scholarly journals Differences in the molecular structure of the blood-brain barrier in the cerebral cortex and white matter: an in silico, in vitro, and ex vivo study

2016 ◽  
Vol 310 (11) ◽  
pp. H1702-H1714 ◽  
Author(s):  
Ádám Nyúl-Tóth ◽  
Maria Suciu ◽  
Judit Molnár ◽  
Csilla Fazakas ◽  
János Haskó ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Cortex ◽  
White Matter ◽  
Blood Brain Barrier ◽  
In Silico ◽  
Grey Matter ◽  
Ex Vivo ◽  
Cortical Grey Matter ◽  
The Brain

The blood-brain barrier (BBB) is the main interface controlling molecular and cellular traffic between the central nervous system (CNS) and the periphery. It consists of cerebral endothelial cells (CECs) interconnected by continuous tight junctions, and closely associated pericytes and astrocytes. Different parts of the CNS have diverse functions and structures and may be subject of different pathologies, in which the BBB is actively involved. It is largely unknown, however, what are the cellular and molecular differences of the BBB in different regions of the brain. Using in silico, in vitro, and ex vivo techniques we compared the expression of BBB-associated genes and proteins (i.e., markers of CECs, brain pericytes, and astrocytes) in the cortical grey matter and white matter. In silico human database analysis (obtained from recalculated data of the Allen Brain Atlas), qPCR, Western blot, and immunofluorescence studies on porcine and mouse brain tissue indicated an increased expression of glial fibrillary acidic protein in astrocytes in the white matter compared with the grey matter. We have also found increased expression of genes of the junctional complex of CECs (occludin, claudin-5, and α-catenin) in the white matter compared with the cerebral cortex. Accordingly, occludin, claudin-5, and α-catenin proteins showed increased expression in CECs of the white matter compared with endothelial cells of the cortical grey matter. In parallel, barrier properties of white matter CECs were superior as well. These differences might be important in the pathogenesis of diseases differently affecting distinct regions of the brain.

Anthropogenic Iron Oxide Nanoparticles Induce Damage to Brain Microvascular Endothelial Cells Forming the Blood-Brain Barrier

2021 ◽  
Author(s):  
Lorena Gárate-Vélez ◽  
Claudia Escudero-Lourdes ◽  
Daniela Salado-Leza ◽  
Armando González-Sánchez ◽  
Ildemar Alvarado-Morales ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Brain Microvascular Endothelial Cells ◽  
Blood Brain ◽  
Fe3o4 Nps ◽  
Microvascular Endothelial ◽  
The Brain

Background: Iron nanoparticles, mainly in magnetite phase (Fe3O4 NPs), are released to the environment in areas with high traffic density and braking frequency. Fe3O4 NPs were found in postmortem human brains and are assumed to get directly into the brain through the olfactory nerve. However, these pollution-derived NPs may also translocate from the lungs to the bloodstream and then, through the blood-brain barrier (BBB), into the brain inducing oxidative and inflammatory responses that contribute to neurodegeneration. Objective: To describe the interaction and toxicity of pollution-derived Fe3O4 NPs on primary rat brain microvascular endothelial cells (rBMECs), main constituents of in vitro BBB models. Methods: Synthetic bare Fe3O4 NPs that mimic the environmental ones (miFe3O4) were synthesized by co-precipitation and characterized using complementary techniques. The rBMECs were cultured in Transwell® plates. The NPs-cell interaction was evaluated through transmission electron microscopy and standard colorimetric in vitro assays. Results: The miFe3O4 NPs, with a mean diameter of 8.45 ± 0.14 nm, presented both magnetite and maghemite phases, and showed super-paramagnetic properties. Results suggest that miFe3O4 NPs are internalized by rBMECs through endocytosis and that they are able to cross the cells monolayer. The lowest miFe3O4 NPs concentration tested induced mid cytotoxicity in terms of 1) membrane integrity (LDH release) and 2) metabolic activity (MTS transformation). Conclusion: Pollution-derived Fe3O4 NPs may interact and cross the microvascular endothelial cells forming the BBB and cause biological damage.

Real Brains and Model Brains

1989 ◽  
Author(s):  
Roger Penrose ◽  
Martin Gardner
Keyword(s):  
Cerebral Cortex ◽  
White Matter ◽  
Grey Matter ◽  
Cerebral Hemispheres ◽  
Human Beings ◽  
Surface Layers ◽  
Alan Turing ◽  
The World ◽  
Left And Right ◽  
The Brain

Inside our heads is a magnificent structure that controls our actions and somehow evokes an awareness of the world around. Yet, as Alan Turing once put it, it resembles nothing so much as a bowl of cold porridge! It is hard to see how an object of such unpromising appearance can achieve the miracles that we know it to be capable of. Closer examination, however, begins to reveal the brain as having a much more intricate structure and sophisticated organization. The large convoluted (and most porridge-like) portion on top is referred to as the cerebrum. It is divided cleanly down the middle into left and right cerebral hemispheres, and considerably less cleanly front and back into the frontal lobe and three other lobes: the parietal, temporal and occipital. Further down, and at the back lies a rather smaller, somewhat spherical portion of the brain - perhaps resembling two balls of wool - the cerebellum. Deep inside, and somewhat hidden under the cerebrum, lie a number of curious and complicated-looking different structures: the pons and medulla (including the reticular formation, a region that will concern us later) which constitute the brain-stem, the thalamus, hypothalamus, hippocampus, corpus callosum, and many other strange and oddly named constructions. The part that human beings feel that they should be proudest of is the cerebrum - for that is not only the largest part of the human brain, but it is also larger, in its proportion of the brain as a whole, in man than in other animals. (The cerebellum is also larger in man than in most other animals.) The cerebrum and cerebellum have comparatively thin outer surface layers of grey matter and larger inner regions of white matter. These regions of grey matter are referred to as, respectively, the cerebral cortex and the cerebellar cortex. The grey matter is where various kinds of computational task appear to be performed, while the white matter consists of long nerve fibres carrying signals from one part of the brain to another. Various parts of the cerebral cortex are associated with very specific functions.

Capabilities of selenoneine to cross the in vitro blood-brain barrier model

Metallomics ◽  
2020 ◽  
Author(s):  
Evgenii Drobyshev ◽  
Stefanie Raschke ◽  
Ronald A Glabonjat ◽  
Julia Bornhorst ◽  
Franziska Ebert ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Culture Media ◽  
Speciation Analysis ◽  
Biological Properties ◽  
Brain Barrier ◽  
Blood Brain ◽  
Icp Ms ◽  
The Brain

Abstract The naturally occurring selenoneine (SeN), the selenium analogue of the sulfur-containing antioxidant ergothioneine, can be found in high abundance in several marine fish species. However, data on biological properties of SeN and its relevance for human health is still scarce. This study aims to investigate the transfer and presystemic metabolism of SeN in a well-established in vitro model of the blood-brain barrier (BBB). Therefore, the SeN and the reference Se species selenite and Se-methylselenocysteine (MeSeCys) were applied to primary porcine endothelial cells (PBCECs). Se content of culture media and cell lysates were measured via ICP-MS-MS. Speciation analysis was conducted by HPLC-ICP-MS. Barrier integrity was shown to be unaffected during transfer experiments. SeN demonstrated the lowest transfer rates and permeability coefficient (6.7 × 10−7 cm s−1) in comparison to selenite and MeSeCys. No side-directed accumulation was observed after both-sided application of SeN. However, concentration dependent transfer of SeN indicate possible presence of transporters on the both sides of the barrier. Speciation analysis demonstrated no methylation of SeN by the PBCECs. Several derivatives of SeN detected in the media of the BBB model were also found in cell free media containing SeN and hence not considered to be true metabolites of the PBCEC cells. Concluding, SeN is likely to have a slow transfer rate to the brain and not being metabolized by the brain endothelial cells. Since this study demonstrates, that SeN may reach the brain tissue, further studies are needed to investigate possible health-promoting effects of SeN in humans.

scholarly journals The insulin receptor is expressed and functional in cultured blood-brain barrier endothelial cells but does not mediate insulin entry from blood to brain

2018 ◽  
Vol 315 (4) ◽  
pp. E531-E542 ◽  
Author(s):  
Maria Hersom ◽  
Hans C. Helms ◽  
Christoffer Schmalz ◽  
Thomas Å. Pedersen ◽  
Stephen T. Buckley ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Insulin Receptor ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Insulin Transport ◽  
Blood Brain ◽  
The Brain ◽  
Receptor Inhibitor

Insulin and its receptor are known to be present and functional in the brain. Insulin cerebrospinal fluid concentrations have been shown to correlate with plasma levels of insulin in a nonlinear fashion, indicative of a saturable transport pathway from the blood to the brain interstitial fluid. The aim of the present study was to investigate whether insulin was transported across brain endothelial cells in vitro via an insulin receptor-dependent pathway. The study showed that the insulin receptor was expressed at both the mRNA and protein levels in bovine brain endothelial cells. Luminally applied radiolabeled insulin showed insulin receptor-mediated binding to the endothelial cells. This caused a dose-dependent increase in Akt-phosphorylation, which was inhibited by coapplication of an insulin receptor inhibitor, s961, demonstrating activation of insulin receptor signaling pathways. Transport of insulin across the blood-brain barrier in vitro was low and comparable to that of a similarly sized paracellular marker. Furthermore, insulin transport was not inhibited by coapplication of an excess of unlabeled insulin or an insulin receptor inhibitor. The insulin transport and uptake studies were repeated in mouse brain endothelial cells demonstrating similar results. Although it cannot be ruled out that culture-induced changes in the cell model could have impaired a potential insulin transport mechanism, these in vitro data indicate that peripheral insulin must reach the brain parenchyma through alternative pathways rather than crossing the blood-brain barrier via receptor mediated transcytosis.

Clinical experience with the E.M.I. scanner

1977 ◽  
Vol 195 (1119) ◽  
pp. 291-297
Keyword(s):  
White Matter ◽  
Grey Matter ◽  
Wide Spectrum ◽  
Three Dimensional ◽  
Cerebral Atrophy ◽  
Ventricular System ◽  
Presenile Dementia ◽  
Dimensional Reconstruction ◽  
Cortical Grey Matter ◽  
The Brain

Computerized tomography of the head using the E.M.I. scanner is a revolutionary method for diagnosing a wide spectrum of intracranial diseases. Because small differences in tissue density can be measured accurately the technique is sufficiently sensitive to demonstrate the ventricular system and major subarachnoid cisterns. The cortical grey matter, basal ganglia and thalami can be distinguished from white matter. A three-dimensional reconstruction of the brain is possible by examining a vertical sequence of transverse ‘slices’. Dilatation of the ventricular system is readily seen and since cortical sulcal enlargement is also shown, a diagnosis of cerebral atrophy can be made. This removes the need for pneumoencephalography in the majority of patients presenting with presenile dementia.

scholarly journals Cryptococcal Yeast Cells Invade the Central Nervous System via Transcellular Penetration of the Blood-Brain Barrier

2004 ◽  
Vol 72 (9) ◽  
pp. 4985-4995 ◽  
Author(s):  
Yun C. Chang ◽  
Monique F. Stins ◽  
Michael J. McCaffery ◽  
Georgina F. Miller ◽  
Dan R. Pare ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Yeast Cells ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Brain

ABSTRACT Cryptococcal meningoencephalitis develops as a result of hematogenous dissemination of inhaled Cryptococcus neoformans from the lung to the brain. The mechanism(s) by which C. neoformans crosses the blood-brain barrier (BBB) is a key unresolved issue in cryptococcosis. We used both an in vivo mouse model and an in vitro model of the human BBB to investigate the cryptococcal association with and traversal of the BBB. Exposure of human brain microvascular endothelial cells (HBMEC) to C. neoformans triggered the formation of microvillus-like membrane protrusions within 15 to 30 min. Yeast cells of C. neoformans adhered to and were internalized by the HBMEC, and they crossed the HBMEC monolayers via a transcellular pathway without affecting the monolayer integrity. The histopathology of mouse brains obtained after intravenous injection of C. neoformans showed that the yeast cells either were associated with endothelial cells or escaped from the brain capillary vessels into the neuropil by 3 h. C. neoformans was found in the brain parenchyma away from the vessels by 22 h. Association of C. neoformans with the choroid plexus, however, was not detected during up to 10 days of observation. Our findings indicate that C. neoformans cells invade the central nervous system by transcellular crossing of the endothelium of the BBB.

scholarly journals Mechanical property alterations across the cerebral cortex due to Alzheimer’s disease

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Lucy V Hiscox ◽  
Curtis L Johnson ◽  
Matthew D J McGarry ◽  
Helen Marshall ◽  
Craig W Ritchie ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Mechanical Property ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
White Matter ◽  
Grey Matter ◽  
Region Of Interest ◽  
Voxel Based Morphometry ◽  
Cortical Grey Matter ◽  
Post Hoc

Abstract Alzheimer’s disease is a personally devastating neurodegenerative disorder and a major public health concern. There is an urgent need for medical imaging techniques that better characterize the early stages and monitor the progression of the disease. Magnetic resonance elastography (MRE) is a relatively new and highly sensitive MRI technique that can non-invasively assess tissue microstructural integrity via measurement of brain viscoelastic mechanical properties. For the first time, we use high-resolution MRE methods to conduct a voxel-wise MRE investigation and state-of-the-art post hoc region of interest analysis of the viscoelastic properties of the cerebral cortex in patients with Alzheimer’s disease (N = 11) compared with cognitively healthy older adults (N = 12). We replicated previous findings that have reported significant volume and stiffness reductions at the whole-brain level. Significant reductions in volume were also observed in Alzheimer’s disease when white matter, cortical grey matter and subcortical grey matter compartments were considered separately; lower stiffness was also observed in white matter and cortical grey matter, but not in subcortical grey matter. Voxel-based morphometry of both cortical and subcortical grey matter revealed localized reductions in volume due to Alzheimer’s disease in the hippocampus, fusiform, middle, superior temporal gyri and precuneus. Similarly, voxel-based MRE identified lower stiffness in the middle and superior temporal gyri and precuneus, although the spatial distribution of these effects was not identical to the pattern of volume reduction. Notably, MRE additionally identified stiffness deficits in the operculum and precentral gyrus located within the frontal lobe; regions that did not undergo volume loss identified through voxel-based morphometry. Voxel-based-morphometry and voxel-based MRE results were confirmed by a complementary post hoc region-of-interest approach in native space where the viscoelastic changes remained significant even after statistically controlling for regional volumes. The pattern of reduction in cortical stiffness observed in Alzheimer’s disease patients raises the possibility that MRE may provide unique insights regarding the neural mechanisms which underlie the development and progression of the disease. The measured mechanical property changes that we have observed warrant further exploration to investigate the diagnostic usefulness of MRE in cases of Alzheimer’s disease and other dementias.

The First Step into the Brain: Uptake of NIO-PBCA Nanoparticles by Endothelial Cells in vitro and in vivo, and Direct Evidence for their Blood-Brain Barrier Permeation

ChemMedChem ◽  
2008 ◽  
Vol 3 (9) ◽  
pp. 1395-1403 ◽  
Author(s):  
Clemens K. Weiss ◽  
Maria-Verena Kohnle ◽  
Katharina Landfester ◽  
Thomas Hauk ◽  
Dietmar Fischer ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Direct Evidence ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Blood Brain ◽  
The Brain

scholarly journals Is LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?

2021 ◽  
Vol 22 (9) ◽  
pp. 4998
Author(s):  
Elvira S. Sandin ◽  
Julica Folberth ◽  
Helge Müller-Fielitz ◽  
Claus U. Pietrzik ◽  
Elisabeth Herold ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Leptin Receptor ◽  
Brain Barrier ◽  
Blood Brain ◽  
In Vitro Bbb Model ◽  
Porcine Endothelial Cells ◽  
The Brain

The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described.

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.

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