scholarly journals Mycobacterium tuberculosisInvasion and Traversal across an In Vitro Human Blood‐Brain Barrier as a Pathogenic Mechanism for Central Nervous System Tuberculosis

2006 ◽  
Vol 193 (9) ◽  
pp. 1287-1295 ◽  
Author(s):  
Sanjay K. Jain ◽  
Maneesh Paul‐Satyaseela ◽  
Gyanu Lamichhane ◽  
Kwang S. Kim ◽  
William R. Bishai
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Human Blood ◽  
Pathogenic Mechanism ◽  
Brain Barrier ◽  
Blood Brain

Understanding the Physiology of the Blood-Brain Barrier: In Vitro Models

Physiology ◽  
1998 ◽  
Vol 13 (6) ◽  
pp. 287-293 ◽  
Author(s):  
Gerald A. Grant ◽  
N. Joan Abbott ◽  
Damir Janigro
Keyword(s):  
Central Nervous System ◽  
Tissue Culture ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
In Vitro Models ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Tissue Culture ◽  
The Brain

Endothelial cells exposed to inductive central nervous system factors differentiate into a blood-brain barrier phenotype. The blood-brain barrier frequently obstructs the passage of chemotherapeutics into the brain. Tissue culture systems have been developed to reproduce key properties of the intact blood-brain barrier and to allow for testing of mechanisms of transendothelial drug permeation.

scholarly journals Novel Blood–Brain Barrier Shuttle Peptides Discovered through the Phage Display Method

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 874 ◽  
Author(s):  
Petra Majerova ◽  
Jozef Hanes ◽  
Dominika Olesova ◽  
Jakub Sinsky ◽  
Emil Pilipcinec ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Phage Display ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Phage Display Technology ◽  
Blood Brain ◽  
Display Technology ◽  
The Brain

Delivery of therapeutic agents into the brain is a major challenge in central nervous system drug development. The blood–brain barrier (BBB) prevents access of biotherapeutics to their targets in the central nervous system and, therefore, prohibits the effective treatment of many neurological disorders. To find blood–brain barrier shuttle peptides that could target therapeutics to the brain, we applied a phage display technology on a primary endothelial rat cellular model. Two identified peptides from a 12 mer phage library, GLHTSATNLYLH and VAARTGEIYVPW, were selected and their permeability was validated using the in vitro BBB model. The permeability of peptides through the BBB was measured by ultra-performance liquid chromatography-tandem mass spectrometry coupled to a triple-quadrupole mass spectrometer (UHPLC-MS/MS). We showed higher permeability for both peptides compared to N–C reversed-sequence peptides through in vitro BBB: for peptide GLHTSATNLYLH 3.3 × 10−7 cm/s and for peptide VAARTGEIYVPW 1.5 × 10−6 cm/s. The results indicate that the peptides identified by the in vitro phage display technology could serve as transporters for the administration of biopharmaceuticals into the brain. Our results also demonstrated the importance of proper BBB model for the discovery of shuttle peptides through phage display libraries.

scholarly journals Blood–brain barrier-on-a-chip: Microphysiological systems that capture the complexity of the blood–central nervous system interface

2017 ◽  
Vol 242 (17) ◽  
pp. 1669-1678 ◽  
Author(s):  
Duc TT Phan ◽  
R Hugh F Bender ◽  
Jillian W Andrejecsk ◽  
Agua Sobrino ◽  
Stephanie J Hachey ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Vascular Malformations ◽  
Three Dimensional ◽  
Brain Barrier ◽  
Blood Brain ◽  
Microphysiological Systems ◽  
The Central Nervous System

The blood–brain barrier is a dynamic and highly organized structure that strictly regulates the molecules allowed to cross the brain vasculature into the central nervous system. The blood–brain barrier pathology has been associated with a number of central nervous system diseases, including vascular malformations, stroke/vascular dementia, Alzheimer’s disease, multiple sclerosis, and various neurological tumors including glioblastoma multiforme. There is a compelling need for representative models of this critical interface. Current research relies heavily on animal models (mostly mice) or on two-dimensional (2D) in vitro models, neither of which fully capture the complexities of the human blood–brain barrier. Physiological differences between humans and mice make translation to the clinic problematic, while monolayer cultures cannot capture the inherently three-dimensional (3D) nature of the blood–brain barrier, which includes close association of the abluminal side of the endothelium with astrocyte foot-processes and pericytes. Here we discuss the central nervous system diseases associated with blood–brain barrier pathology, recent advances in the development of novel 3D blood–brain barrier -on-a-chip systems that better mimic the physiological complexity and structure of human blood–brain barrier, and provide an outlook on how these blood–brain barrier-on-a-chip systems can be used for central nervous system disease modeling. Impact statement The field of microphysiological systems is rapidly evolving as new technologies are introduced and our understanding of organ physiology develops. In this review, we focus on Blood–Brain Barrier (BBB) models, with a particular emphasis on how they relate to neurological disorders such as Alzheimer’s disease, multiple sclerosis, stroke, cancer, and vascular malformations. We emphasize the importance of capturing the three-dimensional nature of the brain and the unique architecture of the BBB – something that until recently had not been well modeled by in vitro systems. Our hope is that this review will provide a launch pad for new ideas and methodologies that can provide us with truly physiological BBB models capable of yielding new insights into the function of this critical interface.

scholarly journals Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes

2020 ◽  
Vol 26 (6) ◽  
pp. 952-963 ◽  
Author(s):  
Joel W. Blanchard ◽  
Michael Bula ◽  
Jose Davila-Velderrain ◽  
Leyla Anne Akay ◽  
Lena Zhu ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Human Blood ◽  
Pathogenic Mechanism ◽  
Brain Barrier ◽  
Blood Brain

In Vitro Models of Central Nervous System Barriers for Blood-Brain Barrier Permeation Studies

2020 ◽  
pp. 235-253
Author(s):  
Sounak Bagchi ◽  
Behnaz Lahooti ◽  
Tanya Chhibber ◽  
Sree-pooja Varahachalam ◽  
Rahul Mittal ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
In Vitro Models ◽  
Brain Barrier ◽  
Blood Brain ◽  
Permeation Studies

scholarly journals Overcoming the Blood–Brain Barrier. Challenges and Tricks for CNS Drug Delivery

2019 ◽  
Vol 87 (1) ◽  
pp. 6 ◽  
Author(s):  
Luca Bors ◽  
Franciska Erdő
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
New Technologies ◽  
Brain Barrier ◽  
Therapeutic Drug ◽  
Blood Brain ◽  
Drug Concentrations ◽  
The Brain

Treatment of certain central nervous system disorders, including different types of cerebral malignancies, is limited by traditional oral or systemic administrations of therapeutic drugs due to possible serious side effects and/or lack of the brain penetration and, therefore, the efficacy of the drugs is diminished. During the last decade, several new technologies were developed to overcome barrier properties of cerebral capillaries. This review gives a short overview of the structural elements and anatomical features of the blood–brain barrier. The various in vitro (static and dynamic), in vivo (microdialysis), and in situ (brain perfusion) blood–brain barrier models are also presented. The drug formulations and administration options to deliver molecules effectively to the central nervous system (CNS) are presented. Nanocarriers, nanoparticles (lipid, polymeric, magnetic, gold, and carbon based nanoparticles, dendrimers, etc.), viral and peptid vectors and shuttles, sonoporation and microbubbles are briefly shown. The modulation of receptors and efflux transporters in the cell membrane can also be an effective approach to enhance brain exposure to therapeutic compounds. Intranasal administration is a noninvasive delivery route to bypass the blood–brain barrier, while direct brain administration is an invasive mode to target the brain region with therapeutic drug concentrations locally. Nowadays, both technological and mechanistic tools are available to assist in overcoming the blood–brain barrier. With these techniques more effective and even safer drugs can be developed for the treatment of devastating brain disorders.

scholarly journals Bortezomib at therapeutic doses poorly passes the blood–brain barrier and does not impair cognition

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Petra Huehnchen ◽  
Andreas Springer ◽  
Johannes Kern ◽  
Ute Kopp ◽  
Siegfried Kohler ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Tissue ◽  
Blood Brain Barrier ◽  
Cumulative Dose ◽  
26S Proteasome ◽  
Brain Barrier ◽  
Central Nervous System Toxicity ◽  
Blood Brain

Abstract The 26S proteasome inhibitor bortezomib is currently used to treat multiple myeloma but also is effective in the treatment of antibody-mediated autoimmune disorders. One clinical concern is bortezomib’s toxicity towards the (central) nervous system. We used standardized neuropsychological testing to assess cognitive function in six patients with myasthenia gravis and systemic lupus erythematodes before and after treatment with a mean cumulative dose of 9.4 mg m−2 bortezomib. In addition, cognitive performance was measured in adult C57Bl/6 mice after treatment with a human equivalent cumulative dose of 15.6 mg m−2. Bortezomib concentrations were analysed in the human CSF as well as the brain tissue and serum of adult C57Bl/6 mice at various time points after the injection of 1.3 mg m−2 bortezomib with liquid chromatography–tandem mass spectrometry. Neither patients nor mice showed signs of cognitive impairment after bortezomib therapy. Bortezomib concentrations in the human CSF and murine brain tissue reached only 5–7% of serum concentrations with comparable concentrations measured in the hippocampus and the neocortex. Five-fold higher concentrations were needed to damage neuronal cells in vitro. In conclusion, penetration of the intact blood–brain barrier by bortezomib is low. Overall, our data show that bortezomib is a safe medication in terms of central nervous system toxicity.

scholarly journals Drug Development for Central Nervous System Diseases Using In vitro Blood-brain Barrier Models and Drug Repositioning

2020 ◽  
Vol 26 (13) ◽  
pp. 1466-1485 ◽  
Author(s):  
Yoichi Morofuji ◽  
Shinsuke Nakagawa
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Drug Development ◽  
Blood Brain Barrier ◽  
Drug Repositioning ◽  
Brain Barrier ◽  
Nervous System Diseases ◽  
Central Nervous System Diseases ◽  
Blood Brain

An important goal of biomedical research is to translate basic research findings into practical clinical implementation. Despite the advances in the technology used in drug discovery, the development of drugs for central nervous system diseases remains challenging. The failure rate for new drugs targeting important central nervous system diseases is high compared to most other areas of drug discovery. The main reason for the failure is the poor penetration efficacy across the blood-brain barrier. The blood-brain barrier represents the bottleneck in central nervous system drug development and is the most important factor limiting the future growth of neurotherapeutics. Meanwhile, drug repositioning has been becoming increasingly popular and it seems a promising field in central nervous system drug development. In vitro blood-brain barrier models with high predictability are expected for drug development and drug repositioning. In this review, the recent progress of in vitro BBB models and the drug repositioning for central nervous system diseases will be discussed.

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