A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity

AbstractThe blood–brain barrier is playing a critical role in controlling the influx and efflux of biological substances essential for the brain’s metabolic activity as well as neuronal function. Thus, the functional and structural integrity of the BBB is pivotal to maintain the homeostasis of the brain microenvironment. The different cells and structures contributing to developing this barrier are summarized along with the different functions that BBB plays at the brain–blood interface. We also explained the role of shear stress in maintaining BBB integrity. Furthermore, we elaborated on the clinical aspects that correlate between BBB disruption and different neurological and pathological conditions. Finally, we discussed several biomarkers that can help to assess the BBB permeability and integrity in-vitro or in-vivo and briefly explain their advantages and disadvantages.

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The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽

10.3390/nu13061833 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1833

Author(s):

Shannon Morgan McCabe ◽

Ningning Zhao

Keyword(s):

Cerebrospinal Fluid ◽

Blood Brain Barrier ◽

Blood Circulation ◽

Critical Role ◽

Systemic Circulation ◽

Brain Parenchyma ◽

Brain Barrier ◽

Blood Brain ◽

The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

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Baicalein as a Potential Inhibitor against BACE1 and AChE: Mechanistic Comprehension through In Vitro and Computational Approaches

Nutrients ◽

10.3390/nu11112694 ◽

2019 ◽

Vol 11 (11) ◽

pp. 2694 ◽

Cited By ~ 8

Author(s):

Jin Han ◽

Yeongseon Ji ◽

Kumju Youn ◽

GyuTae Lim ◽

Jinhyuk Lee ◽

...

Keyword(s):

Blood Brain Barrier ◽

Efflux Pump ◽

Critical Role ◽

Brain Barrier ◽

Hydroxyl Groups ◽

Binding Interaction ◽

In Silico Docking ◽

Blood Brain

One of the major neurodegenerative features of Alzheimer’s disease (AD) is the presence of neurotoxic amyloid plaques composed of amyloid beta peptide (Aβ). β-Secretase (BACE1) and acetylcholinesterase (AChE), which promote Aβ fibril formation, have become attractive therapeutic targets for AD. P-glycoprotein (P-gp), the major efflux pump of the blood-brain barrier (BBB), plays a critical role in limiting therapeutic molecules. In pursuit of discovering a natural anti-AD candidate, the bioactivity, physicochemical, drug-likeness, and molecular docking properties of baicalein, a major compound from Scutellaria baicalensis, was investigated. Baicalein exhibited strong BACE1 and AChE inhibitory properties (IC50 23.71 ± 1.91 µM and 45.95 ± 3.44 µM, respectively) and reacted in non-competitive and competitive manners with substrates, respectively. in Silico docking analysis was in full agreement with the in vitro results, demonstrating that the compound exhibited powerful binding interaction with target enzymes. Particularly, three continuous hydroxyl groups on the A ring demonstrated strong H-bond binding properties. It is also noteworthy that baicalein complied with all requirements of Lipinski’s rule of five by its optimal physicochemical properties for both oral bioavailability and blood–brain barrier permeability. Overall, the present study strongly demonstrated the possibility of baicalein having in vivo pharmacological efficacy for specific targets in the prevention and/or treatment of AD.

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Correlation of MPTP neurotoxicity in vivo with oxidation of MPTP by the brain and blood-brain barrier in vitro in five rat strains

Brain Research ◽

10.1016/0006-8993(91)90854-o ◽

1991 ◽

Vol 555 (1) ◽

pp. 19-24 ◽

Cited By ~ 22

Author(s):

Naji J. Riachi ◽

Ramin A. Behmand ◽

Sami I. Harik

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Rat Strains ◽

Blood Brain ◽

The Brain

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Lysozyme transport to the brain by liposomes

Precision Nanomedicine ◽

10.33218/prnano1(2).180712.1 ◽

2018 ◽

Vol 1 (2) ◽

pp. 146-161 ◽

Cited By ~ 2

Author(s):

Mirjam M Nordling-David ◽

Elior Rachamin ◽

Etty Grad ◽

Gershon Golomb

Keyword(s):

Blood Brain Barrier ◽

White Blood Cells ◽

Brain Barrier ◽

Immunofluorescent Staining ◽

Phagocytic Cells ◽

Blood Brain ◽

The Brain ◽

Positively Charged

Delivery of drugs into the brain is limited due to poor penetrability of many drugs via the blood-brain barrier. Previous studies have shown that the brain is kept under close surveillance by the immune system, implying that circulating phagocytic cells, such as neutrophils and monocytes, are crossing the blood-brain barrier. We hypothesized that charged liposomes could be transported to the brain following their phagocytosis by circulating monocytes. In this work, we investigated the capacity of circulating monocytes to be exploited as a drug delivery system following IV administration of nano-sized, positively fluorescently labeled liposomes containing the protein lysozyme. Negatively charged fluorescently labeled liposomes were used for comparison. By using a modified thin-film hydration technique, the desired properties of the liposomal formulations were achieved including size, polydispersity index, high drug concentration, and stability. In vitro results showed a significant time-dependent uptake of positively charged liposomes by RAW264.7 cells. In vivo results revealed that circulating white blood cells (mainly monocytes) contained high levels of fluorescently labeled liposomes. Screening of brain sections using confocal microscopy uncovered that a substantial amount of fluorescently labeled liposomes, in contrast to the fluorescent markers in solution, was transported into the brain. In addition, anti-CD68 immunofluorescent staining of brain sections demonstrated co-localization of positively charged liposomes and macrophages in different brain sections. Furthermore, significantly higher levels of lysozyme were detected in brain lysates from rats treated with positively charged liposomes compared to rats treated with lysozyme solution. Taken together this confirms our hypothesis that the designed liposomes were transported to the brain following their phagocytosis by circulating monocytes.

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Lipid Nanoformulations in the Treatment of Neuropsychiatric Diseases: An Approach to Overcome the Blood Brain Barrier

Current Drug Metabolism ◽

10.2174/1573399816666200627214129 ◽

2020 ◽

Vol 21 (9) ◽

pp. 674-684 ◽

Cited By ~ 1

Author(s):

Saleha Rehman ◽

Bushra Nabi ◽

Faheem Hyder Pottoo ◽

Sanjula Baboota ◽

Javed Ali

Keyword(s):

Blood Brain Barrier ◽

Water Solubility ◽

Oral Absorption ◽

Brain Barrier ◽

Therapeutic Drug ◽

Blood Brain ◽

Neuropsychiatric Diseases ◽

The Brain

Background: Neuropsychiatric diseases primarily characterized by dementia stand third in the global list of diseases causing disability. The poor water solubility, erratic oral absorption, low bioavailability, poor intestinal absorption, and the impeding action of the blood-brain barrier (BBB) are the major factors limiting the therapeutic feasibility of the antipsychotics. Only a small percentage of antipsychotics reaches the therapeutic target site, which warrants administration of high doses, consequently leading to unwanted side-effects. Hence the main struggle for the effective treatment of neuropsychiatric diseases occurs “at the gates” of the brain, which can be mitigated with the use of a nanotechnology-based platform. Methods: The goal of this review is to undertake a comprehensive study about the role of lipid nanoformulations in facilitating the delivery of antipsychotics across BBB along with the available in vitro and in vivo evidence. Results: Lipid nanoformulations have attained great popularity for the delivery of therapeutics into the brain. Their nanosize helps in overcoming the biological barriers, thereby providing easy BBB translocation of the drugs. Besides, they offer numerous advantages like controlled and targeted drug release, minimizing drug efflux, long storage stability, augmented bioavailability, and reduced adverse drug effects to attain an optimal therapeutic drug concentration in the brain. Moreover, employing alternative routes of administration has also shown promising results. Conclusion: Thus, it can be concluded that the lipid nanoformulations bear immense potential in overcoming the challenges associated with the treatment of neuropsychiatric disorders. However, the area warrants further clinical studies to ensure their commercialization, which could revolutionize the treatment of neuropsychiatric diseases in the coming decades.

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Overcoming the Blood-Brain Barrier: Functionalised Chitosan Nanocarriers

Pharmaceutics ◽

10.3390/pharmaceutics12111013 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1013 ◽

Cited By ~ 2

Author(s):

Anna E. Caprifico ◽

Peter J. S. Foot ◽

Elena Polycarpou ◽

Gianpiero Calabrese

Keyword(s):

Blood Brain Barrier ◽

Chemical Properties ◽

Brain Barrier ◽

Hydroxyl Groups ◽

Blood Brain ◽

The Brain ◽

Major Impediment ◽

And Chemical Properties

The major impediment to the delivery of therapeutics to the brain is the presence of the blood-brain barrier (BBB). The BBB allows for the entrance of essential nutrients while excluding harmful substances, including most therapeutic agents; hence, brain disorders, especially tumours, are very difficult to treat. Chitosan is a well-researched polymer that offers advantageous biological and chemical properties, such as mucoadhesion and the ease of functionalisation. Chitosan-based nanocarriers (CsNCs) establish ionic interactions with the endothelial cells, facilitating the crossing of drugs through the BBB by adsorptive mediated transcytosis. This process is further enhanced by modifications of the structure of chitosan, owing to the presence of reactive amino and hydroxyl groups. Finally, by permanently binding ligands or molecules, such as antibodies or lipids, CsNCs have showed a boosted passage through the BBB, in both in vivo and in vitro studies which will be discussed in this review.

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Nanoparticles Based on Quaternary Ammonium Chitosan-methyl-β-cyclodextrin Conjugate for the Neuropeptide Dalargin Delivery to the Central Nervous System: An In Vitro Study

Pharmaceutics ◽

10.3390/pharmaceutics13010005 ◽

2020 ◽

Vol 13 (1) ◽

pp. 5

Author(s):

Chiara Migone ◽

Letizia Mattii ◽

Martina Giannasi ◽

Stefania Moscato ◽

Andrea Cesari ◽

...

Keyword(s):

Blood Brain Barrier ◽

Quaternary Ammonium ◽

Oral Absorption ◽

In Vitro Study ◽

Brain Barrier ◽

Mucosal Barrier ◽

Blood Brain ◽

The Brain

Peptide oral administration is a hard goal to reach, especially if the brain is the target site. The purpose of the present study was to set up a vehicle apt to promote oral absorption of the neuropeptide dalargin (DAL), allowing it to cross the intestinal mucosal barrier, resist enzymatic degradation, and transport drugs to the brain after crossing the blood–brain barrier. Therefore, a chitosan quaternary ammonium derivative was synthesized and conjugated with methyl-β-cyclodextrin to prepare DAL-medicated nanoparticles (DAL-NP). DAL-NP particle size was 227.7 nm, zeta potential +8.60 mV, encapsulation efficiency 89%. DAL-NP protected DAL from degradation by chymotrypsin or pancreatin and tripled DAL degradation time compared to non-encapsulated DAL. Use of DAL-NP was safe for either Caco-2 or bEnd.3 cells, with the latter selected as a blood–brain barrier model. DAL-NP could also cross either the Caco-2 or bEnd.3 monolayer by the transepithelial route. The results suggest a potential DAL-NP ability to transport to the brain a DAL dose fraction administered orally, although in vivo experiments will be needed to confirm the present data obtained in vitro.

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Organic Cation Transporters are Involved in Fluoxetine Transport Across the Blood-Brain Barrier in Vivo and in Vitro

Current Drug Delivery ◽

10.2174/1567201818666210708122326 ◽

2021 ◽

Vol 18 ◽

Author(s):

Min Wang ◽

Yingying Sun ◽

Bingying Hu ◽

Zhisheng He ◽

Shanshan Chen ◽

...

Keyword(s):

Blood Brain Barrier ◽

Cellular Uptake ◽

Organic Cation ◽

Brain Barrier ◽

Organic Cation Transporters ◽

Cellular Accumulation ◽

Blood Brain ◽

The Brain

Background : The research and development of drugs for the treatment of central nervous system diseases faces many challenges at present. One of the most important questions to be answered is, how does the drug cross the blood-brain barrier to get to the target site for pharmacological action. Fluoxetine is widely used in clinical antidepressant therapy. However, the mechanism by which fluoxetine passes through the BBB also remains unclear. Under physiological pH conditions, fluoxetine is an organic cation with a relatively small molecular weight (<500), which is in line with the substrate characteristics of organic cation transporters (OCTs). Therefore, this study aimed to investigate the interaction of fluoxetine with OCTs at the BBB and BBB-associated efflux transporters. This is of great significance for fluoxetine to better treat depression. Moreover, it can provide a theoretical basis for clinical drug combinations. Methods: In vitro BBB model was developed using human brain microvascular endothelial cells (hCMEC/D3), and the cellular accumulation was tested in the presence or absence of transporter inhibitors. In addition, an in vivo trial was performed in rats to investigate the effect of OCTs on the distribution of fluoxetine in the brain tissue. Fluoxetine concentration was determined by a validated UPLC-MS/MS method. Results: The results showed that amantadine (an OCT1/2 inhibitor) and prazosin (an OCT1/3 inhibitor) significantly decreased the cellular accumulation of fluoxetine (P <.001). Moreover, we found that N-methylnicotinamide (an OCT2 inhibitor) significantly inhibited the cellular uptake of 100 and 500 ng/mL fluoxetine (P <.01 and P <.05 respectively). In contrast, corticosterone (an OCT3 inhibitor) only significantly inhibited the cellular uptake of 1000 ng/mL fluoxetine (P <.05). The P-glycoprotein (P-gp) inhibitor, verapamil, and the multidrug resistance resistance-associated proteins (MRPs) inhibitor, MK571, significantly decreased the cellular uptake of fluoxetine. However, intracellular accumulation of fluoxetine was not significantly changed when fluoxetine was incubated with the breast cancer resistance protein (BCRP) inhibitor Ko143. Furthermore, in vivo experiments proved that corticosterone and prazosin significantly inhibited the brain-plasma ratio of fluoxetine at 5.5 h and 12 h, respectively. Conclusion: OCTs might play a significant role in the transport of fluoxetine across the BBB. In addition, P-gp, BCRP, and MRPs seemed not to mediate the efflux transport of fluoxetine.

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