scholarly journals Propofol-induced damage to the blood-brain barrier endothelium evinces a vascular endothelial growth factor (VEGF) -dependent mechanism.

2020 ◽  
Vol 3 ◽  
Author(s):  
Dustin Parsons ◽  
Jason Hughes ◽  
Scott Canfield
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Vegf Receptor ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Vitro Model ◽  
Induced Pluripotent ◽  
Endothelial Growth Factor ◽  
Dependent Mechanism

Background and Hypothesis:  Propofol is an anesthetic commonly used to induce general anesthesia for a myriad of medical procedures. However, a growing corpus of evidence suggests that propofol-induced increases in VEGF may contribute to blood-brain barrier (BBB) leakiness in varying animal models. The BBB is a neurovascular structure which protects the central nervous system from pathogens, toxins, and other deleterious metabolites; therefore, considerations regarding BBB integrity in humans are indispensable to the practice of anesthesia. We hypothesize that propofol-induced BBB dysfunction in human models is partially mediated by an increase in VEGF expression.    Methods:  We utilized human induced pluripotent stem cells (hiPSC) to derive brain microvascular endothelial cells (BMECs)—the barrier forming cell type of the BBB. BMECs were then subjected to clinically relevant doses of propofol for 3 hours, and barrier integrity was monitored via transendothelial electrical resistance (TEER) and para-cellular permeability for up to 72 hours. Propofol-induced VEGF levels were determined with an ELISA assay. Axitinib, a VEGF receptor blocker, was further utilized to assess the role of VEGF in propofol-induced BBB breakdown.    Results:  Prior works, including this study, have shown that propofol induces BBB damage, as demonstrated by decreases in TEER; here, preliminary work with ELISA assays further suggest that BMECs treated with propofol demonstrate an upregulation of VEGF. Pretreatment of BMECs with Axitinib before the addition of propofol partially rescues TEER and thus attenuates the propofol-mediated diminution of TEER. These observations thereby implicate VEGF as a damage mediator after propofol treatment.    Conclusion and Potential Impact:  This study utilized an in vitro model to demonstrate that propofol may mediate, in part, damage to blood- brain barrier endothelium via a VEGF dependent mechanism; thus, this work may guide future investigations to facilitate the development of safer anesthetic alternatives, or towards additional pharmacologic interventions that counteract propofol-mediated damage during anesthetic induction. 

scholarly journals Photostimulation of Extravasation of Beta-Amyloid through the Model of Blood-Brain Barrier

Electronics ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1056
Author(s):  
Ekaterina Zinchenko ◽  
Maria Klimova ◽  
Aysel Mamedova ◽  
Ilana Agranovich ◽  
Inna Blokhina ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Beta Amyloid ◽  
Brain Barrier ◽  
Therapeutic Effects ◽  
Cervical Lymph Nodes ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Vitro Model ◽  
The Brain

Alzheimer’s disease (AD) is an incurable pathology associated with progressive decline in memory and cognition. Phototherapy might be a new promising and alternative strategy for the effective treatment of AD, and has been actively discussed over two decades. However, the mechanisms of therapeutic photostimulation (PS) effects on subjects with AD remain poorly understood. The goal of this study was to determine the mechanisms of therapeutic PS effects in beta-amyloid (Aβ)-injected mice. The neurological severity score and the new object recognition tests demonstrate that PS 9 J/cm2 attenuates the memory and neurological deficit in mice with AD. The immunohistochemical assay revealed a decrease in the level of Aβ in the brain and an increase of Aβ in the deep cervical lymph nodes obtained from mice with AD after PS. Using the in vitro model of the blood-brain barrier (BBB), we show a PS-mediated decrease in transendothelial resistance and in the expression of tight junction proteins as well an increase in the BBB permeability to Aβ. These findings suggest that a PS-mediated BBB opening and the activation of the lymphatic clearance of Aβ from the brain might be a crucial mechanism underlying therapeutic effects of PS in mice with AD. These pioneering data open new strategies in the development of non-pharmacological methods for therapy of AD and contribute to a better understanding of the PS effects on the central nervous system.

scholarly journals Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function, drug penetration, and antibody shuttling properties

2018 ◽  
Author(s):  
Tae-Eun Park ◽  
Nur Mustafaoglu ◽  
Anna Herland ◽  
Ryan Hasselkus ◽  
Robert Mannix ◽  
...  
Keyword(s):  
Human Brain ◽  
Blood Brain Barrier ◽  
Efflux Pumps ◽  
Brain Barrier ◽  
Microvascular Endothelium ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Induced Pluripotent

The highly specialized human brain microvascular endothelium forms a selective blood-brain barrier (BBB) with adjacent pericytes and astrocytes that restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic ‘organ-on-a-chip’ (Organ Chip) model of the BBB lined by induced pluripotent stem cell-derived human brain microvascular endothelium (iPS-BMVEC) interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins, multiple functional efflux pumps, and displays selective transcytosis of peptides and anti-transferrin receptor antibodies previously observed in vivo. This increased level of barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.The human blood-brain barrier (BBB) is a unique and selective physiological barrier that controls transport between the blood and the central nervous system (CNS) to maintain homeostasis for optimal brain function. The BBB is composed of brain microvascular endothelial cells (BMVECs) that line the capillaries as well as surrounding extracellular matrix (ECM), pericytes, and astrocytes, which create a microenvironment that is crucial to BBB function1. The brain microvascular endothelium differs from that found in peripheral capillaries based on its complex tight junctions, which restrict paracellular transit and instead, require that transcytosis be used to transport molecules from the blood through the endothelium and into the CNS2. BMVECs also express multiple broad-spectrum efflux pumps on their luminal surface that inhibit uptake of lipophilic molecules, including many drugs, into the brain3,4. The astrocytes and pericytes provide signals that are required for differentiation of the BMVECs5,6, and all three cell types are needed to maintain BBB integrity in vivo as well as in vitro7–9. The BBB is also of major clinical relevance because dysfunction of the BBB associated is observed in many neurological diseases, and the efficacy of drugs designed to treat neurological disorders is often limited by their inability to cross the BBB10. Unfortunately, neither animal models of the BBB nor in vitro cultures of primary or immortalized human BMVECs alone effectively mimic the barrier and transporter functions of the BBB observed in humans11–14. Thus, there is a great need for a human BBB model that could be used to develop new and more effective CNS-targeting therapeutics and delivery technologies as well as advance fundamental and translational research8,9.Development of human induced pluripotent stem (iPS) cell technology has enabled differentiation of brain-like microvascular endothelial cells (iPS-BMVECs) that exhibit many properties of the human BBB, including well-organized tight junctions, expression of nutrient transporters and polarized efflux transporter activity15,16. The trans-endothelial electrical resistance (TEER) values exhibited by the permeability barrier generated by these human iPS-BMVECs reach physiological levels (∼3000-5000 Ω·cm2) within 24-48 h when cultured in Transwell inserts or within a microfluidic organ-on-a-chip (Organ Chip) device15,17–19, a level that is more than an order of magnitude higher than TEER values previously reported in other in vitro human BBB models6,17,20.However, the usefulness of these iPS-BMVEC models for studies on targeted delivery to the CNS is limited because they can only maintain these high TEER levels for ∼2 days, and the expression of efflux pumps in these iPS-BMVECs does not fully mimic those of human brain endothelium in vivo21. Here, we describe the development of an enhanced human BBB model created with microfluidic Organ Chip culture technology22,23 that contains human iPS-BMVECs interfaced with primary human pericytes and astrocytes, and that uses a developmentally-inspired differentiation protocol24–26. The resulting human BBB Chip exhibits physiologically relevant levels of human BBB function for at least one week in vitro, including low barrier permeability and expression of multiple efflux pumps and transporter functions that are required for analysis of drug and therapeutic antibody transport.

scholarly journals Comparative analysis of neuroinvasion by Japanese encephalitis virulent and vaccine viral strains in an in vitro model of human blood-brain barrier

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252595
Author(s):  
Cécile Khou ◽  
Marco Aurelio Díaz-Salinas ◽  
Anaelle da Costa ◽  
Christophe Préhaud ◽  
Patricia Jeannin ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Japanese Encephalitis ◽  
In Vitro Model ◽  
Molecular Mechanisms ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Vitro Model ◽  
Viral Determinants

Japanese encephalitis virus (JEV) is the major cause of viral encephalitis in South East Asia. It has been suggested that, as a consequence of the inflammatory process during JEV infection, there is disruption of the blood-brain barrier (BBB) tight junctions that in turn allows the virus access to the central nervous system (CNS). However, what happens at early times of JEV contact with the BBB is poorly understood. In the present work, we evaluated the ability of both a virulent and a vaccine strain of JEV (JEV RP9 and SA14-14-2, respectively) to cross an in vitro human BBB model. Using this system, we demonstrated that both JEV RP9 and SA14-14-2 are able to cross the BBB without disrupting it at early times post viral addition. Furthermore, we find that almost 10 times more RP9 infectious particles than SA14-14 cross the model BBB, indicating this BBB model discriminates between the virulent RP9 and the vaccine SA14-14-2 strains of JEV. Beyond contributing to the understanding of early events in JEV neuroinvasion, we demonstrate this in vitro BBB model can be used as a system to study the viral determinants of JEV neuroinvasiveness and the molecular mechanisms by which this flavivirus crosses the BBB during early times of neuroinvasion.

scholarly journals Senescence and associated blood–brain barrier alterations in vitro

2021 ◽  
Author(s):  
Ellaine Salvador ◽  
Malgorzata Burek ◽  
Mario Löhr ◽  
Michiaki Nagai ◽  
Carsten Hagemann ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Intercellular Junctions ◽  
In Vitro Models ◽  
Brain Barrier ◽  
Initial Attempt ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Vitro Model ◽  
The Relationship

AbstractProgressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood–brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within.

Permeability of an In Vitro Model of Blood Brain Barrier (BBB)

2009 ◽  
pp. 81-84 ◽  
Author(s):  
Rashid Amin ◽  
Temiz A. Artmann ◽  
Gerhard Artmann ◽  
Philip Lazarovici ◽  
Peter I. Lelkes
Keyword(s):  
Blood Brain Barrier ◽  
In Vitro Model ◽  
Brain Barrier ◽  
Blood Brain ◽  
Vitro Model

A Neurovascular Blood–Brain Barrier In Vitro Model

2014 ◽  
pp. 403-413 ◽  
Author(s):  
Christoph M. Zehendner ◽  
Robin White ◽  
Jana Hedrich ◽  
Heiko J. Luhmann
Keyword(s):  
Blood Brain Barrier ◽  
In Vitro Model ◽  
Brain Barrier ◽  
Blood Brain ◽  
Vitro Model

Dynamic In Vitro Model of the Blood–Brain Barrier: Gene Profiling Using cDNA Microarray Analysis

2003 ◽  
pp. 419-434 ◽  
Author(s):  
Matteo Marroni ◽  
Kelly M. Kight ◽  
Mohammed Hossain ◽  
Luca Cucullo ◽  
Shailesh Y. Desai ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Microarray Analysis ◽  
Cdna Microarray ◽  
In Vitro Model ◽  
Gene Profiling ◽  
Brain Barrier ◽  
Cdna Microarray Analysis ◽  
Blood Brain ◽  
Vitro Model
Sign in / Sign up

Export Citation Format

Share Document