Blood-Brain Barrier Overview: Structural and Functional Correlation

The blood-brain barrier (BBB) is a semipermeable and extremely selective system in the central nervous system of most vertebrates, that separates blood from the brain’s extracellular fluid. It plays a vital role in regulating the transport of necessary materials for brain function, furthermore, protecting it from foreign substances in the blood that could damage it. In this review, we searched in Google Scholar, Pubmed, Web of Science, and Saudi Digital Library for the various cells and components that support the development and function of this barrier, as well as the different pathways to transport the various molecules between blood and the brain. We also discussed the aspects that lead to BBB dysfunction and its neuropathological consequences, with the identification of some of the most important biomarkers that might be used as a biomarker to predict the BBB disturbances. This comprehensive overview of BBB will pave the way for future studies to focus on developing more specific targeting systems in material delivery as a future approach that assists in combinatorial therapy or nanotherapy to destroy or modify this barrier in pathological conditions such as brain tumors and brain stem cell carcinomas.

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Pseudogene ACTBP2 increases blood–brain barrier permeability by promoting KHDRBS2 transcription through recruitment of KMT2D/WDR5 in Aβ1–42 microenvironment

Cell Death Discovery ◽

10.1038/s41420-021-00531-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Qianshuo Liu ◽

Xiaobai Liu ◽

Defeng Zhao ◽

Xuelei Ruan ◽

Rui Su ◽

...

Keyword(s):

Blood Brain Barrier ◽

Molecular Mechanisms ◽

Rna Binding ◽

Vital Role ◽

Brain Barrier ◽

Blood Brain ◽

Bbb Permeability ◽

Novel Target ◽

And Function

AbstractThe blood–brain barrier (BBB) has a vital role in maintaining the homeostasis of the central nervous system (CNS). Changes in the structure and function of BBB can accelerate Alzheimer’s disease (AD) development. β-Amyloid (Aβ) deposition is the major pathological event of AD. We elucidated the function and possible molecular mechanisms of the effect of pseudogene ACTBP2 on the permeability of BBB in Aβ1–42 microenvironment. BBB model treated with Aβ1–42 for 48 h were used to simulate Aβ-mediated BBB dysfunction in AD. We proved that pseudogene ACTBP2, RNA-binding protein KHDRBS2, and transcription factor HEY2 are highly expressed in ECs that were obtained in a BBB model in vitro in Aβ1–42 microenvironment. In Aβ1–42-incubated ECs, ACTBP2 recruits methyltransferases KMT2D and WDR5, binds to KHDRBS2 promoter, and promotes KHDRBS2 transcription. The interaction of KHDRBS2 with the 3′UTR of HEY2 mRNA increases the stability of HEY2 and promotes its expression. HEY2 increases BBB permeability in Aβ1–42 microenvironment by transcriptionally inhibiting the expression of ZO-1, occludin, and claudin-5. We confirmed that knocking down of Khdrbs2 or Hey2 increased the expression levels of ZO-1, occludin, and claudin-5 in APP/PS1 mice brain microvessels. ACTBP2/KHDRBS2/HEY2 axis has a crucial role in the regulation of BBB permeability in Aβ1–42 microenvironment, which may provide a novel target for the therapy of AD.

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Structural, Molecular, and Functional Alterations of the Blood-Brain Barrier during Epileptogenesis and Epilepsy: A Cause, Consequence, or Both?

International Journal of Molecular Sciences ◽

10.3390/ijms21020591 ◽

2020 ◽

Vol 21 (2) ◽

pp. 591 ◽

Cited By ~ 17

Author(s):

Wolfgang Löscher ◽

Alon Friedman

Keyword(s):

Endothelial Cells ◽

Blood Brain Barrier ◽

Defense Mechanism ◽

Extracellular Fluid ◽

Cell Types ◽

Therapeutic Interventions ◽

Brain Barrier ◽

Transport Systems ◽

Blood Brain ◽

The Brain

The blood-brain barrier (BBB) is a dynamic, highly selective barrier primarily formed by endothelial cells connected by tight junctions that separate the circulating blood from the brain extracellular fluid. The endothelial cells lining the brain microvessels are under the inductive influence of neighboring cell types, including astrocytes and pericytes. In addition to the anatomical characteristics of the BBB, various specific transport systems, enzymes and receptors regulate molecular and cellular traffic across the BBB. While the intact BBB prevents many macromolecules and immune cells from entering the brain, following epileptogenic brain insults the BBB changes its properties. Among BBB alterations, albumin extravasation and diapedesis of leucocytes from blood into brain parenchyma occur, inducing or contributing to epileptogenesis. Furthermore, seizures themselves may modulate BBB functions, permitting albumin extravasation, leading to activation of astrocytes and the innate immune system, and eventually modifications of neuronal networks. BBB alterations following seizures are not necessarily associated with enhanced drug penetration into the brain. Increased expression of multidrug efflux transporters such as P-glycoprotein likely act as a ‘second line defense’ mechanism to protect the brain from toxins. A better understanding of the complex alterations in BBB structure and function following seizures and in epilepsy may lead to novel therapeutic interventions allowing the prevention and treatment of epilepsy as well as other detrimental neuro-psychiatric sequelae of brain injury.

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Development and Cell Biology of the Blood-Brain Barrier

Annual Review of Cell and Developmental Biology ◽

10.1146/annurev-cellbio-100617-062608 ◽

2019 ◽

Vol 35 (1) ◽

pp. 591-613 ◽

Cited By ~ 23

Author(s):

Urs H. Langen ◽

Swathi Ayloo ◽

Chenghua Gu

Keyword(s):

Blood Brain Barrier ◽

Brain Function ◽

Cell Biology ◽

Brain Barrier ◽

Cns Drug Delivery ◽

Blood Brain ◽

Barrier Formation ◽

The Central Nervous System ◽

Barrier Regulation ◽

And Function

The vertebrate vasculature displays high organotypic specialization, with the structure and function of blood vessels catering to the specific needs of each tissue. A unique feature of the central nervous system (CNS) vasculature is the blood-brain barrier (BBB). The BBB regulates substance influx and efflux to maintain a homeostatic environment for proper brain function. Here, we review the development and cell biology of the BBB, focusing on the cellular and molecular regulation of barrier formation and the maintenance of the BBB through adulthood. We summarize unique features of CNS endothelial cells and highlight recent progress in and general principles of barrier regulation. Finally, we illustrate why a mechanistic understanding of the development and maintenance of the BBB could provide novel therapeutic opportunities for CNS drug delivery.

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Blood-brain barrier behavior during temporary concussion

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1960.198.6.1296 ◽

1960 ◽

Vol 198 (6) ◽

pp. 1296-1298 ◽

Cited By ~ 13

Author(s):

Benedict Cassen ◽

Richard Neff

Keyword(s):

Central Nervous System ◽

Blood Brain Barrier ◽

Normal Activity ◽

Brain Barrier ◽

Electrolyte Balance ◽

Barrier Membranes ◽

Phosphate Ions ◽

Blood Brain ◽

The Central Nervous System ◽

The Brain

Experimental evidence is obtained that, coincident with a state of not too severe concussion, the blood-brain barrier system becomes more permeable to phosphate ions. The permeability returns to normal when the animal recovers and shows normal activity. Arguments are presented in favor of the hypothesis that dysfunction of the central nervous system during concussion is related to a disturbed electrolyte balance in the fluids of the brain caused by a piezochemical disturbance of the blood-brain barrier membranes (presumably the astropods of the astrocytic cells).

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

Electronics ◽

10.3390/electronics9061056 ◽

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.

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Tembusu Virus entering the central nervous system caused nonsuppurative encephalitis without disrupting the blood-brain barrier

Journal of Virology ◽

10.1128/jvi.02191-20 ◽

2021 ◽

Author(s):

Sheng Yang ◽

Yufei Huang ◽

Yonghong Shi ◽

Xuebing Bai ◽

Ping Yang ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Blood Brain Barrier ◽

Neurological Symptoms ◽

Brain Barrier ◽

Poultry Industry ◽

Blood Brain ◽

The Central Nervous System ◽

Tembusu Virus ◽

The Brain

Tembusu Virus (TMUV) is an emerging and re-emerging zoonotic pathogen that adversely affects poultry industry in recent years. TMUV disease is characterized by nonsuppurative encephalitis in ducklings. The duckling infection model was established to study the mechanism of TMUV crossing the blood-brain barrier (BBB) into the central nervous system (CNS). Here, we showed that no obvious clinical symptoms and enhancement of BBB permeability occurred at the early stage of infection (3∼5 dpi). While simultaneously virus particles were observed by transmission electron microscopy in the brain, inducing the accumulation of inflammatory cytokines. Neurological symptoms and disruption of BBB appeared at the intermediate stage of infection (7∼9 dpi). It was confirmed that TMUV could survive and propagate in brain microvascular endothelial cells (BMECs), but did not affect the permeability of BBB in vivo and in vitro at an early date. In conclusion, TMUV enters the CNS then causes encephalitis, and finally destruct the BBB, which may be due to the direct effect of TMUV on BMECs and the subsequent response of “inflammatory storm”. IMPORTANCE The TMUV disease has caused huge losses to the poultry industry in Asia, which is potentially harmful to public health. Neurological symptoms and their sequelae are the main characters of this disease. However, the mechanism of how this virus enters the brain and causes encephalitis is unclear. In this study, we confirmed that the virus entered the CNS and then massively destroyed BBB and the BBB damage was closely associated with the subsequent outbreak of inflammation. TMUV may enter the CNS through the transcellular and “Trojan horse” pathways. These findings can fill the knowledge gap in the pathogenesis of TMUV-infected poultry and be benefit for the treatment of TMUV disease. What’s more, TMUV is a representative to study the infection of avian flavivirus. Therefore, our studies have significances both for understanding of the full scope of mechanisms of TMUV and other flavivirus infection, and conceivably, for therapeutics.

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The Dual Role of Microglia in Blood-Brain Barrier Dysfunction after Stroke

Current Neuropharmacology ◽

10.2174/1570159x18666200529150907 ◽

2020 ◽

Vol 18 (12) ◽

pp. 1237-1249 ◽

Cited By ~ 1

Author(s):

Ruiqing Kang ◽

Marcin Gamdzyk ◽

Cameron Lenahan ◽

Jiping Tang ◽

Sheng Tan ◽

...

Keyword(s):

Endothelial Cells ◽

Blood Brain Barrier ◽

Vital Role ◽

Dual Role ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

M2 Microglia ◽

The Brain

It is well-known that stroke is one of the leading causes of death and disability all over the world. After a stroke, the blood-brain barrier subsequently breaks down. The BBB consists of endothelial cells surrounded by astrocytes. Microglia, considered the long-living resident immune cells of the brain, play a vital role in BBB function. M1 microglia worsen BBB disruption, while M2 microglia assist in repairing BBB damage. Microglia can also directly interact with endothelial cells and affect BBB permeability. In this review, we are going to discuss the mechanisms responsible for the dual role of microglia in BBB dysfunction after stroke.

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Disruption of Glial Ca2+ Oscillations at the Drosophila Blood-Brain Barrier Predisposes to Seizure-Like Behavior

10.1101/2020.09.16.285841 ◽

2020 ◽

Author(s):

Shirley Weiss ◽

Lauren C. Clamon ◽

Julia E. Manoim ◽

Kiel G. Ormerod ◽

Moshe Parnas ◽

...

Keyword(s):

Heat Shock ◽

Blood Brain Barrier ◽

Neuronal Development ◽

Brain Barrier ◽

Oscillatory Activity ◽

Distinct Population ◽

Diverse Range ◽

Blood Brain ◽

And Function ◽

The Brain

AbstractGlia play key roles in regulating multiple aspects of neuronal development and function from invertebrates to humans. We recently found microdomain Ca2+ signaling in Drosophila cortex glia and astrocytes regulate extracellular K+ buffering and neurotransmitter uptake, respectively. Here we identify a role for ER store-operated Ca2+ entry (SOCE) in perineurial glia (PG), a distinct population that contributes to the blood-brain barrier (BBB). PG show a diverse range of Ca2+ oscillatory activity that varies based on their locale within the brain. Unlike cortex glia and astrocytes, PG Ca2+ oscillations do not require extracellular Ca2+ and are blocked by inhibition of SOCE or gap junctions. Disruption of these components triggers heat shock and mechanical-induced seizure-like episodes without effecting PG morphology or large molecule BBB permeability. These findings indicate SOCE-mediated Ca2+ oscillations in PG increase the susceptibility of seizure-like episodes in Drosophila, providing an additional link between glial Ca2+ signaling and neuronal activity.

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Iodide and thiocyanate efflux from brain following injection into rat caudate nucleus

AJP Renal Physiology ◽

10.1152/ajprenal.1978.235.4.f331 ◽

1978 ◽

Vol 235 (4) ◽

pp. F331-F337 ◽

Cited By ~ 2

Author(s):

H. F. Cserr ◽

B. J. Berman

Keyword(s):

Caudate Nucleus ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Common Mechanism ◽

Efflux System ◽

Guide Cannula ◽

Blood Brain ◽

The Central Nervous System ◽

Loading Estimates ◽

The Brain

Mechanisms and pathways of 125I and 35SCN efflux from the brain were investigated in anesthetized rats. Tracers were injected into the caudate nucleus through a guide cannula implanted 1 wk previously and concentrations of isotope in brain and cerebrospinal fluid (CSF) were determined at various times after injection. 125I clearance from the brain followed a single exponential curve. In control rats 36.2% of the 125I remained in the brain 30 min after injection and 60.4% in rats pretreated with perchlorate. Comparable values for 35SCN were 25.8% in control rats, 41.0% with perchlorate, and 39.7% with iodide loading. Estimates of 125I and 35SCN effluxes from the brain via the blood-brain barrier and CSF pathways suggest that greater than 95% of efflux crosses the blood-brain barrier. These results indicate that 1)iodide and thiocyanate are transported across the blood-brain barrier by a common mechanism, and 2) this efflux system is an important factor in the control of the distributions of iodide and thiocyanate in the central nervous system.

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A Reevaluation of Chitosan-Decorated Nanoparticles to Cross the Blood-Brain Barrier

Membranes ◽

10.3390/membranes10090212 ◽

2020 ◽

Vol 10 (9) ◽

pp. 212 ◽

Cited By ~ 2

Author(s):

Hernán Cortés ◽

Sergio Alcalá-Alcalá ◽

Isaac H. Caballero-Florán ◽

Sergio A. Bernal-Chávez ◽

Arturo Ávalos-Fuentes ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Diseases ◽

Transport Systems ◽

Future Directions ◽

Blood Brain ◽

Dynamic Interface ◽

And Function ◽

The Brain

The blood-brain barrier (BBB) is a sophisticated and very selective dynamic interface composed of endothelial cells expressing enzymes, transport systems, and receptors that regulate the passage of nutrients, ions, oxygen, and other essential molecules to the brain, regulating its homeostasis. Moreover, the BBB performs a vital function in protecting the brain from pathogens and other dangerous agents in the blood circulation. Despite its crucial role, this barrier represents a difficult obstacle for the treatment of brain diseases because many therapeutic agents cannot cross it. Thus, different strategies based on nanoparticles have been explored in recent years. Concerning this, chitosan-decorated nanoparticles have demonstrated enormous potential for drug delivery across the BBB and treatment of Alzheimer’s disease, Parkinson’s disease, gliomas, cerebral ischemia, and schizophrenia. Our main objective was to highlight the high potential of chitosan adsorption to improve the penetrability through the BBB of nanoformulations for diseases of CNS. Therefore, we describe the BBB structure and function, as well as the routes of chitosan for crossing it. Moreover, we define the methods of decoration of nanoparticles with chitosan and provide numerous examples of their potential utilization in a variety of brain diseases. Lastly, we discuss future directions, mentioning the need for extensive characterization of proposed nanoformulations and clinical trials for evaluation of their efficacy.

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