Mechanism of L-glucose, raffinose, and inulin transport across intact blood-brain barriers

1990 ◽  
Vol 258 (3) ◽  
pp. H695-H705 ◽  
Author(s):  
K. J. Lucchesi ◽  
R. E. Gosselin
Keyword(s):  
Molecular Size ◽  
Compartment Model ◽  
Graphical Analysis ◽  
Capillary Endothelium ◽  
Multiple Time ◽  
Brain Capillary ◽  
Molecular Weights ◽  
Blood Brain ◽  
Two Compartment Model ◽  
The Brain

Brain capillary permeability-surface area products (PS) of hydrophilic solutes were evaluated in terms of a conventional two-compartment model. In rats whose blood-brain barrier (BBB) was presumed to be intact, metabolically inert carbohydrates with different molecular weights were injected in pairs to elucidate whether their transfer into the brain proceeds by diffusion through water- or lipid-filled channels or by vesicular transport. The distribution volume of 70 kDa dextran 10 min after intravenous injection was used as a measure of the residual volume of plasma in brain tissue after death. The two-compartment model yielded larger PS values for inulin and raffinose than for L-glucose, and the PS values of inulin and L-glucose were found to decrease as the labeling time was lengthened (10, 30, and 60 min). These observations were interpreted to mean that a rapidly equilibrating compartment was present between blood and brain, rendering the two-compartment model inadequate for computing true transfer rate constants. When multiple-time uptake data were reanalyzed using the three-compartment graphical analysis of Patlak, Blasberg, and Fenstermacher (J. Cereb. Blood Flow Metab. 3: 1-7, 1983), solutes of differing molecular size were found to enter the brain at approximately equal rates. This observation suggested that the predominant transport mechanism across an intact BBB is vesicular. Specifically, unidirectional transport is likely to be initiated by solute binding to the glycocalyx on the luminal surface of brain capillary endothelium. Apparently more inulin than L-glucose is absorbed, which may account for its slightly faster transfer across the BBB. We suggest that this adsorptive surface is the location of the rapidly equilibrating compartment on the plasma side of the BBB.

scholarly journals The pericyte–glia interface at the blood–brain barrier

2018 ◽  
Vol 132 (3) ◽  
pp. 361-374 ◽  
Author(s):  
Patrizia Giannoni ◽  
Jerome Badaut ◽  
Cyril Dargazanli ◽  
Alexis Fayd’Herbe De Maudave ◽  
Wendy Klement ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Glial Cells ◽  
Outer Wall ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Brain Capillary ◽  
Multicellular Structure ◽  
Blood Brain ◽  
Acute Insult ◽  
The Brain

The cerebrovasculature is a multicellular structure with varying rheological and permeability properties. The outer wall of the brain capillary endothelium is enclosed by pericytes and astrocyte end feet, anatomically assembled to guarantee barrier functions. We, here, focus on the pericyte modifications occurring in disease conditions, reviewing evidence supporting the interplay amongst pericytes, the endothelium, and glial cells in health and pathology. Deconstruction and reactivity of pericytes and glial cells around the capillary endothelium occur in response to traumatic brain injury, epilepsy, and neurodegenerative disorders, impacting vascular permeability and participating in neuroinflammation. As this represents a growing field of research, addressing the multicellular reorganization occurring at the outer wall of the blood-brain barrier (BBB) in response to an acute insult or a chronic disease could disclose novel disease mechanisms and therapeutic targets.

Modulation of p-Glycoprotein Transport Function at the Blood-Brain Barrier

2005 ◽  
Vol 230 (2) ◽  
pp. 118-127 ◽  
Author(s):  
Björn Bauer ◽  
Anika M. S. Hartz ◽  
Gert Fricker ◽  
David S. Miller
Keyword(s):  
Blood Brain Barrier ◽  
Viral Infections ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Brain Capillary ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Junctional Permeability ◽  
Capillary Endothelial Cells ◽  
The Brain

The central nervous system (CNS) effects of many therapeutic drugs are blunted because of restricted entry into the brain. The basis for this poor permeability is the brain capillary endothelium, which comprises the blood-brain barrier. This tissue exhibits very low paracellular (tight-junctional) permeability and expresses potent, multispecific, drug export pumps. Together, these combine to limit use of pharmacotherapy to treat CNS disorders such as brain cancer and bacterial or viral infections. Of all the xenobiotic efflux pumps highly expressed in brain capillary endothelial cells, p-glycoprotein handles the largest fraction of commonly prescribed drugs and thus is an obvious target for manipulation. Here we review recent studies focused on understanding the mechanisms by which p-glycoprotein activity in the blood-brain barrier can be modulated. These include (i) direct inhibition by specific competitors, (ii) functional modulation, and (iii) transcriptional modulation. Each has the potential to specifically reduce p-glycoprotein function and thus selectively increase brain permeability of p-glycoprotein substrates.

Changes in the glucose transporter of brain capillaries

1992 ◽  
Vol 70 (S1) ◽  
pp. S113-S117 ◽  
Author(s):  
Sami I. Harik
Keyword(s):  
Alzheimer Disease ◽  
Blood Brain Barrier ◽  
Glucose Transporter ◽  
Glucose Transporters ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Brain Capillaries ◽  
Glut 1 ◽  
Blood Brain ◽  
The Brain

Brain capillary endothelium has a high density of the GLUT-1 facilitative glucose transporter protein. This is reasonable in view of the brain's high metabolic rate for glucose and its isolation behind unique capillaries with blood – brain barrier properties. Thus, the brain endothelium, which constitutes less than 0.1% of the brain weight, has to transport glucose for the much larger mass of surrounding neurons and glia. I describe here the changes that occur in the density of glucose transporters in brain capillaries of subjects with Alzheimer disease, where there is a decreased cerebral metabolic rate for glucose, and in a novel clinical entity characterized by defective glucose transport at the blood – brain barrier. In subjects with Alzheimer disease, cerebral microvessels showed a marked decrease in the density of the glucose transporter when compared with age-matched controls, but there was no change in the density of glucose transporters in erythrocyte membranes. Thus, I believe that the decreased density of glucose transporters in the brains of subjects with Alzheimer disease is the result rather than the cause of the disease. In contradistinction, the primary defect in glucose transport at the blood – brain barrier in subjects with the recently described entity is associated with decreased density of GLUT-1 in erythrocyte membranes.Key words: brain microvessels, capillary endothelium, blood – brain barrier, glucose transporter, Alzheimer disease, hypoglycorrhachia.

scholarly journals Cerebral Blood Flow and Blood—Brain Influx of Some Neutral Amino Acids in Control and Hypothyroid 16-Day-Old Rats

1985 ◽  
Vol 5 (2) ◽  
pp. 318-326 ◽  
Author(s):  
J. M. Lefauconnier ◽  
P. Lacombe ◽  
G. Bernard
Keyword(s):  
Amino Acids ◽  
Plasma Volume ◽  
Brain Capillary ◽  
Neutral Amino Acids ◽  
Luminal Membrane ◽  
Brain Extraction ◽  
Blood Brain ◽  
Capillary Endothelial Cells ◽  
Capillary Bed ◽  
The Brain

Rats were made hypothyroid by a daily subcutaneous injection of propylthiouracil beginning the first day after birth. CBF, brain plasma volume, blood–brain extraction, and influx of some neutral amino acids were studied in 16-day-old animals. In hypothyroid rats, the brain plasma volume was decreased by ∼30%. CBF was decreased by >50%. This decrease was the highest in cerebellum. Blood–brain extraction of small neutral amino acids (alanine, serine, cysteine) was greatly enhanced. This greater extraction compensated for the decreased supply of alanine brought about by its decreased plasma concentration and the lower CBF. In contrast, the extraction of the large amino acids tested (leucine, phenylalanine) was hardly increased, and the influx of phenylalanine was slightly decreased. These results suggest an alteration in the maturation of the brain capillary bed and capillary transport for neutral amino acids in hypothyroidism. The differential effect of hypothyroidism on some small and large amino acids is an additional argument for the existence of two systems of transport for neutral amino acids at the luminal membrane of brain capillary endothelial cells of immature rats.

scholarly journals Robust Multi-TE ASL-Based Blood–Brain Barrier Integrity Measurements

2021 ◽  
Vol 15 ◽  
Author(s):  
Amnah Mahroo ◽  
Mareike Alicja Buck ◽  
Jörn Huber ◽  
Nora-Josefin Breutigam ◽  
Henk J. M. M. Mutsaerts ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Transit Time ◽  
Grey Matter ◽  
Compartment Model ◽  
Brain Barrier ◽  
Extended Model ◽  
Blood Brain ◽  
Two Compartment Model ◽  
Bbb Permeability

Multiple echo-time arterial spin labelling (multi-TE ASL) offers estimation of blood–tissue exchange dynamics by probing the T2 relaxation of the labelled spins. In this study, we provide a recipe for robust assessment of exchange time (Texch) as a proxy measure of blood–brain barrier (BBB) integrity based on a test-retest analysis. This includes a novel scan protocol and an extension of the two-compartment model with an “intra-voxel transit time” (ITT) to address tissue transit effects. With the extended model, we intend to separate the underlying two distinct mechanisms of tissue transit and exchange. The performance of the extended model in comparison with the two-compartment model was evaluated in simulations. Multi-TE ASL sequence with two different bolus durations was used to acquire in vivo data (n = 10). Cerebral blood flow (CBF), arterial transit time (ATT) and Texch were fitted with the two models, and mean grey matter values were compared. Additionally, the extended model also extracted ITT parameter. The test-retest reliability of Texch was assessed for intra-session, inter-session and inter-visit pairs of measurements. Intra-class correlation coefficient (ICC) and within-subject coefficient of variance (CoV) for grey matter were computed to assess the precision of the method. Mean grey matter Texch and ITT values were found to be 227.9 ± 37.9 ms and 310.3 ± 52.9 ms, respectively. Texch estimated by the extended model was 32.6 ± 5.9% lower than the two-compartment model. A significant ICC was observed for all three measures of Texch reliability (P < 0.05). Texch intra-session CoV, inter-session CoV and inter-visit CoV were found to be 6.6%, 7.9%, and 8.4%, respectively. With the described improvements addressing intra-voxel transit effects, multi-TE ASL shows good reproducibility as a non-invasive measure of BBB permeability. These findings offer an encouraging step forward to apply this potential BBB permeability biomarker in clinical research.

scholarly journals Dynamic Study of Blood–Brain Barrier Closure after its Disruption using Ultrasound: A Quantitative Analysis

2012 ◽  
Vol 32 (10) ◽  
pp. 1948-1958 ◽  
Author(s):  
Benjamin Marty ◽  
Benoit Larrat ◽  
Maxime Van Landeghem ◽  
Caroline Robic ◽  
Philippe Robert ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Focal Point ◽  
Molecular Size ◽  
Brain Barrier ◽  
Hydrodynamic Diameter ◽  
Power Ultrasound ◽  
Blood Brain ◽  
Ultrasound Sonication ◽  
The Brain ◽  
Bbb Opening

Delivery of therapeutic or diagnostic agents to the brain is majorly hindered by the blood–brain barrier (BBB). Recently, many studies have demonstrated local and transient disruption of the BBB using low power ultrasound sonication combined with intravascular microbubbles. However, BBB opening and closure mechanisms are poorly understood, especially the maximum gap that may be safely generated between endothelial cells and the duration of opening of the BBB. Here, we studied BBB opening and closure under magnetic resonance (MR) guidance in a rat model. First, MR contrast agents (CA) of different hydrodynamic diameters (1 to 65 nm) were employed to estimate the largest molecular size permissible across the cerebral tissues. Second, to estimate the duration of the BBB opening, the CA were injected at various times post-BBB disruption (12 minutes to 24 hours). A T1 mapping strategy was developed to assess CA concentration at the ultrasound (US) focal point. Based on our experimental data and BBB closure modeling, a calibration curve was obtained to compute the half closure time as a function of CA hydrodynamic diameter. These findings and the model provide an invaluable basis for optimal design and delivery of nanoparticles to the brain.

scholarly journals A New Function for the LDL Receptor: Transcytosis of LDL across the Blood–Brain Barrier

1997 ◽  
Vol 138 (4) ◽  
pp. 877-889 ◽  
Author(s):  
Bénédicte Dehouck ◽  
Laurence Fenart ◽  
Marie-Pierre Dehouck ◽  
Annick Pierce ◽  
Gérard Torpier ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cytoplasmic Domain ◽  
Brain Barrier ◽  
Classical Pathway ◽  
Brain Capillary ◽  
Blood Brain ◽  
The Brain

Lipoprotein transport across the blood–brain barrier (BBB) is of critical importance for the delivery of essential lipids to the brain cells. The occurrence of a low density lipoprotein (LDL) receptor on the BBB has recently been demonstrated. To examine further the function of this receptor, we have shown using an in vitro model of the BBB, that in contrast to acetylated LDL, which does not cross the BBB, LDL is specifically transcytosed across the monolayer. The C7 monoclonal antibody, known to interact with the LDL receptor-binding domain, totally blocked the transcytosis of LDL, suggesting that the transcytosis is mediated by the receptor. Furthermore, we have shown that cholesterol-depleted astrocytes upregulate the expression of the LDL receptor at the BBB. Under these conditions, we observed that the LDL transcytosis parallels the increase in the LDL receptor, indicating once more that the LDL is transcytosed by a receptor-mediated mechanism. The nondegradation of the LDL during the transcytosis indicates that the transcytotic pathway in brain capillary endothelial cells is different from the LDL receptor classical pathway. The switch between a recycling receptor to a transcytotic receptor cannot be explained by a modification of the internalization signals of the cytoplasmic domain of the receptor, since we have shown that LDL receptor messengers in growing brain capillary ECs (recycling LDL receptor) or differentiated cells (transcytotic receptor) are 100% identical, but we cannot exclude posttranslational modifications of the cytoplasmic domain, as demonstrated for the polymeric immunoglobulin receptor. Preliminary studies suggest that caveolae are likely to be involved in the potential transport of LDL from the blood to the brain.

scholarly journals Quantification of monoacylglycerol lipase and its occupancy by an exogenous ligand in rhesus monkey brains using [18F]T-401 and PET

2021 ◽  
pp. 0271678X2110582
Author(s):  
Yasushi Hattori ◽  
Chie Seki ◽  
Jun Maeda ◽  
Yuji Nagai ◽  
Kazunobu Aoyama ◽  
...  
Keyword(s):  
Rhesus Monkey ◽  
Specific Binding ◽  
Rank Order ◽  
Endocannabinoid System ◽  
Compartment Model ◽  
Graphical Analysis ◽  
Monoacylglycerol Lipase ◽  
Serine Hydrolase ◽  
Time Activity ◽  
The Brain

Monoacylglycerol lipase (MAGL) is a cytosolic serine hydrolase that cleaves monoacylglycerols into fatty acids and is a potential target for the novel treatment of CNS disorders related to the endocannabinoid system and neuroinflammation. We have developed [18F]T-401 as a selective Positron emission tomography (PET) imaging agent for MAGL. In this study, we determined an analytical method to quantify MAGL availability and its occupancy by an exogenous inhibitor in rhesus monkey brains using [18F]T-401-PET. In rhesus monkeys, regional time-activity curves were described well when using an extended 2-tissue compartment model that accommodated the formation of a radiometabolite in the brain. This model yielded reliable estimates of the total distribution volume ( VT), and the rank order of VT was consistent with known regional activity of MAGL enzyme in primates. The pretreatment of monkeys with JW642 resulted in a dose-dependent reduction of [18F]T-401 retentions in the brain, and VT. Lassen's graphical analysis indicated a VND of 0.69 mL/cm3 and a plasma JW642 concentration of 126 ng/mL for inhibiting the specific binding by 50%. [18F]T-401 and the method established can be used for quantification of MAGL in healthy brain and in disease conditions, and is suitable for evaluations of target engagement at cerebral MAGL.

scholarly journals The Role of Cytoskeletal Proteins in the Formation of a Functional In Vitro Blood-Brain Barrier Model

2022 ◽  
Vol 23 (2) ◽  
pp. 742
Author(s):  
Shireen Mentor ◽  
Khayelihle Brian Makhathini ◽  
David Fisher
Keyword(s):  
Blood Brain Barrier ◽  
Cellular Proliferation ◽  
Cytoskeletal Proteins ◽  
Brain Barrier ◽  
Capillary Endothelium ◽  
Brain Capillary ◽  
Blood Brain ◽  
Blood Brain Barrier Model

The brain capillary endothelium is highly regulatory, maintaining the chemical stability of the brain’s microenvironment. The role of cytoskeletal proteins in tethering nanotubules (TENTs) during barrier-genesis was investigated using the established immortalized mouse brain endothelial cell line (bEnd5) as an in vitro blood-brain barrier (BBB) model. The morphology of bEnd5 cells was evaluated using both high-resolution scanning electron microscopy and immunofluorescence to evaluate treatment with depolymerizing agents Cytochalasin D for F-actin filaments and Nocodazole for α-tubulin microtubules. The effects of the depolymerizing agents were investigated on bEnd5 monolayer permeability by measuring the transendothelial electrical resistance (TEER). The data endorsed that during barrier-genesis, F-actin and α-tubulin play a cytoarchitectural role in providing both cell shape dynamics and cytoskeletal structure to TENTs forming across the paracellular space to provide cell-cell engagement. Western blot analysis of the treatments suggested a reduced expression of both proteins, coinciding with a reduction in the rates of cellular proliferation and decreased TEER. The findings endorsed that TENTs provide alignment of the paracellular (PC) spaces and tight junction (TJ) zones to occlude bEnd5 PC spaces. The identification of specific cytoskeletal structures in TENTs endorsed the postulate of their indispensable role in barrier-genesis and the maintenance of regulatory permeability across the BBB.

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