scholarly journals Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation

2020 ◽  
Vol 21 (12) ◽  
pp. 4407 ◽  
Author(s):  
William A. Banks ◽  
Priyanka Sharma ◽  
Kristin M. Bullock ◽  
Kim M. Hansen ◽  
Nils Ludwig ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Extracellular Vesicles ◽  
Surface Proteins ◽  
Brain Barrier ◽  
Multiple Time ◽  
Blood Brain ◽  
Cancerous Cell ◽  
Wheatgerm Agglutinin ◽  
Mannose 6 Phosphate

Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system.

scholarly journals Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology

2017 ◽  
Vol 79 ◽  
pp. 12-22 ◽  
Author(s):  
Ibolya E. András ◽  
Ana Leda ◽  
Marta Garcia Contreras ◽  
Luc Bertrand ◽  
Minseon Park ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Extracellular Vesicles ◽  
Amyloid Beta ◽  
Brain Barrier ◽  
Blood Brain ◽  
Hiv 1

Bidirectional saturable transport of LHRH across the blood-brain barrier

1991 ◽  
Vol 261 (3) ◽  
pp. E312-E318 ◽  
Author(s):  
C. M. Barrera ◽  
A. J. Kastin ◽  
M. B. Fasold ◽  
W. A. Banks
Keyword(s):  
Blood Brain Barrier ◽  
Ovarian Function ◽  
Brain Barrier ◽  
Multiple Time ◽  
Blood Brain ◽  
Permeability Surface ◽  
Cerebrovascular Permeability ◽  
The Difference ◽  
Single Time Point ◽  
Time Point

Systemic administration of luteinizing hormone-releasing hormone (LHRH) in rats has been found to influence behavior independently of pituitary or ovarian function. A previous study has shown that LHRH can cross the blood-brain barrier in one direction, but it was not known whether this was due to a saturable transport system. The rate of entry of 125I-labeled LHRH from blood to brain was determined by two different single-pass methods of carotid perfusion. The first, a multiple time point method, measures Ki from the slope of the linear regression when brain-to-blood ratios of radioiodinated LHRH are plotted against time. Saturable transport was determined by the difference between the Ki of rats perfused with 125I-LHRH (12.51 X 10(-3) mg.g-1.min-1) vs. rats perfused with 125I-LHRH and unlabeled LHRH (10 nmol/ml; 2.20 X 10(-3) ml.g-1.min-1). The inhibition by the unlabeled peptide was statistically significant (P less than 0.001). The second method, a single time point technique, measures the cerebrovascular permeability-surface area coefficient (PA). Saturable transport was determined in rats by the competition of unlabeled LHRH with 125I-LHRH. The PA value for 125I-LHRH (20.00 X 10(-3) ml.g-1.min-1) was significantly greater (P less than 0.05) than for 125I-LHRH with the addition of 10 nmol/ml unlabeled LHRH (4.14 X 10(-3) ml.g-1.min-1). Saturable transport of LHRH from brain to blood in mice was also determined.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals In Vitro Blood-Brain-Barrier Permeability and Cytotoxicity of Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

2019 ◽  
Author(s):  
Michael M Lübtow ◽  
Sabrina Oertner ◽  
Sabina Quader ◽  
Elisabeth Jeanclos ◽  
Alevtina Cubukova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Oral Administration ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Drug Loading ◽  
3D Models ◽  
Physicochemical Characteristics ◽  
Brain Barrier ◽  
Blood Brain

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with potential to cross the blood-brain-barrier, however, the concentrations necessary for a cytotoxic effect against cancer cells exceeds the concentration achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the 3D models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain-barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration, however, if transport across the blood-brain-barrier is sufficient to reach therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.<br>

Refining In Vitro Neurotoxicity Testing — The Development of Blood–Brain Barrier Models

2003 ◽  
Vol 31 (3) ◽  
pp. 273-276 ◽  
Author(s):  
Hanna Tähti ◽  
Heidi Nevala ◽  
Tarja Toimela
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Culture Methods ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
In Vitro Bbb Model

The purpose of this paper is to review the current state of development of advanced in vitro blood–brain barrier (BBB) models. The BBB is a special capillary bed that separates the blood from the central nervous system (CNS) parenchyma. Astrocytes maintain the integrity of the BBB, and, without astrocytic contacts, isolated brain capillary endothelial cells in culture lose their barrier characteristics. Therefore, when developing in vitro BBB models, it is important to add astrocytic factors into the culture system. Recently, novel filter techniques and co-culture methods have made it possible to develop models which resemble the in vivo functions of the BBB in an effective way. With a BBB model, kinetic factors can be added into the in vitro batteries used for evaluating the neurotoxic potential of chemicals. The in vitro BBB model also represents a useful tool for the in vitro prediction of the BBB permeability of drugs, and offers the possibility to scan a large number of drugs for their potential to enter the CNS. Cultured monolayers of brain endothelial cell lines or selected epithelial cell lines, combined with astrocyte and neuron cultures, form a novel three-dimensional technique for the screening of neurotoxic compounds.

scholarly journals DRES-12. QUANTIFYING INDIVIDUALIZED ABT-414 SENSITIVITY AND BLOOD-BRAIN BARRIER PENETRANCE FROM SERIAL IMAGING OF PATIENT-DERIVED XENOGRAFTS MODELS OF GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi73-vi74
Author(s):  
Javier Urcuyo ◽  
Susan Christine Massey ◽  
Bianca-Maria Marin ◽  
Jann Sarkaria ◽  
Kristin Swanson
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Study Drug ◽  
Primary Brain Tumor ◽  
Equation Model ◽  
Brain Barrier ◽  
Valuable Insight ◽  
Survival Times ◽  
Antibody Drug Conjugate ◽  
Blood Brain

Abstract INTRODUCTION Glioblastoma (GBM) is an aggressive primary brain tumor, known for its poor prognosis. Due to its diffuse invasiveness into normal-appearing brain, localized treatments such as surgical resection and radiotherapy are typically supplemented with chemotherapy. However, to reach invading tumor cells, such antineoplastic drugs must cross the blood-brain barrier (BBB). That is, while angiogenesis induces BBB breakdown in dense tumor regions, the BBB remains rather intact for invading GBM cells. As a result, it is unclear whether BBB-impermeable drugs are delivered at a sufficient level to be effective. METHODS In order to study heterogeneity in BBB breakdown, experiments were conducted using both flank and intracranial patient-derived xenografts (PDXs) treated with the EGFR-targeted monoclonal antibody drug conjugate, depatuxizumab mafodotin (ABT-414). Time-series bioluminescence imaging (BLI) data was used to develop a differential equation model of tumor growth for three PDX cell lines. Data from untreated PDXs, both in flank and intracranially, were used to parameterize tumor proliferation rates. Flank PDX data were used to parameterize individual sensitivity to ABT-414, whereas intracranial PDX data were used to determine the proportion of drug exposed to the tumor. RESULTS Each PDX line differed in response to the study drug ABT-414. As expected, such heterogeneous responses can primarily be attributed to differences in both drug sensitivity and the proportion of drug that reached the tumor. Notably, the estimated proportion of drug that reached the tumor was highest in the PDX line with the longest survival times, despite also having higher estimates of resistance. This suggests that PDXs with greater overall BBB breakdown may respond better to this agent. CONCLUSIONS Although more cell lines are needed to validate our approach, parameterizing this model for PDXs gives valuable insight into the extent of BBB breakdown in patient GBMs and may aid in determining optimal therapies for individual patients.

Immortalized endothelial cell lines for in vitro blood–brain barrier models: A systematic review

2016 ◽  
Vol 1642 ◽  
pp. 532-545 ◽  
Author(s):  
Nurul Adhwa Rahman ◽  
Alifah Nur’ain Haji Mat Rasil ◽  
Uta Meyding-Lamade ◽  
Eva Maria Craemer ◽  
Suwarni Diah ◽  
...  
Keyword(s):  
Systematic Review ◽  
Endothelial Cell ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients

Oncotarget ◽  
2016 ◽  
Vol 8 (1) ◽  
pp. 1416-1428 ◽  
Author(s):  
Noemí García-Romero ◽  
Josefa Carrión-Navarro ◽  
Susana Esteban-Rubio ◽  
Elisa Lázaro-Ibáñez ◽  
María Peris-Celda ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Extracellular Vesicles ◽  
Dna Sequences ◽  
Peripheral Blood ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Differential Sensitivity of Two Endothelial Cell Lines to Hydrogen Peroxide Toxicity: Relevance for In Vitro Studies of the Blood–Brain Barrier

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 403 ◽  
Author(s):  
Olufemi Alamu ◽  
Mariam Rado ◽  
Okobi Ekpo ◽  
David Fisher
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Blood Brain Barrier ◽  
Cell Lines ◽  
Mouse Brain ◽  
Differential Sensitivity ◽  
Brain Barrier ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells

Oxidative stress (OS) has been linked to blood–brain barrier (BBB) dysfunction which in turn has been implicated in the initiation and propagation of some neurological diseases. In this study, we profiled, for the first time, two endothelioma cell lines of mouse brain origin, commonly used as in vitro models of the blood–brain barrier, for their resistance against oxidative stress using viability measures and glutathione contents as markers. OS was induced by exposing cultured cells to varying concentrations of hydrogen peroxide and fluorescence microscopy/spectrometry was used to detect and estimate cellular glutathione contents. A colorimetric viability assay was used to determine changes in the viability of OS-exposed cells. Both the b.End5 and bEnd.3 cell lines investigated showed demonstrable content of glutathione with a statistically insignificant difference in glutathione quantity per unit cell, but with a statistically significant higher capacity for the b.End5 cell line for de novo glutathione synthesis. Furthermore, the b.End5 cells demonstrated greater oxidant buffering capacity to higher concentrations of hydrogen peroxide than the bEnd.3 cells. We concluded that mouse brain endothelial cells, derived from different types of cell lines, differ enormously in their antioxidant characteristics. We hereby recommend caution in making comparisons across BBB models utilizing distinctly different cell lines and require further prerequisites to ensure that in vitro BBB models involving these cell lines are reliable and reproducible.

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