local perivascular S1P gradients, which are important for immune cell trafficking (44). Recent studies suggest the highly dynamic nature of BBB during the sleep-awake cycle (48). The plasticity of the BBB seems to be important to facilitate both the protection of brain from blood-derived toxins and the elimination of deleterious byproducts of brain metabolism.…”

Section: Discussionmentioning

confidence: 99%

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Yanagida

Liu

Faraco

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

185

162

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The vasculature of the central nervous system (CNS) forms a selective barrier termed the blood-brain barrier (BBB). Disruption of the BBB may contribute to various CNS diseases. Conversely, the intact BBB restricts efficient penetration of CNS-targeted drugs. Here, we report the BBB-regulatory role of endothelial sphingosine 1-phosphate (S1P) receptor-1, a G protein-coupled receptor known to promote the barrier function in peripheral vessels. Endothelial-specific S1pr1 knockout mice (S1pr1 iECKO ) showed BBB breach for small-molecular-mass fluorescence tracers (<3 kDa), but not larger tracers (>10 kDa). Chronic BBB leakiness was associated with cognitive impairment, as assessed by the novel object recognition test, but not signs of brain inflammation. Brain microvessels of S1pr1 iECKO mice showed altered subcellular distribution of tight junctional proteins. Pharmacological inhibition of S1P 1 function led to transient BBB breach. These data suggest that brain endothelial S1P 1 maintain the BBB by regulating the proper localization of tight junction proteins and raise the possibility that endothelial S1P 1 inhibition may be a strategy for transient BBB opening and delivery of small molecules into the CNS.blood-brain barrier | sphingosine 1-phosphate | endothelium | tight junction | drug delivery

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Section: Discussionmentioning

confidence: 99%

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Yanagida

Liu

Faraco

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

185

162

View full text Add to dashboard Cite

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“…To the best of our knowledge, the regulation of this process by glucocorticoids had not been studied before. Our vitro model using DEX treated HUVEC and CORT treated rats to integrate the established observations that glucocorticoids can restrict paracellular transport across various endothelia (Keaney and Campbell 2015; Rao, et al 2015; Rochfort and Cummins 2015) with the fact that glucocorticoids, commonly prescribed medications, have numerous side effects, including insulin resistance and diabetes (Beaudry et al 2015). Furthermore, we examined whether the emerging phenomenon that transendothelial movement of Ad may regulate the anti-diabetic effects of this hormone and whether this was regulated by glucocorticoids (Rutkowski et al 2014; Yoon et al 2014).…”

Section: Discussionmentioning

confidence: 99%

Transendothelial movement of adiponectin is restricted by glucocorticoids

Dang

Yoon

Chasiotis

et al. 2017

Journal of Endocrinology

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Altered permeability of the endothelial barrier in a variety of tissues has implications both in disease pathogenesis and treatment. Glucocorticoids are potent mediators of endothelial permeability and this forms the basis for their heavily-prescribed use as medications to treat ocular disease. However, the effect of glucocorticoids on endothelial barriers elsewhere in the body is less well-studied. Here we investigated glucocorticoid-mediated changes in endothelial flux of Adiponectin (Ad), a hormone with a critical role in diabetes. First, we used monolayers of endothelial cells in vitro and found that the glucocorticoid dexamethasone increased transendothelial electrical resistance and reduced permeability of polyethylene glycol (PEG, molecular weight 4000kDa). Dexamethasone reduced flux of Ad from the apical to basolateral side, measured both by ELISA and Western blotting. We then examined a diabetic rat model induced by treatment with exogenous corticosterone, which was characterized by glucose intolerance and hyperinsulinemia. There was no change in circulating Ad but less Ad protein in skeletal muscle homogenates, despite slightly higher mRNA levels, in diabetic versus control muscles. Dexamethasone-induced changes in Ad flux across endothelial monolayers were associated with alterations in the abundance of select claudin (CLDN) tight junction (TJ) proteins. shRNA-mediated knockdown of one such gene, claudin-7, in HUVEC resulted in decreased TEER and increased adiponectin flux, confirming the functional significance of Dex-induced changes in its expression. In conclusion, our study identifies glucocorticoid-mediated reductions in flux of Ad across endothelial monolayers in vivo and in vitro. This suggests that impaired Ad action in target tissues, as a consequence of reduced transendothelial flux, may contribute to the glucocorticoid-induced diabetic phenotype.

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“…The BBB is formed by specialized brain endothelial cells called cerebral endothelial cells (CECs) along with other perivascular cells such as pericytes, astrocytes and perivascular macrophages 20 . These CECs are bound by tight junctions in order to limit the movement mostly of metabolites across the cells in a transcellular transport but also between adjacent cells in a paracellular transport as in most endothelial cells 22 . The BBB is essential for proper brain functions for the selective supply of oxygen and nutrients such as glucose 23 .…”

Section: The Blood-brain Barrier (Bbb)mentioning

confidence: 99%

Harnessing nanomedicine for therapeutic intervention in glioblastoma

Gutkin

Peer

2016

Expert Opinion on Drug Delivery

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Glioblastoma is a type of brain cancer arises from glial cells. Glioblastoma multiforme (GBM), a subtype of glioblastoma, is the most common and most aggressive primary brain tumor. Currently, GBM therapy includes surgery and post-operative high-doses of radiation and chemotherapy. This therapeutic strategy has a limited contribution in extending the survival rate of GBM patients. Areas covered: Herein, we focus on harnessing nanoscale drug delivery strategies to treat brain malignancies. Specifically, we briefly discuss the challenges facing GBM therapy such as restricted passage across the blood-brain barrier (BBB) and low enhanced permeability and retention effect. Next, we describe different pathways to address these challenges. Finally, we discuss the field of nanomedicine, which emerged as a promising platform for drug delivery to brain malignancies. Expert opinion: Countless strategies have been applied in preclinical and clinical settings to treat GBM. Among them is the use of different types of nanoparticles (NPs) and viruses with different approaches to cross or bypass the BBB. We suggest here a paradigm shift in thinking about crossing the BBB and tumor penetration as fundamental issues that need to be address in order to improve the therapeutic outcome in GBM.

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The dynamic blood–brain barrier

Cited by 500 publications

References 112 publications

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Size-selective opening of the blood–brain barrier by targeting endothelial sphingosine 1–phosphate receptor 1

Transendothelial movement of adiponectin is restricted by glucocorticoids

Harnessing nanomedicine for therapeutic intervention in glioblastoma

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