scholarly journals A microfluidic model of human brain (μHuB) for assessment of blood brain barrier

2019 ◽  
Vol 4 (2) ◽  
Author(s):  
Tyler D. Brown ◽  
Maksymilian Nowak ◽  
Alexandra V. Bayles ◽  
Balabhaskar Prabhakarpandian ◽  
Pankaj Karande ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Competitive apnea and its effect on the human brain: focus on the redox regulation of blood‐brain barrier permeability and neuronal‐parenchymal integrity

2018 ◽  
Vol 32 (4) ◽  
pp. 2305-2314 ◽  
Author(s):  
Anthony R. Bain ◽  
Philip N. Ainslie ◽  
Ryan L. Hoiland ◽  
Otto F. Barak ◽  
Ivan Drvis ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Redox Regulation ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability

scholarly journals Proof-of-Concept Study of Drug Brain Permeability Between in Vivo Human Brain and an in Vitro iPSCs-Human Blood-Brain Barrier Model

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Gwenaëlle Le Roux ◽  
Rafika Jarray ◽  
Anne-Cécile Guyot ◽  
Serena Pavoni ◽  
Narciso Costa ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Apparent Permeability ◽  
Clinical Drug Development ◽  
Blood Brain

Abstract The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.

scholarly journals Human Brain Endothelial CXCR2 is Inflammation-Inducible and Mediates CXCL5- and CXCL8-Triggered Paraendothelial Barrier Breakdown

2019 ◽  
Vol 20 (3) ◽  
pp. 602 ◽  
Author(s):  
Axel Haarmann ◽  
Michael Schuhmann ◽  
Christine Silwedel ◽  
Camelia-Maria Monoranu ◽  
Guido Stoll ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Tight Junction ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Morphological Changes ◽  
Brain Barrier ◽  
Microvascular Endothelial Cell ◽  
Inflammatory Conditions ◽  
Blood Brain

Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood–brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood–brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood–brain barrier stabilization.

scholarly journals Human brain microvascular endothelial cell pairs model tissue-level blood–brain barrier function

2020 ◽  
Vol 12 (3) ◽  
pp. 64-79
Author(s):  
Blakely B O’Connor ◽  
Thomas Grevesse ◽  
John F Zimmerman ◽  
Herdeline Ann M Ardoña ◽  
Jorge A Jimenez ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Cytoskeletal Proteins ◽  
Fiber Formation ◽  
Brain Barrier ◽  
Actin Stress Fiber ◽  
Barrier Permeability ◽  
Blood Brain

Abstract The blood–brain barrier plays a critical role in delivering oxygen and nutrients to the brain while preventing the transport of neurotoxins. Predicting the ability of potential therapeutics and neurotoxicants to modulate brain barrier function remains a challenge due to limited spatial resolution and geometric constraints offered by existing in vitro models. Using soft lithography to control the shape of microvascular tissues, we predicted blood–brain barrier permeability states based on structural changes in human brain endothelial cells. We quantified morphological differences in nuclear, junction, and cytoskeletal proteins that influence, or indicate, barrier permeability. We established a correlation between brain endothelial cell pair structure and permeability by treating cell pairs and tissues with known cytoskeleton-modulating agents, including a Rho activator, a Rho inhibitor, and a cyclic adenosine monophosphate analog. Using this approach, we found that high-permeability cell pairs showed nuclear elongation, loss of junction proteins, and increased actin stress fiber formation, which were indicative of increased contractility. We measured traction forces generated by high- and low-permeability pairs, finding that higher stress at the intercellular junction contributes to barrier leakiness. We further tested the applicability of this platform to predict modulations in brain endothelial permeability by exposing cell pairs to engineered nanomaterials, including gold, silver–silica, and cerium oxide nanoparticles, thereby uncovering new insights into the mechanism of nanoparticle-mediated barrier disruption. Overall, we confirm the utility of this platform to assess the multiscale impact of pharmacological agents or environmental toxicants on blood–brain barrier integrity.

Comparison of ABC Transporter Modulation by Atazanavir in Lymphocytes and Human Brain Endothelial Cells: ABC Transporters Are Involved in the Atazanavir-Limited Passage across anin VitroHuman Model of the Blood–Brain Barrier

2008 ◽  
Vol 24 (9) ◽  
pp. 1147-1154 ◽  
Author(s):  
Laurence Bousquet ◽  
Camille Roucairol ◽  
Alexandra Hembury ◽  
Marie-Claire Nevers ◽  
Christophe Creminon ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Human Brain ◽  
Blood Brain Barrier ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Blood Brain
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