Benzophenone-3 Passes Through the Blood-Brain Barrier, Increases the Level of Extracellular Glutamate, and Induces Apoptotic Processes in the Hippocampus and Frontal Cortex of Rats

2019 ◽  
Vol 171 (2) ◽  
pp. 485-500 ◽  
Author(s):  
Bartosz Pomierny ◽  
Weronika Krzyżanowska ◽  
Żaneta Broniowska ◽  
Beata Strach ◽  
Beata Bystrowska ◽  
...  
Keyword(s):  
Spatial Memory ◽  
Blood Brain Barrier ◽  
Brain Structures ◽  
Glutamate Transporters ◽  
Brain Barrier ◽  
Short Term ◽  
Extracellular Glutamate ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

Abstract Benzophenone-3 is the most commonly used UV filter. It is well absorbed through the skin and gastrointestinal tract. Its best-known side effect is the impact on the function of sex hormones. Little is known about the influence of BP-3 on the brain. The aim of this study was to show whether BP-3 crosses the blood-brain barrier (BBB), to determine whether it induces nerve cell damage in susceptible brain structures, and to identify the mechanism of its action in the central nervous system. BP-3 was administered dermally during the prenatal period and adulthood to rats. BP-3 effect on short-term and spatial memory was determined by novel object and novel location recognition tests. BP-3 concentrations were assayed in the brain and peripheral tissues. In brain structures, selected markers of brain damage were measured. The study showed that BP-3 is absorbed through the rat skin, passes through the BBB. BP-3 raised oxidative stress and induced apoptosis in the brain. BP-3 increased the concentration of extracellular glutamate in examined brain structures and changed the expression of glutamate transporters. BP-3 had no effect on short-term memory but impaired spatial memory. The present study showed that dermal BP-3 exposure may cause damage to neurons what might be associated with the increase in the level of extracellular glutamate, most likely evoked by changes in the expression of GLT-1 and xCT glutamate transporters. Thus, exposure to BP-3 may be one of the causes that increase the risk of developing neurodegenerative diseases.

scholarly journals Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 892
Author(s):  
Elisa L. J. Moya ◽  
Elodie Vandenhaute ◽  
Eleonora Rizzi ◽  
Marie-Christine Boucau ◽  
Johan Hachani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Blood Brain Barrier ◽  
Early Stage ◽  
Molecular Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Cns Drugs ◽  
The Impact ◽  
The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

scholarly journals Massive Inborn Angiogenesis in the Brain Scarcely Raises Cerebral Blood Flow

2004 ◽  
Vol 24 (8) ◽  
pp. 849-859 ◽  
Author(s):  
Johannes Vogel ◽  
Mathias Gehrig ◽  
Wolfgang Kuschinsky ◽  
Hugo H. Marti
Keyword(s):  
Transgenic Mice ◽  
Blood Brain Barrier ◽  
Brain Structures ◽  
Capillary Density ◽  
Brain Barrier ◽  
Metabolic Effects ◽  
Blood Brain ◽  
Functional Consequences ◽  
Endothelial Growth Factor ◽  
The Brain

The functional consequences of increased capillary densities in the brain resulting from vascular endothelial growth factor (VEGF165) overexpression are unknown. Therefore, the authors measured local CBF using the iodo-[14C]antipyrine technique in transgenic mice expressing brain-specifically sixfold higher VEGF165 levels and in nontransgenic littermates. To reveal possible compensatory vasoconstriction, CBF was also measured during severe hypercapnia (PaCO2 > 130 mm Hg). Simultaneously, local capillary density, perfusion state, and blood–brain-barrier permeability were assessed. Using the 2-[14C]deoxyglucose method, metabolic effects of VEGF overexpression could be excluded. In transgenic mice all capillaries showed normal morphology and a tight blood–brain barrier. However, 3% nonperfused capillaries in some brain structures indicate ongoing angiogenesis. Capillary density was drastically increased in transgenic mice in white matter structures (70% to 185%), the dentate gyrus (143%), and caudate nucleus (86%). In all other brain structures investigated, capillary densities were moderately increased by approximately 20%. Normocapnic CBF did not differ between transgenic and nontransgenic mice. During maximal hypercapnic vasodilation, CBF was 20% to 30% higher in transgenic mice, although only in brain structures where capillary density was increased more than twofold. These findings suggest that attenuated CBF in transgenic mice during normocapnia is only partly due to a compensatory vasoconstriction, and that microvascular networks in transgenic brains might be ineffectively constructed.

scholarly journals Blood-brain Barrier Crossing using Magnetic Stimulated Nanoparticles

2021 ◽  
Author(s):  
Jingfan Chen ◽  
Muzhaozi Yuan ◽  
Caitlin Madison ◽  
Shoshana Eitan ◽  
Ya Wang
Keyword(s):  
Blood Brain Barrier ◽  
Pbpk Model ◽  
Superparamagnetic Iron Oxide ◽  
Brain Barrier ◽  
Control Group ◽  
Pbpk Models ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs' in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly(ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.825) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the brain bioavailability under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47 % in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91 % compared to the group without SMF.

Hormones and the blood-brain barrier

2015 ◽  
Vol 21 (3) ◽  
Author(s):  
Richard Hampl ◽  
Marie Bičíková ◽  
Lucie Sosvorová
Keyword(s):  
Endothelial Cells ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Energy Homeostasis ◽  
Brain Structures ◽  
Brain Barrier ◽  
Selection Function ◽  
Membrane Structures ◽  
Blood Brain ◽  
The Brain

AbstractHormones exert many actions in the brain, and brain cells are also hormonally active. To reach their targets in brain structures, hormones must overcome the blood-brain barrier (BBB). The BBB is a unique device selecting desired/undesired molecules to reach or leave the brain, and it is composed of endothelial cells forming the brain vasculature. These cells differ from other endothelial cells in their almost impermeable tight junctions and in possessing several membrane structures such as receptors, transporters, and metabolically active molecules, ensuring their selection function. The main ways how compounds pass through the BBB are briefly outlined in this review. The main part concerns the transport of major classes of hormones: steroids, including neurosteroids, thyroid hormones, insulin, and other peptide hormones regulating energy homeostasis, growth hormone, and also various cytokines. Peptide transporters mediating the saturable transport of individual classes of hormones are reviewed. The last paragraph provides examples of how hormones affect the permeability and function of the BBB either at the level of tight junctions or by various transporters.

scholarly journals Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

2013 ◽  
Vol 57 (9) ◽  
pp. 4336-4342 ◽  
Author(s):  
Liang Jin ◽  
Roger L. Nation ◽  
Jian Li ◽  
Joseph A. Nicolazzo
Keyword(s):  
Blood Brain Barrier ◽  
Bacterial Species ◽  
Specific Effect ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Necrosis Factor Alpha ◽  
Content Type ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

ABSTRACTThe aim of this study was to usein vitroandin vivomodels to assess the impact of lipopolysaccharide (LPS) from two different bacterial species on blood-brain barrier (BBB) integrity and brain uptake of colistin. Following repeated administration of LPS fromPseudomonas aeruginosa, the brain-to-plasma ratio of [14C]sucrose in Swiss outbred mice was not significantly increased. Furthermore, while the brain uptake of colistin in mice increased 3-fold following administration of LPS fromSalmonella enterica, LPS fromP. aeruginosahad no significant effect on colistin brain uptake. This apparent species-dependent effect did not appear to correlate with differences in plasma cytokine levels, as the concentrations of tumor necrosis factor alpha and interleukin-6 following administration of each LPS were not different (P> 0.05). To clarify whether this species-specific effect of LPS was due to direct effects on the BBB, human brain capillary endothelial (hCMEC/D3) cells were treated with LPS fromP. aeruginosaorS. entericaand claudin-5 expression was measured by Western blotting.S. entericaLPS significantly (P< 0.05) reduced claudin-5 expression at a concentration of 7.5 μg/ml. In contrast,P. aeruginosaLPS decreased (P< 0.05) claudin-5 expression only at the highest concentration tested (i.e., 30 μg/ml). Coadministration of therapeutic concentrations of colistin ameliorated theS. entericaLPS-induced reduction in claudin-5 expression in hCMEC/D3 cells and the perturbation in BBB function in mice. This study demonstrates that BBB disruption induced by LPS is species dependent, at least betweenP. aeruginosaandS. enterica, and can be ameliorated by colistin.

scholarly journals In VitroandIn VivoEvidence for Amphotericin B as a P-Glycoprotein Substrate on the Blood-Brain Barrier

2014 ◽  
Vol 58 (8) ◽  
pp. 4464-4469 ◽  
Author(s):  
Ji-Qin Wu ◽  
Kun Shao ◽  
Xuan Wang ◽  
Rui-Ying Wang ◽  
Ya-Hui Cao ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Blood Brain Barrier ◽  
Fungal Infections ◽  
Brain Barrier ◽  
Content Type ◽  
P Glycoprotein ◽  
Blood Brain ◽  
The Impact ◽  
The Brain

ABSTRACTAmphotericin B (AMB) has been a mainstay therapy for fungal infections of the central nervous system, but its use has been limited by its poor penetration into the brain, the mechanism of which remains unclear. In this study, we aimed to investigate the role of P-glycoprotein (P-gp) in AMB crossing the blood-brain barrier (BBB). The uptake of AMB by primary brain capillary endothelial cellsin vitrowas significantly enhanced after inhibition of P-gp by verapamil. The impact of two model P-gp inhibitors, verapamil and itraconazole, on brain/plasma ratios of AMB was examined in both uninfected CD-1 mice and those intracerebrally infected withCryptococcus neoformans. In uninfected mice, the brain/plasma ratios of AMB were increased 15 min (3.5 versus 2.0;P< 0.05) and 30 min (5.2 versus 2.8;P< 0.05) after administration of verapamil or 45 min (6.0 versus 3.9;P< 0.05) and 60 min (5.4 versus 3.8;P< 0.05) after itraconazole administration. The increases in brain/plasma ratios were also observed in infected mice treated with AMB and P-gp inhibitors. The brain tissue fungal CFU in infected mice were significantly lower in AMB-plus-itraconazole or verapamil groups than in the untreated group (P< 0.005), but none of the treatments protected the mice from succumbing to the infection. In conclusion, we demonstrated that P-gp inhibitors can enhance the uptake of AMB through the BBB, suggesting that AMB is a P-gp substrate.

scholarly journals Non-Human Primate Blood–Brain Barrier and In Vitro Brain Endothelium: From Transcriptome to the Establishment of a New Model

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 967
Author(s):  
Catarina Chaves ◽  
Tuan-Minh Do ◽  
Céline Cegarra ◽  
Valérie Roudières ◽  
Sandrine Tolou ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Structures ◽  
Brain Regions ◽  
Brain Barrier ◽  
Brain Endothelium ◽  
Slc Transporters ◽  
Blood Brain ◽  
The Brain ◽  
Human Primate

The non-human primate (NHP)-brain endothelium constitutes an essential alternative to human in the prediction of molecule trafficking across the blood–brain barrier (BBB). This study presents a comparison between the NHP transcriptome of freshly isolated brain microcapillaries and in vitro-selected brain endothelial cells (BECs), focusing on important BBB features, namely tight junctions, receptors mediating transcytosis (RMT), ABC and SLC transporters, given its relevance as an alternative model for the molecule trafficking prediction across the BBB and identification of new brain-specific transport mechanisms. In vitro BECs conserved most of the BBB key elements for barrier integrity and control of molecular trafficking. The function of RMT via the transferrin receptor (TFRC) was characterized in this NHP-BBB model, where both human transferrin and anti-hTFRC antibody showed increased apical-to-basolateral passage in comparison to control molecules. In parallel, eventual BBB-related regional differences were Investig.igated in seven-day in vitro-selected BECs from five brain structures: brainstem, cerebellum, cortex, hippocampus, and striatum. Our analysis retrieved few differences in the brain endothelium across brain regions, suggesting a rather homogeneous BBB function across the brain parenchyma. The presently established NHP-derived BBB model closely mimics the physiological BBB, thus representing a ready-to-use tool for assessment of the penetration of biotherapeutics into the human CNS.

scholarly journals Endothelial cells are critical regulators of iron transport in a model of the human blood–brain barrier

2018 ◽  
Vol 39 (11) ◽  
pp. 2117-2131 ◽  
Author(s):  
Brian Chiou ◽  
Emma H Neal ◽  
Aaron B Bowman ◽  
Ethan S Lippmann ◽  
Ian A Simpson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Iron Deficiency ◽  
Blood Brain Barrier ◽  
Iron Transport ◽  
Brain Barrier ◽  
Brain Iron ◽  
Blood Brain ◽  
Iron Delivery ◽  
The Impact ◽  
The Brain

Iron delivery to the brain is essential for multiple neurological processes such as myelination, neurotransmitter synthesis, and energy production. Loss of brain iron homeostasis is a significant factor in multiple neurological disorders. Understanding the mechanism by which the transport of iron across the blood–brain barrier (BBB) is regulated is crucial to address the impact of iron deficiency on brain development and excessive accumulation of iron in neurodegenerative diseases. Using induced pluripotent stem cell (iPSC)-derived brain endothelial cells (huECs) as a human BBB model, we demonstrate the ability of transferrin, hepcidin, and DMT1 to impact iron transport and release. Our model reveals a new function for H-ferritin to transport iron across the BBB by binding to the T-cell immunoglobulin and mucin receptor 1. We show that huECs secrete both transferrin and H-ferritin, which can serve as iron sources for the brain. Based on our data, brain iron status can exert control of iron transport across the endothelial cells that constitute the BBB. These data address a number of pertinent questions such as how brain iron uptake is regulated at the regional level, the source of iron delivery to the brain, and the clinical strategies for attempting to treat brain iron deficiency.

Ligand and Structure-based Modeling of Passive Diffusion through the Blood-Brain Barrier

2018 ◽  
Vol 25 (9) ◽  
pp. 1073-1089 ◽  
Author(s):  
Santiago Vilar ◽  
Eduardo Sobarzo-Sanchez ◽  
Lourdes Santana ◽  
Eugenio Uriarte
Keyword(s):  
Blood Brain Barrier ◽  
In Silico ◽  
Passive Diffusion ◽  
Brain Barrier ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Different Types ◽  
The Brain

Background: Blood-brain barrier transport is an important process to be considered in drug candidates. The blood-brain barrier protects the brain from toxicological agents and, therefore, also establishes a restrictive mechanism for the delivery of drugs into the brain. Although there are different and complex mechanisms implicated in drug transport, in this review we focused on the prediction of passive diffusion through the blood-brain barrier. Methods: We elaborated on ligand-based and structure-based models that have been described to predict the blood-brain barrier permeability. Results: Multiple 2D and 3D QSPR/QSAR models and integrative approaches have been published to establish quantitative and qualitative relationships with the blood-brain barrier permeability. We explained different types of descriptors that correlate with passive diffusion along with data analysis methods. Moreover, we discussed the applicability of other types of molecular structure-based simulations, such as molecular dynamics, and their implications in the prediction of passive diffusion. Challenges and limitations of experimental measurements of permeability and in silico predictive methods were also described. Conclusion: Improvements in the prediction of blood-brain barrier permeability from different types of in silico models are crucial to optimize the process of Central Nervous System drug discovery and development.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease

2020 ◽  
Vol 26 (37) ◽  
pp. 4721-4737 ◽  
Author(s):  
Bhumika Kumar ◽  
Mukesh Pandey ◽  
Faheem H. Pottoo ◽  
Faizana Fayaz ◽  
Anjali Sharma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Drug Delivery ◽  
Parkinson's Disease ◽  
Side Effects ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Targeting ◽  
Neural Cells ◽  
Blood Brain ◽  
The Brain

Parkinson’s disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson’s disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson’s disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson’s disease.

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