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Sample records for brain barrier permeability

  1. Endocannabinoids modulate human blood–brain barrier permeability in vitro

    Science.gov (United States)

    Hind, William H; Tufarelli, Cristina; Neophytou, Maria; Anderson, Susan I; England, Timothy J; O'Sullivan, Saoirse E

    2015-01-01

    Background and Purpose Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood–brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model. Experimental Approach Human brain microvascular endothelial cell and astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Endocannabinoids or endocannabinoid-like compounds were assessed for their ability to modulate baseline permeability or OGD-induced hyperpermeability. Target sites of action were investigated using receptor antagonists and subsequently identified with real-time PCR. Key Results Anandamide (10 μM) and oleoylethanolamide (OEA, 10 μM) decreased BBB permeability (i.e. increased resistance). This was mediated by cannabinoid CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) channels, calcitonin gene-regulated peptide (CGRP) receptor (anandamide only) and PPARα (OEA only). Application of OEA, palmitoylethanolamide (both PPARα mediated) or virodhamine (all 10 μM) decreased the OGD-induced increase in permeability during reperfusion. 2-Arachidonoyl glycerol, noladin ether and oleamide did not affect BBB permeability in normal or OGD conditions. N-arachidonoyl-dopamine increased permeability through a cytotoxic mechanism. PPARα and γ, CB1 receptors, TRPV1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB2 receptors was only present in astrocytes. Conclusion and Implication The endocannabinoids may play an important modulatory role in normal BBB physiology, and also afford protection to the BBB during ischaemic stroke, through a number of target sites. PMID:25651941

  2. Endocannabinoids modulate human blood-brain barrier permeability in vitro.

    Science.gov (United States)

    Hind, William H; Tufarelli, Cristina; Neophytou, Maria; Anderson, Susan I; England, Timothy J; O'Sullivan, Saoirse E

    2015-06-01

    Endocannabinoids alter permeability at various epithelial barriers, and cannabinoid receptors and endocannabinoid levels are elevated by stroke, with potential neuroprotective effects. We therefore explored the role of endocannabinoids in modulating blood-brain barrier (BBB) permeability in normal conditions and in an ischaemia/reperfusion model. Human brain microvascular endothelial cell and astrocyte co-cultures modelled the BBB. Ischaemia was modelled by oxygen-glucose deprivation (OGD) and permeability was measured by transepithelial electrical resistance. Endocannabinoids or endocannabinoid-like compounds were assessed for their ability to modulate baseline permeability or OGD-induced hyperpermeability. Target sites of action were investigated using receptor antagonists and subsequently identified with real-time PCR. Anandamide (10 μM) and oleoylethanolamide (OEA, 10 μM) decreased BBB permeability (i.e. increased resistance). This was mediated by cannabinoid CB2 receptors, transient receptor potential vanilloid 1 (TRPV1) channels, calcitonin gene-regulated peptide (CGRP) receptor (anandamide only) and PPARα (OEA only). Application of OEA, palmitoylethanolamide (both PPARα mediated) or virodhamine (all 10 μM) decreased the OGD-induced increase in permeability during reperfusion. 2-Arachidonoyl glycerol, noladin ether and oleamide did not affect BBB permeability in normal or OGD conditions. N-arachidonoyl-dopamine increased permeability through a cytotoxic mechanism. PPARα and γ, CB1 receptors, TRPV1 channels and CGRP receptors were expressed in both cell types, but mRNA for CB2 receptors was only present in astrocytes. The endocannabinoids may play an important modulatory role in normal BBB physiology, and also afford protection to the BBB during ischaemic stroke, through a number of target sites. © 2015 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  3. Blood-brain barrier permeability imaging using perfusion computed tomography

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    Avsenik Jernej

    2015-06-01

    Full Text Available Background. The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood-brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with pathologies such as acute stroke, tumors, inflammatory and neurodegenerative diseases.

  4. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis

    DEFF Research Database (Denmark)

    Cramer, Stig P; Modvig, Signe; Simonsen, Helle Juhl

    2015-01-01

    in the permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison...... with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging...... fluid as well as levels of CXCL10 and MMP9 in the cerebrospinal fluid. These findings suggest that blood-brain barrier permeability, as measured by magnetic resonance imaging, may provide novel pathological information as a marker of neuroinflammation related to multiple sclerosis, to some extent...

  5. Change in blood– brain barrier permeability during pediatric diabetic ketoacidosis treatment*

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    Vavilala, Monica S.; Richards, Todd L.; Roberts, Joan S.; Chiu, Harvey; Pihoker, Catherine; Bradford, Heidi; Deeter, Kristina; Marro, Ken I.; Shaw, Dennis

    2010-01-01

    Objective Cerebral edema is a devastating complication of pediatric diabetic ketoacidosis. We aimed to examine blood– brain barrier permeability during treatment of diabetic ketoacidosis in children. Design Prospective observational study. Setting Seattle Children’s Hospital, Seattle, WA. Patients Children admitted with diabetic ketoacidosis (pH 300 mg/dL, and ketosis). Interventions None. Measurements and Main Results Subjects underwent two serial paired contrast-enhanced perfusion (gadolinium) and diffusion magnetic resonance imaging scans. Change in whole brain and regional blood– brain barrier permeability (permeability ratio*100 and % permeability ratio change) between illness and recovery were determined. Time 0 reflects start of insulin treatment. Thirteen children (median age 10.0 ± 1.1 yrs; seven female) with diabetic ketoacidosis were enrolled. Permeability ratio increased from time 1 (first magnetic resonance image after time 0) to time 2 (second magnetic resonance image after time 0) in the frontal cortex (ten of 13 subjects), occipital cortex (ten of 13 subjects), and basal ganglia (nine of 13). Whole brain permeability ratio increased from time 1 to time 2 (160%) and regional increase in permeability ratio was greatest in the frontal cortex (148%) compared with the occipital cortex (128%) and basal ganglia (112%). Conclusions Overall, whole brain and regional blood– brain barrier permeability increased in most subjects during diabetic ketoacidosis treatment. The frontal region had more blood– brain barrier permeability than other brain regions examined. PMID:19838141

  6. Blood-brain barrier permeability and brain uptake mechanism of kainic Acid and dihydrokainic Acid

    DEFF Research Database (Denmark)

    Gynther, Mikko; Petsalo, Aleksanteri; Hansen, Steen Honoré

    2015-01-01

    tools in various in vivo central nervous system disease models in rodents, as well as being templates in the design of novel ligands affecting the glutamatergic system. Both molecules are highly polar but yet capable of crossing the blood-brain barrier (BBB). We used an in situ rat brain perfusion...... technique to determine the brain uptake mechanism and permeability across the BBB. To determine KA and DHK concentrations in the rat brain, simple and rapid sample preparation and liquid chromatography mass spectrometer methods were developed. According to our results the BBB permeability of KA and DHK...... is low, 0.25 × 10(-6) and 0.28 × 10(-6) cm/s for KA and DHK, respectively. In addition, the brain uptake is mediated by passive diffusion, and not by active transport. Furthermore, the non-specific plasma and brain protein binding of KA and DHK was determined to be low, which means that the unbound drug...

  7. Rapid and reversible enhancement of blood–brain barrier permeability using lysophosphatidic acid

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    On, Ngoc H; Savant, Sanjot; Toews, Myron; Miller, Donald W

    2013-01-01

    The present study characterizes the effects of lysophosphatidic acid (LPA) on blood–brain barrier (BBB) permeability focusing specifically on the time of onset, duration, and magnitude of LPA-induced changes in cerebrovascular permeability in the mouse using both magnetic resonance imaging (MRI) and near infrared fluorescence imaging (NIFR). Furthermore, potential application of LPA for enhanced drug delivery to the brain was also examined by measuring the brain accumulation of radiolabeled methotrexate. Exposure of primary cultured brain microvessel endothelial cells (BMECs) to LPA produced concentration-dependent increases in permeability that were completely abolished by clostridium toxin B. Administration of LPA disrupted BBB integrity and enhanced the permeability of small molecular weight marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRdye800cwPEG, and the P-glycoprotein efflux transporter probe, Rhodamine 800 (R800). The increase in BBB permeability occurred within 3 minutes after LPA injection and barrier integrity was restored within 20 minutes. A decreased response to LPA on large macromolecule BBB permeability was observed after repeated administration. The administration of LPA also resulted in 20-fold enhancement of radiolabeled methotrexate in the brain. These studies indicate that administration of LPA in combination with therapeutic agents may increase drug delivery to the brain. PMID:24045401

  8. The rights and wrongs of blood-brain barrier permeability studies

    DEFF Research Database (Denmark)

    Saunders, Norman R; Dreifuss, Jean-Jacques; Dziegielewska, Katarzyna M

    2014-01-01

    . The original concept of a blood-brain barrier is often attributed to Ehrlich; however, he did not accept that permeability of cerebral vessels was different from other organs. Goldmann is often credited with the first experiments showing dye (trypan blue) exclusion from the brain when injected systemically...

  9. Permeability of the blood-brain barrier to lead.

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    Bradbury, M W; Deane, R

    1993-01-01

    This review examines the kinetics and possible mechanisms of lead transport into brain across the microvessel endothelium (the blood-brain barrier). Although severe lead poisoning both in neonatal rats and in young children may cause microvessel damage, there is little evidence that there is either damage or even disturbance of specific transport mechanisms at blood leads linear with time up to 4 hours, reaching spaces in relation to plasma of 6.6 - 8.2 ml/100 g in cerebral tissues at one hour. The concentration of free Pb+ in serum is of the order of 10(-12)M, the majority of lead being bound to protein and to sulfhydryl compounds, such as L-cysteine. Transport into brain has been further studied during short vascular perfusion of one cerebral hemisphere of the rat with oxygenated and buffered physiological saline. This allows total control of the fluid perfusing the cerebral microvessels. In the absence of organic ligands for lead, 203Pb entered brain very fast, with a space of 9.7 ml/100 g in frontal cortex at one min. The presence of albumin, L-cysteine or EDTA abolished measurable uptake. Experiments designed to reveal a role for the anion exchanger or calcium channels gave negative results. However, the effects of potassium depolarization and of varying pH indicated that the lead species passively entering the endothelium might be PbOH+. Experiments with various metabolic inhibitors, including vanadate, suggested that Pb uptake in the endothelium is mitigated by active back transport of lead into blood by the Ca-ATPase pump.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. /GD-Tracker/ A software for blood-brain barrier permeability assessment\

    Czech Academy of Sciences Publication Activity Database

    Kala, David; Svoboda, Jan; Litvinec, Andrej; Pošusta, Antonín; Lisý, J.; Šulc, V.; Tomek, A.; Marusič, P.; Jiruška, Přemysl; Otáhal, Jakub

    2017-01-01

    Roč. 47, č. 2 (2017), s. 43-48 ISSN 0301-5491 R&D Projects: GA MZd(CZ) NV15-33115A; GA MŠk(CZ) LM2015062 Institutional support: RVO:67985823 Keywords : blood-brain barrier * MRI * Gd-DTPA * permeability * stroke * epileptogenesis * MATLAB * freeware * Gd-Tracker Subject RIV: FH - Neurology

  11. The diffusion permeability to water of the rat blood-brain barrier

    DEFF Research Database (Denmark)

    Bolwig, T G; Lassen, N A

    1975-01-01

    The diffusion permeability to water of the rat blood-brain-barrier (BBB) was studied. Preliminary data obtained with the Oldendorf tissue uptake method (Oldendorf 1970) in seizure experiments suggested that the transfer from blood to brain of labelled water is diffusion-limited. More definite evi...... passage increased from 0.26 to 0.67 when the arterial carbon dioxide tension was changed from 15 to 85 mm Hg, a change increasing the cerebral blood flow about sixfold. This finding suggests that water does not pass the blood-brain barrier as freely as lipophilic gases....

  12. [Changes in the permeability of the blood-brain barrier to oxythiamine].

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    Ostrovskiĭ, Iu M; Zimatkina, T I; Oparin, D A

    1985-01-01

    Activity of transketolase was distinctly inhibited in mice brain after simultaneous administration of hydroxythiamine and 3,3-dimethyl-l-phenyl-l-phthalyl acetic acid. The rate of the enzyme inhibition correlated with an increase of the acid concentration in the mixture studied. The data obtained suggest that permeability of blood-brain barrier for hydroxythiamine was altered in simultaneous administration of the vitamin with some biologically active preparations.

  13. Brain pericytes from stress-susceptible pigs increase blood-brain barrier permeability in vitro

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    Vandenhaute Elodie

    2012-06-01

    Full Text Available Abstract Background The function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is now emerging. The porcine stress syndrome (PSS is the only confirmed, homologous model of malignant hyperthermia (MH in veterinary medicine. Affected animals can experience upon slaughter a range of symptoms, including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, similar to the human syndrome. Symptoms are due to an enhanced calcium release from intracellular stores. These conditions are associated with a point mutation in ryr1/hal gene, encoding the ryanodine receptor, a calcium channel. Important blood vessel wall muscle modifications have been described in PSS, but potential brain vessel changes have never been documented in this syndrome. Methods In the present work, histological and ultrastructural analyses of brain capillaries from wild type and ryr1 mutated pigs were conducted to investigate the potential impairment of pericytes, in this pathology. In addition, brain pericytes were isolated from the three porcine genotypes (wild-type NN pigs; Nn and nn pigs, bearing one or two (n mutant ryr1/hal alleles, respectively, and tested in vitro for their influence on the permeability of BBB endothelial monolayers. Results Enlarged perivascular spaces were observed in ryr1-mutant samples, corresponding to a partial or total detachment of the astrocytic endfeet. These spaces were electron lucent and sometimes filled with lipid deposits and swollen astrocytic feet. At the ultrastructural level, brain pericytes did not seem to be affected because they showed regular morphology and characteristics, so we aimed to check their ability to maintain BBB properties in vitro. Our results indicated

  14. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier.

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    Shize Jiang

    Full Text Available The blood-brain barrier (BBB impedes entry of many drugs into the brain, limiting clinical efficacy. A safe and efficient method for reversibly increasing BBB permeability would greatly facilitate central nervous system (CNS drug delivery and expand the range of possible therapeutics to include water soluble compounds, proteins, nucleotides, and other large molecules. We examined the effect of vascular endothelial growth factor (VEGF on BBB permeability in Kunming (KM mice. Human VEGF165 was administered to treatment groups at two concentrations (1.6 or 3.0 µg/mouse, while controls received equal-volume saline. Changes in BBB permeability were measured by parenchymal accumulation of the contrast agent Gd-DTPA as assessed by 7 T magnetic resonance imaging (MRI. Mice were then injected with Evans blue, sacrificed 0.5 h later, and perfused transcardially. Brains were removed, fixed, and sectioned for histological study. Both VEGF groups exhibited a significantly greater signal intensity from the cerebral cortex and basal ganglia than controls (P<0.001. Evans blue fluorescence intensity was higher in the parenchyma and lower in the cerebrovasculature of VEGF-treated animals compared to controls. No significant brain edema was observed by diffusion weighted MRI (DWI or histological staining. Exogenous application of VEGF can increase the permeability of the BBB without causing brain edema. Pretreatment with VEGF may be a feasible method to facilitate drug delivery into the CNS.

  15. Abnormal blood-brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI

    DEFF Research Database (Denmark)

    Cramer, Stig Præstekær; Simonsen, Helle Juhl; Frederiksen, Jette Lautrup Battistini

    2013-01-01

    To investigate whether blood-brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics.......To investigate whether blood-brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics....

  16. Sirt1-Sirt3 axis regulates human blood-brain barrier permeability in response to ischemia

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    Tao Chen

    2018-04-01

    Full Text Available Sirtuin1 (Sirt1 and Sirtuin3 (Sirt3 are two well-characterized members of the silent information regulator 2 (Sir2 family of proteins. Both Sirt1 and Sirt3 have been shown to play vital roles in resistance to cellular stress, but the interaction between these two sirtuins has not been fully determined. In this study, we investigated the role of Sirt1-Sirt3 axis in blood-brain barrier (BBB permeability after ischemia in vitro. Human brain microvascular endothelial cells and astrocytes were co-cultured to model the BBB in vitro and oxygen and glucose deprivation (OGD was performed to mimic ischemia. The results of transepithelial electrical resistance (TEER showed that suppression of Sirt1 via siRNA or salermide significantly decreased BBB permeability, whereas Sirt3 knockdown increased BBB permeability. In addition, Sirt1 was shown to regulate Sirt3 expression after OGD through inhibiting the AMPK-PGC1 pathway. Application of the AMPK inhibitor compound C partially prevented the effects of Sirt1-Sirt3 axis on BBB permeability after OGD. The results of flow cytometry and cytochrome c release demonstrated that Sirt1 and Sirt3 exert opposite effects on OGD-induced apoptosis. Furthermore, suppression of Sirt1 was shown to attenuate mitochondrial reactive oxygen species (ROS generation, which contribute to the Sirt1-Sirt3 axis-induced regulation of BBB permeability and cell damage. In summary, these findings demonstrate that the Sirt1-Sirt3 axis might act as an important modulator in BBB physiology, and could be a therapeutic target for ischemic stroke via regulating mitochondrial ROS generation. Keywords: Stroke, Blood-brain barrier, Sirt1, Sirt3, Mitochondrial ROS

  17. Computational Prediction of Blood-Brain Barrier Permeability Using Decision Tree Induction

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    Jörg Huwyler

    2012-08-01

    Full Text Available Predicting blood-brain barrier (BBB permeability is essential to drug development, as a molecule cannot exhibit pharmacological activity within the brain parenchyma without first transiting this barrier. Understanding the process of permeation, however, is complicated by a combination of both limited passive diffusion and active transport. Our aim here was to establish predictive models for BBB drug permeation that include both active and passive transport. A database of 153 compounds was compiled using in vivo surface permeability product (logPS values in rats as a quantitative parameter for BBB permeability. The open source Chemical Development Kit (CDK was used to calculate physico-chemical properties and descriptors. Predictive computational models were implemented by machine learning paradigms (decision tree induction on both descriptor sets. Models with a corrected classification rate (CCR of 90% were established. Mechanistic insight into BBB transport was provided by an Ant Colony Optimization (ACO-based binary classifier analysis to identify the most predictive chemical substructures. Decision trees revealed descriptors of lipophilicity (aLogP and charge (polar surface area, which were also previously described in models of passive diffusion. However, measures of molecular geometry and connectivity were found to be related to an active drug transport component.

  18. Plasma from patients with HELLP syndrome increases blood-brain barrier permeability.

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    Wallace, Kedra; Tremble, Sarah M; Owens, Michelle Y; Morris, Rachael; Cipolla, Marilyn J

    2015-03-01

    Circulating inflammatory factors and endothelial dysfunction have been proposed to contribute to the pathophysiology of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. To date, the occurrence of neurological complications in these women has been reported, but few studies have examined whether impairment in blood-brain barrier (BBB) permeability or cerebrovascular reactivity is present in women having HELLP syndrome. We hypothesized that plasma from women with HELLP syndrome causes increased BBB permeability and cerebrovascular dysfunction. Posterior cerebral arteries from female nonpregnant rats were perfused with 20% serum from women with normal pregnancies (n = 5) or women with HELLP syndrome (n = 5), and BBB permeability and vascular reactivity were compared. Plasma from women with HELLP syndrome increased BBB permeability while not changing myogenic tone and reactivity to pressure. Addition of the nitric oxide (NO) synthase inhibitor N(ω)-nitro-L-arginine methyl ester caused constriction of arteries that was not different with the different plasmas nor was dilation to the NO donor sodium nitroprusside different between the 2 groups. However, dilation to the small- and intermediate-conductance, calcium-activated potassium channel activator NS309 was decreased in vessels exposed to HELLP plasma. Thus, increased BBB permeability in response to HELLP plasma was associated with selective endothelial dysfunction. © The Author(s) 2014.

  19. Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling.

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    Amburgey, Odül A; Chapman, Abbie C; May, Victor; Bernstein, Ira M; Cipolla, Marilyn J

    2010-11-01

    Circulating factors in preeclamptic women are thought to cause endothelial dysfunction and thereby contribute to the progression of this hypertensive condition. Despite the involvement of neurological complications in preeclampsia, there is a paucity of data regarding the effect of circulating factors on cerebrovascular function. Using a rat model of pregnancy, we investigated blood-brain barrier permeability, myogenic activity, and the influence of endothelial vasodilator mechanisms in cerebral vessels exposed intraluminally to plasma from normal pregnant or preeclamptic women. In addition, the role of vascular endothelial growth factor signaling in mediating changes in permeability in response to plasma was investigated. A 3-hour exposure to 20% normal pregnant or preeclamptic plasma increased blood-brain barrier permeability by ≈6.5- and 18.0-fold, respectively, compared with no plasma exposure (Pvascular endothelial growth factor receptor kinase activity prevented the increase in permeability in response to preeclamptic plasma but had no effect on changes in permeability of vessels exposed to normal pregnant plasma. Circulating factors in preeclamptic plasma did not affect myogenic activity or the influence of endothelium on vascular tone. These findings demonstrate that acute exposure to preeclamptic plasma has little effect on reactivity of cerebral arteries but significantly increases blood-brain barrier permeability. Prevention of increased permeability by inhibition of vascular endothelial growth factor signaling suggests that activation of this pathway may be responsible for increased blood-brain barrier permeability after exposure to preeclamptic plasma.

  20. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.

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    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea; Smieško, Martin; Culot, Maxime; Gosselet, Fabien; Cecchelli, Romeo; Helms, Hans Christian Cederberg; Brodin, Birger; Wimmer, Laurin; Mihovilovic, Marko D; Hamburger, Matthias; Oufir, Mouhssin

    2016-06-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Bexarotene reduces blood-brain barrier permeability in cerebral ischemia-reperfusion injured rats.

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    Lu Xu

    Full Text Available Matrix metalloproteinase-9 (MMP-9 over-expression disrupts the blood-brain barrier (BBB in the ischemic brain. The retinoid X receptor agonist bexarotene suppresses MMP-9 expression in endothelial cells and displays neuroprotective effects. Therefore, we hypothesized that bexarotene may have a beneficial effect on I/R-induced BBB dysfunction.A total of 180 rats were randomized into three groups (n = 60 each: (i a sham-operation group, (ii a cerebral ischemia-reperfusion (I/R group, and (iii an I/R+bexarotene group. Brain water content was measured by the dry wet weight method. BBB permeability was analyzed by Evans Blue staining and the magnetic resonance imaging contrast agent Omniscan. MMP-9 mRNA expression, protein expression, and activity were assessed by reverse transcription polymerase chain reaction, Western blotting, and gelatin zymography, respectively. Apolipoprotein E (apoE, claudin-5, and occludin expression were analyzed by Western blotting.After 24 h, 48 h, and 72 h post-I/R, several effects were observed with bexarotene administration: (i brain water content and BBB permeability were significantly reduced; (ii MMP-9 mRNA and protein expression as well as activity were significantly decreased; (iii claudin-5 and occludin expression were significantly increased; and (iv apoE expression was significantly increased.Bexarotene decreases BBB permeability in rats with cerebral I/R injury. This effect may be due in part to bexarotene's upregulation of apoE expression, which has been previously shown to reduce BBB permeability through suppressing MMP-9-mediated degradation of the tight junction proteins claudin-5 and occludin. This work offers insight to aid future development of therapeutic agents for cerebral I/R injury in human patients.

  2. Effects of GSM modulated radio-frequency electromagnetic radiation on permeability of blood-brain barrier in male & female rats.

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    Sırav, Bahriye; Seyhan, Nesrin

    2016-09-01

    With the increased use of mobile phones, their biological and health effects have become more important. Usage of mobile phones near the head increases the possibility of effects on brain tissue. This study was designed to investigate the possible effects of pulse modulated 900MHz and 1800MHz radio-frequency radiation on the permeability of blood-brain barrier of rats. Study was performed with 6 groups of young adult male and female wistar albino rats. The permeability of blood-brain barrier to intravenously injected evans blue dye was quantitatively examined for both control and radio-frequency radiarion exposed groups. For male groups; Evans blue content in the whole brain was found to be 0.08±0.01mg% in the control, 0.13±0.03mg% in 900MHz exposed and 0.26±0.05mg% in 1800MHz exposed animals. In both male radio-frequency radiation exposed groups, the permeability of blood-brain barrier found to be increased with respect to the controls (pradiation exposure was found more effective on the male animals (p0.01). However 900MHz pulse modulated radio-frequency exposure was found effective on the permeability of blood-brain barrier of female animals. Results have shown that 20min pulse modulated radio-frequency radiation exposure of 900MHz and 1800MHz induces an effect and increases the permeability of blood-brain barrier of male rats. For females, 900MHz was found effective and it could be concluded that this result may due to the physiological differences between female and male animals. The results of this study suggest that mobile phone radation could lead to increase the permeability of blood-brain barrier under non-thermal exposure levels. More studies are needed to demonstrate the mechanisms of that breakdown. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Effect of losartan on the blood-brain barrier permeability in diabetic hypertensive rats.

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    Kaya, M; Kalayci, R; Küçük, M; Arican, N; Elmas, I; Kudat, H; Korkut, F

    2003-11-07

    Our previous publication has stressed the benefits of losartan, an angiotensin II receptor blocker, on the permeability of blood-brain barrier (BBB) and blood pressure during L-NAME-induced hypertension. This study reports the impacts of anti-hypertensive treatment by losartan on the brain endothelial barrier function and the arterial blood pressure, during acute hypertension episode, in experimentally diabetic hypertensive rats. Systolic blood pressure measurements were taken with tail cuff method before and during administration of L-NAME (0.5 mg/ml). We induced diabetes by using alloxan (50 mg/kg, i.p). Losartan (3 mg/kg, i.v) was given to rats following the L-NAME treatment. Acute hypertensive vascular injury was induced by epinephrine (40 microg/kg). The BBB disruption was quantified according to the extravasation of the Evans blue (EB) dye. L-NAME induced a significant increase in arterial blood pressure on day 14 in normoglycemic and hyperglycemic rats (p hypertensive and diabetic hypertensive rats (p hypertension in diabetic hypertensive rats increased the content of EB dye dramatically in cerebellum and diencephalon (p cerebral cortex (p hypertensive rats treated with epinephrine (p hypertensive rats, epinephrine administration leads to an increase in microvascular-EB-albumin efflux to brain, however losartan treatment significantly attenuates this protein's transport to brain tissue.

  4. Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability.

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    Heye, Anna K; Thrippleton, Michael J; Armitage, Paul A; Valdés Hernández, Maria Del C; Makin, Stephen D; Glatz, Andreas; Sakka, Eleni; Wardlaw, Joanna M

    2016-01-15

    There is evidence that subtle breakdown of the blood-brain barrier (BBB) is a pathophysiological component of several diseases, including cerebral small vessel disease and some dementias. Dynamic contrast-enhanced MRI (DCE-MRI) combined with tracer kinetic modelling is widely used for assessing permeability and perfusion in brain tumours and body tissues where contrast agents readily accumulate in the extracellular space. However, in diseases where leakage is subtle, the optimal approach for measuring BBB integrity is likely to differ since the magnitude and rate of enhancement caused by leakage are extremely low; several methods have been reported in the literature, yielding a wide range of parameters even in healthy subjects. We hypothesised that the Patlak model is a suitable approach for measuring low-level BBB permeability with low temporal resolution and high spatial resolution and brain coverage, and that normal levels of scanner instability would influence permeability measurements. DCE-MRI was performed in a cohort of mild stroke patients (n=201) with a range of cerebral small vessel disease severity. We fitted these data to a set of nested tracer kinetic models, ranking their performance according to the Akaike information criterion. To assess the influence of scanner drift, we scanned 15 healthy volunteers that underwent a "sham" DCE-MRI procedure without administration of contrast agent. Numerical simulations were performed to investigate model validity and the effect of scanner drift. The Patlak model was found to be most appropriate for fitting low-permeability data, and the simulations showed vp and K(Trans) estimates to be reasonably robust to the model assumptions. However, signal drift (measured at approximately 0.1% per minute and comparable to literature reports in other settings) led to systematic errors in calculated tracer kinetic parameters, particularly at low permeabilities. Our findings justify the growing use of the Patlak model in low-permeability

  5. Pharmacological modulation of blood-brain barrier increases permeability of doxorubicin into the rat brain

    Science.gov (United States)

    Sardi, Iacopo; la Marca, Giancarlo; Cardellicchio, Stefania; Giunti, Laura; Malvagia, Sabrina; Genitori, Lorenzo; Massimino, Maura; de Martino, Maurizio; Giovannini, Maria G

    2013-01-01

    Our group recently demonstrated in a rat model that pretreatment with morphine facilitates doxorubicin delivery to the brain in the absence of signs of increased acute systemic toxicity. Morphine and other drugs such as dexamethasone or ondansetron seem to inhibit MDR proteins localized on blood-brain barrier, neurons and glial cells increasing the access of doxorubicin to the brain by efflux transporters competition. We explored the feasibility of active modification of the blood-brain barrier protection, by using morphine dexamethasone or ondansetron pretreatment, to allow doxorubicin accumulation into the brain in a rodent model. Rats were pretreated with morphine (10 mg/kg, i.p.), dexamethasone (2 mg/kg, i.p.) or ondansetron (2 mg/kg, i.p.) before injection of doxorubicin (12 mg/kg, i.p.). Quantitative analysis of doxorubicin was performed by mass spectrometry. Acute hearth and kidney damage was analyzed by measuring doxorubicin accumulation, LDH activity and malondialdehyde plasma levels. The concentration of doxorubicin was significantly higher in all brain areas of rats pretreated with morphine (P < 0.001) or ondansetron (P < 0.05) than in control tissues. The concentration of doxorubicin was significantly higher in cerebral hemispheres and brainstem (P < 0.05) but not in cerebellum of rats pretreated with dexamethasone than in control tissues. Pretreatment with any of these drugs did not increase LDH activity or lipid peroxidation compared to controls. Our data suggest that morphine, dexamethasone or ondansetron pretreatment is able to allow doxorubicin penetration inside the brain by modulating the BBB. This effect is not associated with acute cardiac or renal toxicity. This finding might provide the rationale for clinical applications in the treatment of refractory brain tumors and pave the way to novel applications of active but currently inapplicable chemotherapeutic drugs. PMID:23977451

  6. Erythropoietin protects the in vitro blood-brain barrier against VEGF-induced permeability.

    Science.gov (United States)

    Martínez-Estrada, Ofelia María; Rodríguez-Millán, Elisabeth; González-De Vicente, Esther; Reina, Manuel; Vilaró, Senén; Fabre, Myriam

    2003-11-01

    The blood-brain barrier (BBB) ensures the homeostasis of the brain microenvironment, mostly through complex tight junctions between brain endothelial cells that prevent the passage of hydrophilic molecules from blood to brain and vice versa. A recent study has shown in vivo that systemic administration of erythropoietin (Epo) protects against brain injury. Using an in vitro model of the bovine BBB, we observed that the expression of the Epo receptor is modulated by its ligand and hypoxic stimuli such as vascular endothelial growth factor (VEGF) treatment. In addition, Epo protects against the VEGF-induced permeability of the BBB, decreases the levels of endothelial nitric oxide synthase and restores junction proteins. The kinetic transport experiments revealed the capacity of Epo to cross the in vitro BBB in a saturable and specific way. Our results suggest a new mechanism for Epo-induced neuroprotection, in which circulating Epo controls and maintains the BBB through an Epo receptor signalling pathway and the re-establishment of cell junctions.

  7. Early CT perfusion changes and blood-brain barrier permeability after aneurysmal subarachnoid hemorrhage

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, Amanda; Bharatha, Aditya [University of Toronto, Department of Medical Imaging, Toronto, ON (Canada); De Oliveira Manoel, Airton Leonardo; Kouzmina, Ekaterina [St. Michael' s Hospital, Toronto (Canada); Burgers, Kyle; Lee, Ting [Robarts Research Institute, London (Canada); Macdonald, R.L. [St. Michael' s Hospital, Department of Neurosurgery, Toronto (Canada)

    2015-08-15

    Early brain injury (EBI) can occur within 72 h of aneurysmal subarachnoid hemorrhage (aSAH). The objective of this study was to determine if there are differences in early CTP parameters (<72 h) with respect to delayed cerebral ischemia (DCI), cerebral infarction, and functional outcome. We performed a prospective cohort study of aSAH patients admitted to a single tertiary care center. MTT, CBF and blood-brain barrier permeability (PS) were quantified with CTP within 72 h of aneurysm rupture. Primary outcomes were functional outcome by the Modified Rankin Scale (mRS) at 3 months and cerebral infarction. Secondary outcome was the development of DCI. Differences between early CTP parameters were determined with respect to primary and secondary outcomes. Fifty aSAH patients were included in the final analysis. MTT was significantly higher in patients who developed DCI (6.7 ± 1.2 vs 5.9 ± 1.0; p = 0.03) and cerebral infarction (7.0 ± 1.2 vs 5.9 ± 0.9; p = 0.007); however, no difference in MTT was found between patients with and without a poor outcome (mRS > 2). Early CBF and PS did not differ with respect to functional outcome, DCI, and cerebral infarction. Elevated MTT within 72 h of aneurysm rupture is associated with DCI and cerebral infarction but not with long-term functional outcome. Blood-brain barrier permeability, as assessed by CT perfusion, was not associated with DCI or worse outcome in this cohort. (orig.)

  8. Effects of ionizing radiation on the blood brain barrier permeability to pharmacologically active substances

    Energy Technology Data Exchange (ETDEWEB)

    Trnovec, T.; Kallay, Z.; Bezek, S. (Institute of Experimental Pharmacology, Bratislava (Yugoslavia))

    1990-12-01

    Ionizing radiation can impair the integrity of the blood brain barrier (BBB). Data on early and late damage after brain irradiation are usually reported separately, yet a gradual transition between these two types has become evident. Signs appearing within 3 weeks after irradiation are considered to be early manifestations. The mechanism of radiation-effected integrity impairment of the BBB is discussed in relation to changes in morphological structures forming the BBB, the endothelium of intracerebral vessels, and in the surrounding astrocytes. Alterations in the function of the BBB are manifested in the endothelium by changes in the ultrastructural location of the activity of phosphatases and by the activation of pinocytotic vesicular transport, and in astrocyte cytoplasm by glycogen deposition. The changes in ultrastructure were critically surveyed with regard to increasing doses of radiation to the brain in the range of 5 Gy to 960 Gy. The qualitative as well as the semiquantitative and quantitative observations on the passage of substances across the damaged BBB were treated separately. Qualitative changes are based mainly on findings of extravasation of vital stains and of labelled proteins. The quantitative studies established differences in radiation-induced changes in the permeability of the BBB depending on the structure and physico-chemical properties of the barrier penetrating tracers. Indirect evaluation of radiation-induced BBB changes is based on studies of pharmacological effects of substances acting on the CNS. In conclusion, radiation impairs significantly the integrity of the BBB following single irradiation of the brain with a dose exceeding 10-15 Gy. The response of the BBB to ionizing radiation is dependent both on the dose to which the brain is exposed and on specific properties of the tracer. 68 references.

  9. Evaluation of the increase in permeability of the blood-brain barrier during tumor progression after pulsed focused ultrasound.

    Science.gov (United States)

    Yang, Feng-Yi; Wang, Hsin-Ell; Lin, Guan-Liang; Lin, Hui-Hsien; Wong, Tai-Tong

    2012-01-01

    The purpose of this study was to evaluate the permeability of the blood-brain barrier after sonication by pulsed high-intensity focused ultrasound and to determine if such an approach increases the tumor:ipsilateral brain permeability ratio. F98 glioma-bearing Fischer 344 rats were injected intravenously with Evans blue with or without blood-tumor barrier disruption induced by transcranial pulsed high-intensity focused ultrasound. Sonication was applied at a frequency of 1 MHz with a 5% duty cycle and a repetition frequency of 1 Hz. The permeability of the blood-brain barrier was assessed by the extravasation of Evans blue. Contrast-enhanced magnetic resonance images were used to monitor the gadolinium deposition path associated with transcranial pulsed high-intensity focused ultrasound, and the influencing size and location was also investigated. In addition, whole brain histological analysis was performed. The results were compared by two-tailed unpaired t-test. The accumulation of Evans blue in brains and the tumor:ipsilateral brain permeability ratio of Evans blue were significantly increased after pulsed high-intensity focused ultrasound exposure. Evans blue injection followed by sonication showed an increase in the tumor:ipsilateral brain ratio of the target tumors (9.14:1) of about 2.23-fold compared with the control tumors (x4.09) on day 6 after tumor implantation. Magnetic resonance images showed that pulsed high-intensity focused ultrasound locally enhances the permeability of the blood-tumor barrier in the glioma-bearing rats. This method could allow enhanced synergistic effects with respect to other brain tumor treatment regimens.

  10. Accurate determination of blood–brain barrier permeability using dynamic contrast-enhanced T1-weighted MRI

    DEFF Research Database (Denmark)

    Cramer, Stig P; Larsson, Henrik B W

    2014-01-01

    Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is increasingly used to estimate permeability in situations with subtle blood-brain barrier (BBB) leakage. However, the method's ability to differentiate such low values from zero is unknown, and no consensus exists on optimal selection.......25 seconds) greatly improved accuracy and precision for all three models, enabling us to differentiate values of permeability as low as 0.1 ml/100 g/min from zero. The Patlak model yielded highest accuracy and precision for permeability values

  11. Effects of propranolol and clonidine on brain edema, blood-brain barrier permeability, and endothelial glycocalyx disruption after fluid percussion brain injury in the rat

    DEFF Research Database (Denmark)

    Genét, Gustav Folmer; Bentzer, Peter; Hansen, Morten Bagge

    2018-01-01

    ), vehicle (n = 16), or sham (n = 5) for 24 hours. Primary outcome was brain water content at 24 hours. Secondary outcomes were blood-brain barrier permeability and plasma levels of syndecan-1 (glycocalyx disruption), cell damage (histone-complexed DNA fragments), epinephrine, norepinephrine, and animal.......555). We found no effect of propranolol and propranolol/clonidine on blood-brain barrier permeability and animal motor scores. Unexpectedly, propranolol and propranolol/clonidine caused an increase in epinephrine and syndecan-1 levels. CONCLUSION: This study does not provide any support for unselective......BACKGROUND: Traumatic brain injury causes a disruption of the vascular endothelial glycocalyx layer that is associated with an overactivation of the sympathoadrenal system. We hypothesized that early and unselective beta-blockade with propranolol alone or in combination with the alfa2-agonist...

  12. Transcranial direct current stimulation transiently increases the blood-brain barrier solute permeability in vivo

    Science.gov (United States)

    Shin, Da Wi; Khadka, Niranjan; Fan, Jie; Bikson, Marom; Fu, Bingmei M.

    2016-03-01

    Transcranial Direct Current Stimulation (tDCS) is a non-invasive electrical stimulation technique investigated for a broad range of medical and performance indications. Whereas prior studies have focused exclusively on direct neuron polarization, our hypothesis is that tDCS directly modulates endothelial cells leading to transient changes in blood-brain-barrier (BBB) permeability (P) that are highly meaningful for neuronal activity. For this, we developed state-of-the-art imaging and animal models to quantify P to various sized solutes after tDCS treatment. tDCS was administered using a constant current stimulator to deliver a 1mA current to the right frontal cortex of rat (approximately 2 mm posterior to bregma and 2 mm right to sagittal suture) to obtain similar physiological outcome as that in the human tDCS application studies. Sodium fluorescein (MW=376), or FITC-dextrans (20K and 70K), in 1% BSA mammalian Ringer was injected into the rat (SD, 250-300g) cerebral circulation via the ipsilateral carotid artery by a syringe pump at a constant rate of ~3 ml/min. To determine P, multiphoton microscopy with 800-850 nm wavelength laser was applied to take the images from the region of interest (ROI) with proper microvessels, which are 100-200 micron below the pia mater. It shows that the relative increase in P is about 8-fold for small solute, sodium fluorescein, ~35-fold for both intermediate sized (Dex-20k) and large (Dex-70k) solutes, 10 min after 20 min tDCS pretreatment. All of the increased permeability returns to the control after 20 min post treatment. The results confirmed our hypothesis.

  13. Effects of propranolol and clonidine on brain edema, blood-brain barrier permeability, and endothelial glycocalyx disruption after fluid percussion brain injury in the rat.

    Science.gov (United States)

    Genét, Gustav Folmer; Bentzer, Peter; Hansen, Morten Bagge; Ostrowski, Sisse Rye; Johansson, Pär Ingemar

    2018-01-01

    Traumatic brain injury causes a disruption of the vascular endothelial glycocalyx layer that is associated with an overactivation of the sympathoadrenal system. We hypothesized that early and unselective beta-blockade with propranolol alone or in combination with the alfa2-agonist clonidine would decrease brain edema, blood-brain barrier permeability, and glycocalyx disruption at 24 hours after trauma. We subjected 53 adult male Sprague-Dawley rats to lateral fluid percussion brain injury and randomized infusion with propranolol (n = 16), propranolol + clonidine (n = 16), vehicle (n = 16), or sham (n = 5) for 24 hours. Primary outcome was brain water content at 24 hours. Secondary outcomes were blood-brain barrier permeability and plasma levels of syndecan-1 (glycocalyx disruption), cell damage (histone-complexed DNA fragments), epinephrine, norepinephrine, and animal motor function. We found no difference in brain water content (mean ± SD) between propranolol (80.8 ± 0.3%; 95% confidence interval [CI], 80.7-81.0) and vehicle (81.1 ± 0.6%; 95% CI, 80.8-81.4) (p = 0.668) or between propranolol/clonidine (80.8 ± 0.3%; 95% CI, 80.7-81.0) and vehicle (p = 0.555). We found no effect of propranolol and propranolol/clonidine on blood-brain barrier permeability and animal motor scores. Unexpectedly, propranolol and propranolol/clonidine caused an increase in epinephrine and syndecan-1 levels. This study does not provide any support for unselective beta-blockade with propranolol or the combination of propranolol and the alfa2-agonist clonidine on brain water content. The novel finding of an increase in plasma concentrations of epinephrine and syndecan-1 after propranolol treatment in traumatic brain injury is of unclear significance and should be investigated further.

  14. Adult human dental pulp stem cells promote blood-brain barrier permeability through vascular endothelial growth factor-a expression.

    Science.gov (United States)

    Winderlich, Joshua N; Kremer, Karlea L; Koblar, Simon A

    2016-06-01

    Stem cell therapy is a promising new treatment option for stroke. Intravascular administration of stem cells is a valid approach as stem cells have been shown to transmigrate the blood-brain barrier. The mechanism that causes this effect has not yet been elucidated. We hypothesized that stem cells would mediate localized discontinuities in the blood-brain barrier, which would allow passage into the brain parenchyma. Here, we demonstrate that adult human dental pulp stem cells express a soluble factor that increases permeability across an in vitro model of the blood-brain barrier. This effect was shown to be the result of vascular endothelial growth factor-a. The effect could be amplified by exposing dental pulp stem cell to stromal-derived factor 1, which stimulates vascular endothelial growth factor-a expression. These findings support the use of dental pulp stem cell in therapy for stroke. © The Author(s) 2015.

  15. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history

    Directory of Open Access Journals (Sweden)

    Norman Ruthven Saunders

    2014-12-01

    Full Text Available Careful examination of relevant literature shows that many of the most cherished concepts of the blood-brain barrier are incorrect. These include an almost mythological belief in its immaturity that is unfortunately often equated with absence or at least leakiness in the embryo and fetus. The original concept of a blood-brain barrier is often attributed to Ehrlich; however, he did not accept that permeability of cerebral vessels was different from other organs. Goldmann is often credited with the first experiments showing dye (trypan blue exclusion from the brain when injected systemically, but not when injected directly into it. Rarely cited are earlier experiments of Bouffard and of Franke who showed methylene blue and trypan red stained all tissues except the brain. The term blood-brain barrier Blut-Hirnschranke is often attributed to Lewandowsky, but it does not appear in his papers. The first person to use this term seems to be Stern in the early 1920s. Studies in embryos by Stern & colleagues, Weed and Wislocki showed results similar to those in adult animals. These were well-conducted experiments made a century ago, thus the persistence of a belief in barrier immaturity is puzzling. As discussed in this review, evidence for this belief, is of poor experimental quality, often misinterpreted and often not properly cited. The functional state of blood-brain barrier mechanisms in the fetus is an important biological phenomenon with implications for normal brain development. It is also important for clinicians to have proper evidence on which to advise pregnant women who may need to take medications for serious medical conditions. Beliefs in immaturity of the blood-brain barrier have held the field back for decades. Their history illustrates the importance of taking account of all the evidence and assessing its quality, rather than selecting papers that supports a preconceived notion or intuitive belief. This review attempts to right the

  16. [Permeability of blood-brain barrier oxygen-glucose deprivation induced by tetramethylpyrazine-puerarin in vitro].

    Science.gov (United States)

    Li, Jinhui; Che, Lingyan; Wang, Yu; Zhang, Yuyan; Wan, Haitong; Yang, Jiehong

    2010-10-01

    To explore permeability of artificial blood-brain barrier (aBBB) by oxygen-glucose deprivation combined (OGD)-induced using tetramethylpyrazine combined with puerarin in vitro. Rats were divided into normal control group, model group, tetramethylpyrazine group, puerarin group, tetramethylpyrazine-puerarin group and nimodipine group. Culture rat brain microvascular endothelial cells and astrocytes in vitro and build the OGD-induced aBBB damage model. Evaluate aBBB damage characteristics by TEER, gamma-GT, AKP and LDH. Determine contents of tetramethylpyrazine, puerarin, nimodipine and calculate drug permeating concentration of OGD-induced aBBB model by HPLC. Compared with the model, the level of TEER was lower than the control group with significant difference (P permeability of the OGD-induced aBBB.

  17. The rights and wrongs of blood-brain barrier permeability studies

    DEFF Research Database (Denmark)

    Saunders, Norman R; Dreifuss, Jean-Jacques; Dziegielewska, Katarzyna M

    2014-01-01

    important for clinicians to have proper evidence on which to advise pregnant women who may need to take medications for serious medical conditions. Beliefs in immaturity of the blood-brain barrier have held the field back for decades. Their history illustrates the importance of taking account of all...

  18. Lack of IL-6 increases blood–brain barrier permeability in fungal ...

    Indian Academy of Sciences (India)

    − mice ... Interleukin (IL-6) is a multifunctional cytokine, and numerous studies have shown that IL‐6 influences the integrity of the blood–brain barrier. In this study we ... Dates. Manuscript received: 16 June 2014; Accepted: 10 November 2014 ...

  19. A new PAMPA model using an in-house brain lipid extract for screening the blood-brain barrier permeability of drug candidates.

    Science.gov (United States)

    Bicker, Joana; Alves, Gilberto; Fortuna, Ana; Soares-da-Silva, Patrício; Falcão, Amílcar

    2016-03-30

    The determination of the permeability of drug candidates across the blood-brain barrier (BBB) is a fundamental step during drug discovery programs. The parallel artificial membrane permeability assay (PAMPA) is a high throughput screening tool applied to evaluate the passive permeability and adapted to predict BBB penetration. Herein, a new PAMPA model was developed using an in-house brain lipid extract capable of discriminating BBB permeable from non-permeable compounds. The apparent permeability (Papp) of 18 reference molecules and 10 test compounds was assessed and compared with phosphatidylcholine and commercial porcine polar brain lipid (PBL). The physicochemical selectivity of the in-house brain lipid extract was demonstrated by correlating Papp values with physicochemical properties and its predictive capacity estimated by establishing in vitro-in vivo correlations. The strong correlations achieved between 2% (w/v) in-house lipid extract and PBL for reference (r(2)=0.77) and test compounds (r(2)=0.94) support an equivalent discriminatory capacity and validate the presented model. Moreover, PAMPA studies performed with PBL and in-house lipid extract exhibited a higher correlation with the in vivo parameter logBB (r(2)=0.76 and r(2)=0.72, respectively) than phosphatidylcholine (r(2)=0.51). Overall, the applied lipid extraction process was reproducible, economical and provided lipid extracts that can be used to reliably assess BBB permeation. Copyright © 2016. Published by Elsevier B.V.

  20. Non-invasive assessment of blood-brain barrier (BBB) permeability using a gamma camera to detect 99technetium-gluceptate extravasation in rat brain.

    Science.gov (United States)

    Esposito, P; Jacobson, S; Connolly, R; Gheorghe, D; Theoharides, T C

    2001-10-01

    The blood-brain barrier (BBB) is a complex structure of endothelial cells, astroglia, pericytes, and perivascular macrophages enclosed by basal lamina. The BBB regulates the entry of blood-borne molecules and cells into the brain, but it is disrupted in various inflammatory conditions of the central nervous system (CNS). We previously showed that 30 min of immobilization stress increased 99technetium-gluceptate (99Tc) extravasation, measured by a gamma counter, in brain regions containing mast cells, an effect blocked by the mast cell stabilizer disodium cromoglycate [Brain Res. 888 (2001) 117]. Here we report the use of a gamma camera to assess BBB permeability by assessing 99Tc extravasation in the rat brain, during and following acute stress, without having to sacrifice the experimental animals. This method also allows for repeated experimentation on the same animal, since the half-life of 99Tc is only 6 h, and permits testing of potential inhibitors of BBB permeability.

  1. Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, using dynamic contrast-enhanced T(1)-weighted MRI at 3 tesla

    DEFF Research Database (Denmark)

    Larsson, Henrik B W; Courivaud, Frédéric; Rostrup, Egill

    2009-01-01

    Assessment of vascular properties is essential to diagnosis and follow-up and basic understanding of pathogenesis in brain tumors. In this study, a procedure is presented that allows concurrent estimation of cerebral perfusion, blood volume, and blood-brain permeability from dynamic T(1)-weighted...... imaging of a bolus of a paramagnetic contrast agent passing through the brain. The methods are applied in patients with brain tumors and in healthy subjects. Perfusion was estimated by model-free deconvolution using Tikhonov's method (gray matter/white matter/tumor: 72 +/- 16/30 +/- 8/56 +/- 45 mL/100 g...... on a pixel-by-pixel basis of cerebral perfusion, cerebral blood volume, and blood-brain barrier permeability....

  2. Dietary Virgin Olive Oil Reduces Blood Brain Barrier Permeability, Brain Edema, and Brain Injury in Rats Subjected to Ischemia-Reperfusion

    Directory of Open Access Journals (Sweden)

    Fatemeh Mohagheghi

    2010-01-01

    Full Text Available Recent studies suggest that dietary virgin olive oil (VOO reduces hypoxia-reoxygenation injury in rat brain slices. We sought to extend these observations in an in vivo study of rat cerebral ischemia-reperfusion injury. Four groups, each consisting of 18 Wistar rats, were studied. One group (control received saline, while three treatment groups received oral VOO (0.25, 0.5, and 0.75 mL/kg/day, respectively. After 30 days, blood lipid profiles were determined, before a 60-min period of middle cerebral artery occlusion (MCAO. After 24-h reperfusion, neurological deficit scores, infarct volume, brain edema, and blood brain barrier permeability were each assessed in subgroups of six animals drawn from each main group. VOO reduced the LDL/HDL ratio in doses of 0.25, 0.5, and 0.75 mL/kg/day in comparison to the control group (p < 0.05, and offered cerebroprotection from ischemia-reperfusion. For controls vs. doses of 0.25 vs. 0.5 vs. 0.75 mL/kg/day, attenuated corrected infarct volumes were 207.82 ± 34.29 vs. 206.41 ± 26.23 vs. 124.21 ± 14.73 vs. 108.46 ± 31.63 mm3; brain water content of the infarcted hemisphere was 82 ±± 0.25 vs. 81.5 ± 0.56 vs. 80.5 ± 0.22 vs. 80.5 ± 0.34%; and blood brain barrier permeability of the infarcted hemisphere was 11.31 ± 2.67 vs. 9.21 ± 2.28 vs. 5.83 ± 1.6 vs. 4.43 ± 0.93 µg/g tissue (p < 0.05 for measures in doses 0.5 and 0.75 mL/kg/day vs. controls. Oral administration of VOO reduces infarct volume, brain edema, blood brain barrier permeability, and improves neurologic deficit scores after transient MCAO in rats.

  3. Excess soluble CD40L contributes to blood brain barrier permeability in vivo: implications for HIV-associated neurocognitive disorders.

    Directory of Open Access Journals (Sweden)

    Donna C Davidson

    Full Text Available Despite the use of anti-retroviral therapies, a majority of HIV-infected individuals still develop HIV-Associated Neurocognitive Disorders (HAND, indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistently, we have previously shown that levels of the inflammatory mediator soluble CD40L (sCD40L are elevated in the circulation of HIV-infected, cognitively impaired individuals as compared to their infected, non-impaired counterparts. Recent studies from our group suggest a role for the CD40/CD40L dyad in blood brain barrier (BBB permeability and interestingly, sCD40L is thought to regulate BBB permeability in other inflammatory disorders of the CNS. Using complementary multiphoton microscopy and quantitative analyses in wild-type and CD40L deficient mice, we now reveal that the HIV transactivator of transcription (Tat can induce BBB permeability in a CD40L-dependent manner. This permeability of the BBB was found to be the result of aberrant platelet activation induced by Tat, since depletion of platelets prior to treatment reversed Tat-induced BBB permeability. Furthermore, Tat treatment led to an increase in granulocyte antigen 1 (Gr1 positive monocytes, indicating an expansion of the inflammatory subset of cells in these mice, which were found to adhere more readily to the brain microvasculature in Tat treated animals. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets, thereby aiding in the development of adjunct therapies for the management of HAND, which are currently lacking.

  4. Qualitative and quantitative structure-activity relationship modelling for predicting blood-brain barrier permeability of structurally diverse chemicals.

    Science.gov (United States)

    Gupta, S; Basant, N; Singh, K P

    2015-01-01

    In this study, structure-activity relationship (SAR) models have been established for qualitative and quantitative prediction of the blood-brain barrier (BBB) permeability of chemicals. The structural diversity of the chemicals and nonlinear structure in the data were tested. The predictive and generalization ability of the developed SAR models were tested through internal and external validation procedures. In complete data, the QSAR models rendered ternary classification accuracy of >98.15%, while the quantitative SAR models yielded correlation (r(2)) of >0.926 between the measured and the predicted BBB permeability values with the mean squared error (MSE) 82.7% and r(2) > 0.905 (MSE quantitative models for predicting the BBB permeability of chemicals. Moreover, these models showed predictive performance superior to those reported earlier in the literature. This demonstrates the appropriateness of the developed SAR models to reliably predict the BBB permeability of new chemicals, which can be used for initial screening of the molecules in the drug development process.

  5. Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment.

    Science.gov (United States)

    Vincent, Thierry; Saikali, Philippe; Cayrol, Romain; Roth, Alejandro D; Bar-Or, Amit; Prat, Alexandre; Antel, Jack P

    2008-10-15

    Autoantibody neuromyelitis optica-IgG (NMO-IgG) recognizing aquaporin-4 (AQP4) is implicated as playing a central role in the physiopathology of NMO. The aim of this in vitro-based study was to characterize functional consequences of interaction between NMO-IgG and cells of the neurovascular unit (astrocytes and brain endothelium) that would provide insight into recognized features of NMO, namely altered blood-brain barrier (BBB) permeability and granulocyte recruitment. We used sera from NMO and longitudinally extensive transverse myelitis cases shown to bind in a characteristic perivascular pattern to primate cerebellar slices. Using flow cytometry, we found that sera from NMO-IgG-positive patients reacted with CNS-derived human fetal astrocytes, whereas sera from multiple sclerosis patients did not. We demonstrated that NMO-IgG binding to astrocytes alters aquaporin-4 polarized expression and increases permeability of a human BBB endothelium/astrocyte barrier. We further demonstrated that NMO-IgG binding to human fetal astrocytes can result in NK cell degranulation, astrocyte killing by Ab-dependent cellular cytotoxicity and complement-dependent granulocyte attraction through the BBB model. Our study highlights important functional roles for NMO-IgG that could account for pathological lesions and BBB dysfunction observed in NMO.

  6. An in vitro transport model for rapid screening and predicting the permeability of candidate compounds at blood-brain barrier.

    Science.gov (United States)

    Yang, Zhi-Hong; Sun, Xiao; Mei, Chao; Sun, Xiao-Bo; Liu, Xiao-Dong; Chang, Qi

    2011-12-01

    The aim of this study was to design and develop a simple in vitro blood-brain barrier (BBB) permeation model for elementarily and rapidly predicting the permeability of candidate compounds at BBB and further evaluating whether P-glycoprotein (P-gp) affects them across BBB. The model was mainly composed of cultured rat brain microvascular endothelial cells (rBMECs), glass contraption, and micropore membrane. First, we evaluated the model by morphological observation. Second, the restriction effects of paracellular transport were verified by measuring marker probes transport, and monitoring transendothelial electrical resistance (TEER) and leakage. Finally, protein expression and activity of P-gp were confirmed by carrying out Western blot analysis and polarized transport of rhodamine-123 (Rho123) in rBMECs. The rBMECs retained both endothelial cells and BBB features. The rBMECs model reproducibly attained approximately 130 Ω cm² on the steady-state TEER value, and displayed a barrier function to marker probes transport by decreasing the permeability. Protein band of 170 kDa manifested the existence of P-gp in the rBMECs, and the findings of cyclosporin A-sensitive decrease of Rho123 efflux confirmed the presence of P-gp activity. A simple, rapid, and convenient in vitro BBB permeation model was successfully established and applied to evaluate the BBB transport profiles of three natural flavonoids: quercetin, naringenin, and rutin.

  7. Permeability dependence study of the focused ultrasound-induced blood-brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI.

    Science.gov (United States)

    Vlachos, Fotios; Tung, Yao-Sheng; Konofagou, Elisa

    2011-09-01

    Blood-brain barrier opening using focused ultrasound and microbubbles has been experimentally established as a noninvasive and localized brain drug delivery technique. In this study, the permeability of the opening is assessed in the murine hippocampus after the application of focused ultrasound at three different acoustic pressures and microbubble sizes. Using dynamic contrast-enhanced MRI, the transfer rates were estimated, yielding permeability maps and quantitative K(trans) values for a predefined region of interest. The volume of blood-brain barrier opening according to the K(trans) maps was proportional to both the pressure and the microbubble diameter. A K(trans) plateau of ∼0.05 min(-1) was reached at higher pressures (0.45 and 0.60 MPa) for the larger sized bubbles (4-5 and 6-8 μm), which was on the same order as the K(trans) of the epicranial muscle (no barrier). Smaller bubbles (1-2 μm) yielded significantly lower permeability values. A small percentage (7.5%) of mice showed signs of damage under histological examination, but no correlation with permeability was established. The assessment of the blood-brain barrier permeability properties and their dependence on both the pressure and the microbubble diameter suggests that K(trans) maps may constitute an in vivo tool for the quantification of the efficacy of the focused ultrasound-induced blood-brain barrier opening. Copyright © 2011 Wiley-Liss, Inc.

  8. Model-based hypothesis of gut microbe populations and gut/brain barrier permeabilities in the development of regressive autism.

    Science.gov (United States)

    Downs, Ryan; Perna, Jonathon; Vitelli, Andrew; Cook, Daniel; Dhurjati, Prasad

    2014-12-01

    Regressive autism is a devastating disorder affecting children between the ages of 15-30 months. The disorder is characterized by the loss of social interaction and communication ability following otherwise healthy development. In spite of rising autism prevalence, current detection methods and treatment options for this disease are lacking. Therefore, this study introduces a systems-level model, which suggests that gut microbes and intestinal inflammation influence the onset of regressive autism through increasing gut permeability. This computational model provides a framework for quantitative understanding of how imbalances in populations of gut microbes alters the whole-body and brain distributions of neurotoxins produced by GI tract bacteria. Our results indicate that increased levels of the bacteria Bacteroides vulgatus lead to increased brain levels of propionic acid, a neurotoxin which has been known to cause symptoms characteristic of autism when injected into the brain of rats. Our results further indicate that immune response to virulence factors produced by bacteria in the gut leads to increased systemic levels of inflammatory cytokines, such as IL-1β, which significantly alter the permeability of the gut epithelial layer and the blood-brain barrier. Due to the large size of cytokines, however, we predict the time required for concentrations in the brain to stabilize to be on the order of years. This suggests that treatments preventing autism development could be administered after identifying microbial biomarkers of disease but before debilitating brain inflammation leads to regressive autism progression. Future research extending this work could provide new treatment options and diagnostic techniques to help combat regressive autism. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. In vivo assessment of the permeability of the blood-brain barrier and blood-retinal barrier to fluorescent indoline derivatives in zebrafish

    Directory of Open Access Journals (Sweden)

    Watanabe Kohei

    2012-08-01

    Full Text Available Abstract Background Successful delivery of compounds to the brain and retina is a challenge in the development of therapeutic drugs and imaging agents. This challenge arises because internalization of compounds into the brain and retina is restricted by the blood–brain barrier (BBB and blood-retinal barrier (BRB, respectively. Simple and reliable in vivo assays are necessary to identify compounds that can easily cross the BBB and BRB. Methods We developed six fluorescent indoline derivatives (IDs and examined their ability to cross the BBB and BRB in zebrafish by in vivo fluorescence imaging. These fluorescent IDs were administered to live zebrafish by immersing the zebrafish larvae at 7-8 days post fertilization in medium containing the ID, or by intracardiac injection. We also examined the effect of multidrug resistance proteins (MRPs on the permeability of the BBB and BRB to the ID using MK571, a selective inhibitor of MRPs. Results The permeability of these barriers to fluorescent IDs administered by simple immersion was comparable to when administered by intracardiac injection. Thus, this finding supports the validity of drug administration by simple immersion for the assessment of BBB and BRB permeability to fluorescent IDs. Using this zebrafish model, we demonstrated that the length of the methylene chain in these fluorescent IDs significantly affected their ability to cross the BBB and BRB via MRPs. Conclusions We demonstrated that in vivo assessment of the permeability of the BBB and BRB to fluorescent IDs could be simply and reliably performed using zebrafish. The structure of fluorescent IDs can be flexibly modified and, thus, the permeability of the BBB and BRB to a large number of IDs can be assessed using this zebrafish-based assay. The large amount of data acquired might be useful for in silico analysis to elucidate the precise mechanisms underlying the interactions between chemical structure and the efflux transporters at the

  10. Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier permeability in the corpus callosum.

    Science.gov (United States)

    Liu, Qinghai; Radwanski, Ryan; Babadjouni, Robin; Patel, Arati; Hodis, Drew M; Baumbacher, Peter; Zhao, Zhen; Zlokovic, Berislav; Mack, William J

    2017-01-01

    Murine chronic cerebral hypoperfusion (CCH) results in white matter (WM) injury and behavioral deficits. Pericytes influence blood-brain barrier (BBB) integrity and cerebral blood flow. Under hypoxic conditions, pericytes detach from perivascular locations increasing vessel permeability and neuronal injury. This study characterizes the time course of BBB dysfunction and pericyte coverage following murine experimental CCH secondary to bilateral carotid artery stenosis (BCAS). Mice underwent BCAS or sham operation. On post-procedure days 1, 3, 7 and 30, corpus callosum BBB permeability was characterized using Evans blue (EB) extravasation and IgG staining and pericyte coverage/count was calculated. The BCAS cohort demonstrated increased EB extravasation on postoperative days 1 ( p = 0.003) 3 ( p = 0.002), and 7 ( p = 0.001) when compared to sham mice. Further, EB extravasation was significantly greater ( p = 0.05) at day 3 than at day 30 in BCAS mice. BCAS mice demonstrated a nadir in pericyte coverage and count on post-operative day 3 ( p < 0.05, compared to day 7, day 30 and sham). Decreased pericyte coverage/count and increased BBB permeability are most pronounced on postoperative day 3 following murine CCH. This precedes any notable WM injury or behavioral deficits.

  11. Transient blood-brain barrier permeability following profound temporary global ischemia: an experimental study using /sup 14/C-AIB

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    Dobbin, J.; Crockard, H.A.; Ross-Russell, R.

    1989-02-01

    The influence of reperfusion after profound incomplete forebrain ischemia on blood-brain barrier (BBB) permeability to a small protein tracer was studied in male Sprague-Dawley rats. The mean cortical blood to brain transfer constant (Ki) for /sup 14/C-amino isobutyric acid (AIB) was significantly greater at 3 and 6 h of reperfusion, 2.5 times the mean values of controls (p less than 0.05) (2.5 microliter g-1 min-1 and 1.0 microliters g-1 min-1 respectively), but had returned to control values after reperfusion for 24 h. Analysis of distribution of Ki values showed that following 15 min and 30 min of profound ischemia, there was a significant increase in transfer of AIB across the blood-brain barrier (BBB) after recirculation for up to 6 h, though there was no evidence of protein extravasation as assessed by Evans Blue (EB) dye. After 24 h of reperfusion, the BBB to AIB was restored, and Ki values had returned to control values. It is concluded that following transient global ischemia, the BBB may recover rapidly.

  12. Acoustic cavitation-based monitoring of the reversibility and permeability of ultrasound-induced blood-brain barrier opening.

    Science.gov (United States)

    Sun, Tao; Samiotaki, Gesthimani; Wang, Shutao; Acosta, Camilo; Chen, Cherry C; Konofagou, Elisa E

    2015-12-07

    Cavitation events seeded by microbubbles have been previously reported to be associated with MR- or fluorescent-contrast enhancement after focused ultrasound (FUS)-induced blood-brain barrier (BBB) opening. However, it is still unknown whether bubble activity can be correlated with the reversibility (the duration of opening and the likelihood of safe reinstatement) and the permeability of opened BBB, which is critical for the clinical translation of using passive cavitation detection to monitor, predict and control the opening. In this study, the dependence of acoustic cavitation on the BBB opening duration, permeability coefficient and histological damage occurrence were thus investigated. Transcranial pulsed FUS at 1.5 MHz in the presence of systemically circulating microbubbles was applied in the mouse hippocampi (n  =  60). The stable and inertial cavitation activities were monitored during sonication. Contrast-enhanced MRI was performed immediately after sonication and every 24 h up to 6 d thereafter, to assess BBB opening, brain tissue permeability and potential edema. Histological evaluations were used to assess the occurrence of neurovascular damages. It was found that stable cavitation was well correlated with: (1) the duration of the BBB opening (r(2)  =  0.77); (2) the permeability of the opened BBB (r(2)  =  0.82); (3) the likelihood of safe opening (P  cavitation dose was correlated with the resulting BBB permeability (r(2)  =  0.72). Stable cavitation was found to be more reliable than inertial cavitation at assessing the BBB opening within the pressure range used in this study. This study demonstrates that the stable cavitation response during BBB opening holds promise for predicting and controlling the restoration and pharmacokinetics of FUS-opened BBB. The stable cavitation response therefore showed great promise in predicting the BBB opening duration, enabling thus control of opening according to the drug

  13. The role of multidrug resistance protein (MRP-1) as an active efflux transporter on blood-brain barrier (BBB) permeability.

    Science.gov (United States)

    Lingineni, Karthik; Belekar, Vilas; Tangadpalliwar, Sujit R; Garg, Prabha

    2017-05-01

    Drugs acting on central nervous system (CNS) may take longer duration to reach the market as these compounds have a higher attrition rate in clinical trials due to the complexity of the brain, side effects, and poor blood-brain barrier (BBB) permeability compared to non-CNS-acting compounds. The roles of active efflux transporters with BBB are still unclear. The aim of the present work was to develop a predictive model for BBB permeability that includes the MRP-1 transporter, which is considered as an active efflux transporter. A support vector machine model was developed for the classification of MRP-1 substrates and non-substrates, which was validated with an external data set and Y-randomization method. An artificial neural network model has been developed to evaluate the role of MRP-1 on BBB permeation. A total of nine descriptors were selected, which included molecular weight, topological polar surface area, ClogP, number of hydrogen bond donors, number of hydrogen bond acceptors, number of rotatable bonds, P-gp, BCRP, and MRP-1 substrate probabilities for model development. We identified 5 molecules that fulfilled all criteria required for passive permeation of BBB, but they all have a low logBB value, which suggested that the molecules were effluxed by the MRP-1 transporter.

  14. Cellular Apoptosis and Blood Brain Barrier Permeability Changes in the Pre-Incubated Chicken Embryo’s Brain by Effect of Electromagnetic Fields

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    Sima Kalantari

    2015-02-01

    Full Text Available Background: Electromagnetic fields (EMF have teratogenic effects during the embryonic development. In current study, histopathological and physiological effects of sinusoidal EMF on the brain were investigated. We sought to determine the apoptosis level and changes in blood brain barrier permeability in brain tissue of pre-incubated white leghorn hen eggs in the field of EMF. Materials and Methods: In this experimental study, 300 healthy, fresh, and fertilized eggs (55-65 g were divided into experimental (3 groups, N=50, control (N=75 and sham (N=75 groups. Experimental eggs (inside the coil were exposed to 3 different intensities of 1.33, 2.66 and 7.32 mT and sham groups were also located inside the same coil but with no exposure, for 24 hrs before incubation. Control, sham and experimental groups were incubated in an incubator (38±0.5ºC, 60% humidity. Brains of 14 day old chicken embryos of all groups were removed, fixed in formalin (10%, stained with H & E and TUNEL, apoptotic cells were studied under light microscope. Brains of other embryos were prepared for scanning electron microscope. By injections of Evans blue, any possible changes in brain vessels were also investigated. Results: Our results showed electromagnetic fields have toxic effects on cell organelles and cell membranes. EMF would increase the level of cellular apoptosis in the brain. They also would tear up the blood vessels. Thereafter, they would affect the permeability of blood brain barrier of exposed chicken embryos. Conclusion: These findings suggest that electromagnetic fields induce different degrees of brain damages in chicken embryos brain tissue.

  15. Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood–brain barrier permeability

    Directory of Open Access Journals (Sweden)

    Oláh G

    2013-09-01

    Full Text Available Gáspár Oláh,1 Judit Herédi,1 Ákos Menyhárt,1 Zsolt Czinege,2 Dávid Nagy,1 János Fuzik,1 Kitti Kocsis,1 Levente Knapp,1 Erika Krucsó,1 Levente Gellért,1 Zsolt Kis,1 Tamás Farkas,1 Ferenc Fülöp,3 Árpád Párdutz,4 János Tajti,4 László Vécsei,4 József Toldi1 1Department of Physiology, Anatomy and Neuroscience, 2Department of Software Engineering, 3Institute of Pharmaceutical Chemistry and MTA-SZTE Research Group for Stereochemistry, 4Department of Neurology and MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary Abstract: Cortical spreading depression (CSD involves a slowly-propagating depolarization wave in the cortex, which can appear in numerous pathophysiological conditions, such as migraine with aura, stroke, and traumatic brain injury. Neurons and glial cells are also depolarized transiently during the phenomena. CSD is followed by a massive increase in glutamate release and by changes in the brain microcirculation. The aim of this study was to investigate the effects of two N-methyl-D-aspartate receptor antagonists, endogenous kynurenic acid (KYNA and dizocilpine, on CSD and the related blood–brain barrier (BBB permeability in rats. In intact animals, KYNA hardly crosses the BBB but has some positive features as compared with its precursor L-Kynurenine, which is frequently used in animal studies (KYNA cannot be metabolized to excitotoxic agents such as 3-hydroxy-L-kynurenine and quinolinic acid. We therefore investigated the possible effects of peripherally administered KYNA. Repetitive CSD waves were elicited by the application of 1 M KCl solution to the cortex. Direct current-electrocorticograms were measured for 1 hour. Four parameters of the waves were compared. Evans blue dye and fluorescent microscopy were used to study the possible changes in the permeability of the BBB. The results demonstrated that N-methyl-D-aspartate receptor antagonists can reduce the number of CSD waves and decrease

  16. Adrenaline increases blood-brain-barrier permeability after haemorrhagic cardiac arrest in immature pigs.

    Science.gov (United States)

    Semenas, E; Sharma, H S; Wiklund, L

    2014-05-01

    Adrenaline (ADR) and vasopressin (VAS) are used as vasopressors during cardiopulmonary resuscitation. Data regarding their effects on blood-brain barrier (BBB) integrity and neuronal damage are lacking. We hypothesised that VAS given during cardiopulmonary resuscitation (CPR) after haemorrhagic circulatory arrest will preserve BBB integrity better than ADR. Twenty-one anaesthetised sexually immature male piglets (with a weight of 24.3 ± 1.3 kg) were bled 35% via femoral artery to a mean arterial blood pressure of 25 mmHg in the period of 15 min. Afterwards, the piglets were subjected to 8 min of untreated ventricular fibrillation followed by 15 min of open-chest CPR. At 9 min of circulatory arrest, piglets received amiodarone 1.0 mg/kg and hypertonic-hyperoncotic solution 4 ml/kg infusions for 20 min. At the same time, VAS 0.4 U/kg was given intravenously to the VAS group (n = 9) while the ADR group received ADR 20 μg/kg (n = 12). Internal defibrillation was attempted from 11 min of cardiac arrest to achieve restoration of spontaneous circulation. The experiment was terminated 3 h after resuscitation. The intracranial pressure (ICP) in the post-resuscitation phase was significantly greater in ADR group than in VAS group. VAS group piglets exhibited a significantly smaller BBB disruption compared with ADR group. Cerebral pressure reactivity index showed that cerebral blood flow autoregulation was also better preserved in VAS group. Resuscitation with ADR as compared with VAS after haemorrhagic circulatory arrest increased the ICP and impaired cerebrovascular autoregulation more profoundly, as well as exerted an increased BBB disruption though no significant difference in neuronal injury was observed. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  17. [Establishment of MDCK-pHaMDR cell model and standard operation procedure for assessing blood-brain barrier permeability of chemical components of traditional Chinese medicine].

    Science.gov (United States)

    Yang, Yan-Fang; Wu, Ni; Yang, Xiu-Wei

    2016-07-01

    To establish MDCK-pHaMDR cell model and standard operation procedure for assessing the blood-brain barrier permeability of chemical components of traditional Chinese medicine. MDCK-pHaMDR cell model was evaluated by determining the morphology features, transepithelial electrical resistance, bidirectional transport and intracellular accumulation of Rhodamine 123 and the apparent permeability of positive control drugs caffeine and atenolol. The MDCK-pHaMDR cell model had satisfactory integrity and tightness, and stable expression of P-gp. In addition, the transport results of the positive control drugs were consistent with the reported values in literature. All the parameters tested of the MDCK-pHaMDR cell model were consistent with the requirements, so the model can be used to study the blood-brain barrier permeability of chemical components of traditional Chinese medicine. Copyright© by the Chinese Pharmaceutical Association.

  18. Blood-Brain Barrier Permeability of Normal Appearing White Matter in Relapsing-Remitting Multiple Sclerosis

    DEFF Research Database (Denmark)

    Lund, Henrik; Krakauer, Martin; Skimminge, Arnold

    2013-01-01

    and after the intravenous injection of a paramagnetic contrast agent to assess BBB permeability in the normal appearing white matter (NAWM) in patients with relapsing-remitting MS (RR-MS). Methodology/Principal Findings: Fifty-nine patients (38 females) with RR-MS undergoing immunomodulatory treatment...... and nine healthy controls (4 females) underwent quantitative T1 measurements at 3 tesla before and after injection of a paramagnetic contrast agent (0.2 mmol/kg Gd-DTPA). Mean T1 values were calculated for NAWM in patients and total cerebral white matter in healthy subjects for the T1 measurements before...

  19. Side by side comparison between dynamic versus static models of blood-brain barrier in vitro: a permeability study.

    Science.gov (United States)

    Santaguida, Stefano; Janigro, Damir; Hossain, Mohammed; Oby, Emily; Rapp, Edward; Cucullo, Luca

    2006-09-13

    Endothelial cells in vivo are continuously exposed to shear stress, a tangential force generated by the flow of blood across their apical surfaces that affects endothelial cell structure and function. By contrast, the Transwell apparatus cannot reproduce the presence of intraluminal blood flow that is essential for the formation and differentiation of the BBB. In contrast, the dynamic in vitro model of the BBB (DIV-BBB) mimics both functionally and anatomically the brain microvasculature, creating quasi-physiological conditions for co-culturing human and non-human endothelial cells and astrocytes in a capillary-like structure. We used intraluminal bovine aortic endothelial cells (BAEC) co-cultured with extraluminal glial cells (C6) to obtain elevated trans-endothelial electrical resistance (TEER) and selective permeability to sucrose and phenytoin. The experiments were performed in parallel using Transwell systems DIV-BBB models and data were then cross compared. By contrast with Transwell, C6 and BAEC co-cultured in the DIV-BBB demonstrated predominantly aerobic metabolism evidenced by a robust increase in glucose consumption that was paralleled by a similar change in lactate production. BAEC exposed to glia under dynamic conditions grow in a monolayer fashion and developed a more stringent barrier as demonstrated by high TEER values and a selective permeability to [14C] phenytoin and the well-known paracellular marker [3H] sucrose. In conclusion, these data demonstrate that the exposure to intraluminal flow plays an essential role in promoting endothelial cell differentiation and increasing BBB tightness, thus making the use of the DIV-BBB well suited for pharmacological studies.

  20. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs

    DEFF Research Database (Denmark)

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea

    2016-01-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by c...

  1. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism

    DEFF Research Database (Denmark)

    Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik

    2016-01-01

    , risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites......, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data...

  2. Vascular endothelial growth factor blockade alters magnetic resonance imaging biomarkers of vascular function and decreases barrier permeability in a rat model of lung cancer brain metastasis.

    Science.gov (United States)

    Pishko, Gregory L; Muldoon, Leslie L; Pagel, Michael A; Schwartz, Daniel L; Neuwelt, Edward A

    2015-02-17

    Blockade of vascular endothelial growth factor (VEGF) to promote vascular normalization and inhibit angiogenesis has been proposed for the treatment of brain metastases; however, vascular normalization has not been well-characterized in this disease. We investigated the effect of treatment with bevacizumab anti-VEGF antibody on magnetic resonance imaging (MRI) biomarkers of brain tumor vascular characteristics in comparison to small molecule delivery in a rat model of human lung cancer brain metastasis. Athymic rats with A549 human lung adenocarcinoma intracerebral xenografts underwent MRI at 11.75 T before and one day after treatment with bevacizumab (n = 8) or saline control (n = 8) to evaluate tumor volume, free water content (edema), blood volume and vascular permeability (Ktrans). One day later, permeability to 14C-aminoisobutyric acid (AIB) was measured in tumor and brain to assess the penetration of a small drug-like molecule. In saline control animals, tumor volume, edema and permeability increased over the two day assessment period. Compared to controls, bevacizumab treatment slowed the rate of tumor growth (P = 0.003) and blocked the increase in edema (P = 0.033), but did not alter tumor blood volume. Bevacizumab also significantly reduced Ktrans (P = 0.033) and AIB passive permeability in tumor (P = 0.04), but not to peritumoral tissue or normal brain. Post-treatment Ktrans correlated with AIB levels in the bevacizumab-treated rats but not in the saline controls. The correlation of an MRI biomarker for decreased vascular permeability with decreased AIB concentration in tumor after antiangiogenic treatment suggests that bevacizumab partially restored the normal low permeability characteristics of the blood-brain barrier in a model of human lung cancer brain metastasis.

  3. Drug delivery strategies to enhance the permeability of the blood–brain barrier for treatment of glioma

    Directory of Open Access Journals (Sweden)

    Zhang F

    2015-04-01

    Full Text Available Fang Zhang, Chun-Lei Xu, Chun-Mei Liu School of Pharmacy, National First-Class Key Discipline for Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China Abstract: Gliomas are amongst the most insidious and destructive types of brain cancer and are associated with a poor prognosis, frequent recurrences, and extremely high lethality despite combination treatment of surgery, radiotherapy, and chemotherapy. The existence of the blood–brain barrier (BBB restricts the delivery of therapeutic molecules into the brain and offers the clinical efficacy of many pharmaceuticals that have been demonstrated to be effective for other kinds of tumors. This challenge emphasizes the need to be able to deliver drugs effectively across the BBB to reach the brain parenchyma. Enhancement of the permeability of the BBB and being able to transport drugs across it has been shown to be a promising strategy to improve drug absorption and treatment efficacy. This review highlights the innovative technologies that have been introduced to enhance the permeability of the BBB and to obtain an optimal distribution and concentration of drugs in the brain to treat gliomas, such as nanotechniques, hyperthermia techniques, receptor-mediated transport, cell-penetrating peptides, and cell-mediated delivery. Keywords: glioma, blood–brain barrier, drug delivery, nanotechnology, hyperthermia, receptor-mediated transport, cell-penetrating peptides, cell-mediated delivery

  4. Blood-brain barrier permeability and nerve cell damage in rat brain 14 and 28 days after exposure to microwaves from GSM mobile phones.

    Science.gov (United States)

    Eberhardt, Jacob L; Persson, Bertil R R; Brun, Arne E; Salford, Leif G; Malmgren, Lars O G

    2008-01-01

    We investigated the effects of global system for mobile communication (GSM) microwave exposure on the permeability of the blood-brain barrier and signs of neuronal damage in rats using a real GSM programmable mobile phone in the 900 MHz band. Ninety-six non-anaesthetized rats were either exposed to microwaves or sham exposed in TEM-cells for 2 h at specific absorption rates of average whole-body Specific Absorption Rates (SAR) of 0.12, 1.2, 12, or 120 mW/kg. The rats were sacrificed after a recovery time of either 14 or 28 d, following exposure and the extravazation of albumin, its uptake into neurons, and occurrence of damaged neurons was assessed. Albumin extravazation and also its uptake into neurons was seen to be enhanced after 14 d (Kruskal Wallis test: p = 0.02 and 0.002, respectively), but not after a 28 d recovery period. The occurrence of dark neurons in the rat brains, on the other hand, was enhanced later, after 28 d (p = 0.02). Furthermore, in the 28-d brain samples, neuronal albumin uptake was significantly correlated to occurrence of damaged neurons (Spearman r = 0.41; p < 0.01).

  5. Assessment of Blood-Brain Barrier Permeability by Dynamic Contrast-Enhanced MRI in Transient Middle Cerebral Artery Occlusion Model after Localized Brain Cooling in Rats

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    Kim, Eun Soo [Department of Radiology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068 (Korea, Republic of); Lee, Seung-Koo [Department of Radiology, Yonsei University College of Medicine, Seoul 03722 (Korea, Republic of); Kwon, Mi Jung [Department of Pathology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068 (Korea, Republic of); Lee, Phil Hye [Department of Neurology, Yonsei University College of Medicine, Seoul 03722 (Korea, Republic of); Ju, Young-Su [Department of Industrial Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068 (Korea, Republic of); Yoon, Dae Young [Department of Radiology, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 05355 (Korea, Republic of); Kim, Hye Jeong [Department of Radiology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441 (Korea, Republic of); Lee, Kwan Seop [Department of Radiology, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068 (Korea, Republic of)

    2016-11-01

    The purpose of this study was to evaluate the effects of localized brain cooling on blood-brain barrier (BBB) permeability following transient middle cerebral artery occlusion (tMCAO) in rats, by using dynamic contrast-enhanced (DCE)-MRI. Thirty rats were divided into 3 groups of 10 rats each: control group, localized cold-saline (20℃) infusion group, and localized warm-saline (37℃) infusion group. The left middle cerebral artery (MCA) was occluded for 1 hour in anesthetized rats, followed by 3 hours of reperfusion. In the localized saline infusion group, 6 mL of cold or warm saline was infused through the hollow filament for 10 minutes after MCA occlusion. DCE-MRI investigations were performed after 3 hours and 24 hours of reperfusion. Pharmacokinetic parameters of the extended Tofts-Kety model were calculated for each DCE-MRI. In addition, rotarod testing was performed before tMCAO, and on days 1-9 after tMCAO. Myeloperoxidase (MPO) immunohisto-chemistry was performed to identify infiltrating neutrophils associated with the inflammatory response in the rat brain. Permeability parameters showed no statistical significance between cold and warm saline infusion groups after 3-hour reperfusion 0.09 ± 0.01 min{sup -1} vs. 0.07 ± 0.02 min{sup -1}, p = 0.661 for K{sup trans}; 0.30 ± 0.05 min{sup -1} vs. 0.37 ± 0.11 min{sup -1}, p = 0.394 for kep, respectively. Behavioral testing revealed no significant difference among the three groups. However, the percentage of MPO-positive cells in the cold-saline group was significantly lower than those in the control and warm-saline groups (p < 0.05). Localized brain cooling (20℃) does not confer a benefit to inhibit the increase in BBB permeability that follows transient cerebral ischemia and reperfusion in an animal model, as compared with localized warm-saline (37℃) infusion group.

  6. Assessment of blood-brain barrier permeability by dynamic contrast-enhanced MRI in transient middle cerebral artery occlusion model after localized brain cooling in rats

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Soo; Lee, Kwan Seop; Kwon, Mi Jung; Ju, Young Su [Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang (Korea, Republic of); Lee, Seung Koo; Lee, Phil Hye [Yonsei University College of Medicine, Seoul (Korea, Republic of); Yoon, Dae Young [Dept. of Radiology, Hallym University Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul (Korea, Republic of); Kim, Hye Jeong [Dept. of Radiology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul (Korea, Republic of)

    2016-09-15

    The purpose of this study was to evaluate the effects of localized brain cooling on blood-brain barrier (BBB) permeability following transient middle cerebral artery occlusion (tMCAO) in rats, by using dynamic contrast-enhanced (DCE)-MRI. Thirty rats were divided into 3 groups of 10 rats each: control group, localized cold-saline (20 .deg. ) infusion group, and localized warm-saline (37 .deg. ) infusion group. The left middle cerebral artery (MCA) was occluded for 1 hour in anesthetized rats, followed by 3 hours of reperfusion. In the localized saline infusion group, 6 mL of cold or warm saline was infused through the hollow filament for 10 minutes after MCA occlusion. DCE-MRI investigations were performed after 3 hours and 24 hours of reperfusion. Pharmacokinetic parameters of the extended Tofts-Kety model were calculated for each DCE-MRI. In addition, rotarod testing was performed before tMCAO, and on days 1-9 after tMCAO. Myeloperoxidase (MPO) immunohisto-chemistry was performed to identify infiltrating neutrophils associated with the inflammatory response in the rat brain. Permeability parameters showed no statistical significance between cold and warm saline infusion groups after 3-hour reperfusion 0.09 ± 0.01 min{sup -1} vs. 0.07 ± 0.02 min{sup -1},p = 0.661 for K{sup trans}; 0.30 ± 0.05 min{sup -1} vs. 0.37 ± 0.11 min{sup -1},p = 0.394 for kep, respectively. Behavioral testing revealed no significant difference among the three groups. However, the percentage of MPO-positive cells in the cold-saline group was significantly lower than those in the control and warm-saline groups (p < 0.05). Localized brain cooling (20 .deg. ) does not confer a benefit to inhibit the increase in BBB permeability that follows transient cerebral ischemia and reperfusion in an animal model, as compared with localized warm-saline (37 .deg. ) infusion group.

  7. In vivo measurements of blood-brain barrier permeability using micro-dialysis: radiobiological application; Etude in vivo des effets de l'irradiation gamma sur la permeabilite de la barriere hemato-encephalique

    Energy Technology Data Exchange (ETDEWEB)

    Agin, A.; Diserbo, M.; Mauris, J.; Martin, C

    1998-07-01

    The effects of total-body irradiation on the permeability of striatal blood-brain barrier (BBB) to [{sup 3}H] amino-isobutyric acid (AIBA) and [{sup 14}C] sucrose were investigated. Six weeks, three and five months after gamma exposure at the dose of 4.5 Gy, no modification of the transport of AIB or of the diffusion of sucrose from blood to brain was observed. (authors)

  8. Magnetic resonance imaging of blood-brain barrier permeability in ischemic stroke using diffusion-weighted arterial spin labeling in rats.

    Science.gov (United States)

    Tiwari, Yash V; Lu, Jianfei; Shen, Qiang; Cerqueira, Bianca; Duong, Timothy Q

    2017-08-01

    Diffusion-weighted arterial spin labeling magnetic resonance imaging has recently been proposed to quantify the rate of water exchange (K w ) across the blood-brain barrier in humans. This study aimed to evaluate the blood-brain barrier disruption in transient (60 min) ischemic stroke using K w magnetic resonance imaging with cross-validation by dynamic contrast-enhanced magnetic resonance imaging and Evans blue histology in the same rats. The major findings were: (i) at 90 min after stroke (30 min after reperfusion), group K w magnetic resonance imaging data showed no significant blood-brain barrier permeability changes, although a few animals showed slightly abnormal K w . Dynamic contrast-enhanced magnetic resonance imaging confirmed this finding in the same animals. (ii) At two days after stroke, K w magnetic resonance imaging revealed significant blood-brain barrier disruption. Regions with abnormal K w showed substantial overlap with regions of hyperintense T 2 (vasogenic edema) and hyperperfusion. Dynamic contrast-enhanced magnetic resonance imaging and Evans blue histology confirmed these findings in the same animals. The K w values in the normal contralesional hemisphere and the ipsilesional ischemic core two days after stroke were: 363 ± 17 and 261 ± 18 min -1 , respectively (P magnetic resonance imaging is sensitive to blood-brain barrier permeability changes in stroke, consistent with dynamic contrast-enhanced magnetic resonance imaging and Evans blue extravasation. K w magnetic resonance imaging offers advantages over existing techniques because contrast agent is not needed and repeated measurements can be made for longitudinal monitoring or averaging.

  9. Effect of Exercise Intensity on Neurotrophic Factors and Blood-Brain Barrier Permeability Induced by Oxidative-Nitrosative Stress in Male College Students.

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    Roh, Hee-Tae; Cho, Su-Youn; Yoon, Hyung-Gi; So, Wi-Young

    2017-06-01

    We investigated the effects of aerobic exercise intensity on oxidative-nitrosative stress, neurotrophic factor expression, and blood-brain barrier (BBB) permeability. Fifteen healthy men performed treadmill running under low-intensity (LI), moderate-intensity (MI), and high-intensity (HI) conditions. Blood samples were collected immediately before exercise (IBE), immediately after exercise (IAE), and 60 min after exercise (60MAE) to examine oxidative-nitrosative stress (reactive oxygen species [ROS]; nitric oxide [NO]), neurotrophic factors (brain-derived neurotrophic factor [BDNF]; nerve growth factor [NGF]), and blood-brain barrier (BBB) permeability (S-100β; neuron-specific enolase). ROS concentration significantly increased IAE and following HI (4.9 ± 1.7 mM) compared with that after LI (2.8 ± 1.4 mM) exercise (p .05). Moderate- and/or high-intensity exercise may induce higher oxidative-nitrosative stress than may low-intensity exercise, which can increase peripheral neurotrophic factor levels by increasing BBB permeability.

  10. Magnetic-resonance imaging for kinetic analysis of permeability changes during focused ultrasound-induced blood-brain barrier opening and brain drug delivery.

    Science.gov (United States)

    Chai, Wen-Yen; Chu, Po-Chun; Tsai, Meng-Yen; Lin, Yu-Chun; Wang, Jiun-Jie; Wei, Kuo-Chen; Wai, Yau-Yau; Liu, Hao-Li

    2014-10-28

    Focused ultrasound (FUS) with the presence of microbubbles has been shown to induce transient and local opening of the blood-brain barrier (BBB) for the delivery of therapeutic molecules which normally cannot penetrate into the brain. The success of FUS brain-drug delivery relies on its integration with in-vivo imaging to monitor kinetic change of therapeutic molecules into the brain. In this study, we developed a dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) technique for kinetic analysis of delivered molecules during FUS-BBB opening. Three kinetic parameters (Ktrans, Ve, Kep) were characterized dynamically to describe BBB-permeability at two FUS exposure conditions (0.4 or 0.8MPa) over 24h. Ktrans, defined as the influx volume transfer constant from plasma to EES, and Ve, the EES volume fraction, were both found to be pressure-dependent. Ktrans and Ve showed a peak increase of 0.0086-0.0131min(-1) (for 0.4-0.8MPa pressure), and 0.0431-0.0692, respectively, immediately after FUS exposure. Both parameters subsequently decreased exponentially as a function of time, with estimated half-lives of decay of 2.89-5.3 and 2.2-4.93h, respectively. The kinetics of Kep, defined as the efflux rate constant from the extracellular extravascular space (EES) to the plasma, were complementary to Ktrans, with an initial decrease from 0.2010 to 0.1901min(-1) followed by a significantly longer recovery time (half-life of 17.39-99.92h). Our observations strongly supported the existence of imbalanced and mismatched kinetics of influx (Ktrans) and efflux (Kep) between the plasma and EES, indicating the existence of directional permeability during FUS-BBB opening. We further showed that kinetic change determined by DCE-MRI correlated well with the concentration of Evans Blue (EB)-albumin (coefficient of 0.74-0.89). These findings suggest that MRI kinetic monitoring may serve as an alternative method for in-vivo monitoring of pharmacokinetics and pharmacodynamics (PK

  11. A Novel Algorithm for the Assessment of Blood-Brain Barrier Permeability Suggests That Brain Topical Application of Endothelin-1 Does Not Cause Early Opening of the Barrier in Rats

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    D. Jorks

    2011-01-01

    Full Text Available There are a number of different experimental methods for ex vivo assessment of blood-brain barrier (BBB opening based on Evans blue dye extravasation. However, these methods require many different steps to prepare the brain and need special equipment for quantification. We here report a novel, simple, and fast semiquantitative algorithm to assess BBB integrity ex vivo. The method is particularly suitable for cranial window experiments, since it keeps the spatial information about where the BBB opened. We validated the algorithm using sham controls and the established model of brain topical application of the bile salt dehydrocholate for early BBB disruption. We then studied spreading depolarizations in the presence and the absence of the vasoconstrictor endothelin-1 and found no evidence of early BBB opening (three-hour time window. The algorithm can be used, for example, to assess BBB permeability ex vivo in combination with dynamic in vivo studies of BBB opening.

  12. The Blood-Brain Barrier Permeability of Six Indole Alkaloids from Uncariae Ramulus Cum Uncis in the MDCK-pHaMDR Cell Monolayer Model

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    Yi-Nan Zhang

    2017-11-01

    Full Text Available Uncariae Ramulus Cum Uncis (URCU is a widely used traditional Chinese medicine, and is reported to have various central nervous system effects. Alkaloids have been demonstrated to be the predominant pharmacological active components of URCU. In order to evaluate the blood-brain barrier (BBB permeability and transport mechanism of six typical indole alkaloids from URCU, the MDCK-pHaMDR cell monolayer model was used as an in vitro surrogate model for BBB. The samples were analyzed by high-performance liquid chromatography, and the apparent permeability coefficients (Papp were calculated. Among the six alkaloids, isorhynchophylline (2, isocorynoxeine (4, hirsutine (5 and hirsuteine (6 showed high permeability, with Papp values at 10−5 cm/s level in bidirectional transport. For rhynchophylline (1 and corynoxeine (3, they showed moderate permeability, with Papp values from the apical (AP side to the basolateral (BL side at 10−6 cm/s level and efflux ratio (Papp BL→AP/Papp AP→BL above 2. The time- and concentration-dependency experiments indicated that the main mechanism for 2, 4, 5 and 6 through BBB was passive diffusion. The efflux mechanism involved in the transports of compounds 1 and 3 could be reduced significantly by verapamil, and molecular docking screening also showed that 1 and 3 had strong bindings to P-glycoprotein. This study provides useful information for predicting the BBB permeability for 1–6, as well as better understanding of their central nervous system pharmacological activities.

  13. In silico modeling on ADME properties of natural products: Classification models for blood-brain barrier permeability, its application to traditional Chinese medicine and in vitro experimental validation.

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    Zhang, Xiuqing; Liu, Ting; Fan, Xiaohui; Ai, Ni

    2017-08-01

    In silico modeling of blood-brain barrier (BBB) permeability plays an important role in early discovery of central nervous system (CNS) drugs due to its high-throughput and cost-effectiveness. Natural products (NP) have demonstrated considerable therapeutic efficacy against several CNS diseases. However, BBB permeation property of NP is scarcely evaluated both experimentally and computationally. It is well accepted that significant difference in chemical spaces exists between NP and synthetic drugs, which calls into doubt on suitability of available synthetic chemical based BBB permeability models for the evaluation of NP. Herein poor discriminative performance on BBB permeability of NP are first confirmed using internal constructed and previously published drug-derived computational models, which warrants the need for NP-oriented modeling. Then a quantitative structure-property relationship (QSPR) study on a NP dataset was carried out using four different machine learning methods including support vector machine, random forest, Naïve Bayes and probabilistic neural network with 67 selected features. The final consensus model was obtained with approximate 90% overall accuracy for the cross-validation study, which is further taken to predict passive BBB permeability of a large dataset consisting of over 10,000 compounds from traditional Chinese medicine (TCM). For 32 selected TCM molecules, their predicted BBB permeability were evaluated by in vitro parallel artificial membrane permeability assay and overall accuracy for in vitro experimental validation is around 81%. Interestingly, our in silico model successfully predicted different BBB permeation potentials of parent molecules and their known in vivo metabolites. Finally, we found that the lipophilicity, the number of hydrogen bonds and molecular polarity were important molecular determinants for BBB permeability of NP. Our results suggest that the consensus model proposed in current work is a reliable tool for

  14. Effects of salidroside pretreatment on expression of tumor necrosis factor-alpha and permeability of blood brain barrier in rat model of focal cerebralischemia-reperfusion injury.

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    Han, Tian

    2013-02-01

    To observe changes in expression of tumor necrosis factor (TNF)-alpha and permeability of blood brain barrier after salidroside pretreatment in rats with injury induced by focal cerebralischemia-reperfusion. Forty-five male SD rats were randomly divided into three groups (n=15): control group, ischemia-reperfusion (IR) model group, and salidroside pretreatment group. Before the IR model establishment, the rats in the salidroside pretreatment group were intraperitoneally administered with salidroside at a dose of 24 mg/(kg·d) for 7 d. After 30 min post the last administration, the IR model was induced by occlusion of middle cerebral artery with a filament. After 24 h post the operation, the water content and Evens blue content in the ischemia cerebral hemisphere were determined, and the level of TNF-alpha mRNA was detected by the semi-quantitative RT-PCR. Compared with the IR model group, the salidroside pretreatment group had significantly lower (Psalidroside pretreatment alleviated the focal cerebralischemia-reperfusion injury in the rat model, possibly by decreasing the permeability of blood brain barrier, attenuating brain edema and reducing TNF-alpha expression. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  15. A review of the mechanisms of blood-brain barrier permeability by tissue-type plasminogen activator treatment for cerebral ischemia

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    Yasuhiro eSuzuki

    2016-01-01

    Full Text Available Cerebrovascular homeostasis is maintained by the blood-brain barrier (BBB, which forms a mechanical and functional barrier between systemic circulation and the central nervous system. In patients with ischemic stroke, the recombinant tissue-type plasminogen activator (rt-PA is used to accelerate recanalization of the occluded vessels. However, rt-PA is associated with a risk of increasing intracranial bleeding. This effect is thought to be caused by the increase in cerebrovascular permeability though various factors such as ischemic reperfusion injury and the activation of matrix metalloproteinases, but the detailed mechanisms are unknown. It was recently found that rt-PA treatment enhances BBB permeability not by disrupting the BBB, but by activating the vascular endothelial growth factor (VEGF system. The VEGF regulates both the dissociation of endothelial-endothelial cell junctions and endothelial endocytosis, and causes a subsequent increase in vessel permeability through the VEGF receptor-2 activation in endothelial cells. Here, we review the possibility that rt-PA increases the penetration of toxic molecules derived from the bloodstream including rt-PA itself, without disrupting the BBB, and contributes to these detrimental processes in the cerebral parenchyma.

  16. The Blood-Brain Barrier Permeability of Lignans and Malabaricones from the Seeds of Myristica fragrans in the MDCK-pHaMDR Cell Monolayer Model

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    Ni Wu

    2016-01-01

    Full Text Available The blood-brain barrier (BBB permeability of twelve lignans and three phenolic malabaricones from the seeds of Myristica fragrans (nutmeg were studied with the MDCK-pHaMDR cell monolayer model. The samples were measured by high-performance liquid chromatography and the apparent permeability coefficients (Papp were calculated. Among the fifteen test compounds, benzonfuran-type, dibenzylbutane-type and arylnaphthalene-type lignans showed poor to moderate permeabilities with Papp values at 10−8–10−6 cm/s; those of 8-O-4′-neolignan and tetrahydrofuran-lignan were at 10−6–10−5 cm/s, meaning that their permeabilities are moderate to high; the permeabilities of malabaricones were poor as their Papp values were at 10−8–10−7 cm/s. To 5-methoxy-dehydrodiisoeugenol (2, erythro-2-(4-allyl-2,6-dimethoxyphenoxy-1-(3,4-dimethoxyphenyl-propan-1-ol acetate (6, verrucosin (8, and nectandrin B (9, an efflux way was involved and the main transporter for 6, 8 and 9 was demonstrated to be P-glycoprotein. The time and concentration dependency experiments indicated the main transport mechanism for neolignans dehydrodiisoeugenol (1, myrislignan (7 and 8 was passive diffusion. This study summarized the relationship between the BBB permeability and structure parameters of the test compounds, which could be used to preliminarily predict the transport of a compound through BBB. The results provide a significant molecular basis for better understanding the potential central nervous system effects of nutmeg.

  17. Protein kinase C activation modulates reversible increase in cortical blood–brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation

    Science.gov (United States)

    Willis, Colin L; Meske, Diana S; Davis, Thomas P

    2010-01-01

    Hypoxia (Hx) is a component of many disease states including stroke. Ischemic stroke occurs when there is a restriction of cerebral blood flow and oxygen to part of the brain. During the ischemic, and subsequent reperfusion phase of stroke, blood–brain barrier (BBB) integrity is lost with tight junction (TJ) protein disruption. However, the mechanisms of Hx and reoxygenation (HR)-induced loss of BBB integrity are not fully understood. We examined the role of protein kinase C (PKC) isozymes in modifying TJ protein expression in a rat model of global Hx. The Hx (6% O2) induced increased hippocampal and cortical vascular permeability to 4 and 10 kDa dextran fluorescein isothiocyanate (FITC) and endogenous rat-IgG. Cortical microvessels revealed morphologic changes in nPKC-θ distribution, increased nPKC-θ and aPKC-ζ protein expression, and activation by phosphorylation of nPKC-θ (Thr538) and aPKC-ζ (Thr410) residues after Hx treatment. Claudin-5, occludin, and ZO-1 showed disrupted organization at endothelial cell margins, whereas Western blot analysis showed increased TJ protein expression after Hx. The PKC inhibition with chelerythrine chloride (5 mg/kg intraperitoneally) attenuated Hx-induced hippocampal vascular permeability and claudin-5, PKC (θ and ζ) expression, and phosphorylation. This study supports the hypothesis that nPKC-θ and aPKC-ζ signaling mediates TJ protein disruption resulting in increased BBB permeability. PMID:20700133

  18. Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice.

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    Chen, Tsung-Ying; Lee, Ming-Yang; Chen, Hung-Yi; Kuo, Yen-Liang; Lin, Shih-Chieh; Wu, Tian-Shung; Lee, E-Jian

    2006-04-01

    Melatonin protects against transient middle cerebral artery (MCA) occlusion and may be suited as an add-on therapy of tissue plasminogen activator (t-PA) thrombolysis. Herein, we examined whether melatonin would reduce postischemic increase in the blood-brain barrier (BBB) permeability and, therefore, attenuate the risk of hemorrhagic transformation after t-PA therapy in experimental stroke. Twelve mice were subjected to transient occlusion of the MCA for 1 hr, followed by 24 hr of reperfusion. Melatonin (5 mg/kg, i.p.) or vehicle was given at the beginning of reperfusion. BBB permeability was evaluated by quantitation of Evans Blue leakage. An additional 32 mice underwent photothrombotic occlusion of the distal MCA, and were administered vehicle or t-PA (10 mg/kg, i.v.), alone or in combination with melatonin (5 mg/kg, i.p.), at 6 hr postinsult. The animals were then killed after 24 hr for the determination of infarct and hemorrhage volumes. Relative to controls, melatonin-treated animals had significantly reduced BBB permeability (by 52%; P hr after photo-irradiation, either t-PA or melatonin, or a combined administration of t-PA plus melatonin, did not significantly affect brain infarction (P > 0.05), compared with controls. Mice treated with t-PA alone, however, had significantly increased hemorrhagic formation (P transformation after t-PA therapy for ischemic stroke. The findings further highlight melatonin's potential role in the field of thrombolytic treatment for ischemic stroke patients.

  19. Vascular Endothelial Growth Factor Increases during Blood-Brain Barrier-Enhanced Permeability Caused by Phoneutria nigriventer Spider Venom

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    Monique C. P. Mendonça

    2014-01-01

    Full Text Available Phoneutria nigriventer spider accidental envenomation provokes neurotoxic manifestations, which when critical, results in epileptic-like episodes. In rats, P. nigriventer venom (PNV causes blood-brain barrier breakdown (BBBb. The PNV-induced excitotoxicity results from disturbances on Na+, K+ and Ca2+ channels and glutamate handling. The vascular endothelial growth factor (VEGF, beyond its angiogenic effect, also, interferes on synaptic physiology by affecting the same ion channels and protects neurons from excitotoxicity. However, it is unknown whether VEGF expression is altered following PNV envenomation. We found that adult and neonates rats injected with PNV showed immediate neurotoxic manifestations which paralleled with endothelial occludin, β-catenin, and laminin downregulation indicative of BBBb. In neonate rats, VEGF, VEGF mRNA, and Flt-1 receptors, glutamate decarboxylase, and calbindin-D28k increased in Purkinje neurons, while, in adult rats, the BBBb paralleled with VEGF mRNA, Flk-1, and calbindin-D28k increases and Flt-1 decreases. Statistically, the variable age had a role in such differences, which might be due to age-related unequal maturation of blood-brain barrier (BBB and thus differential cross-signaling among components of the glial neurovascular unit. The concurrent increases in the VEGF/Flt-1/Flk-1 system in the cerebellar neuron cells and the BBBb following PNV exposure might imply a cytokine modulation of neuronal excitability consequent to homeostatic perturbations induced by ion channels-acting PNV neuropeptides. Whether such modulation represents neuroprotection needs further investigation.

  20. Blood-brain barrier specific permeability assay reveals N-methylated tyramine derivatives in standardised leaf extracts and herbal products of Ginkgo biloba.

    Science.gov (United States)

    Könczöl, Árpád; Rendes, Kata; Dékány, Miklós; Müller, Judit; Riethmüller, Eszter; Balogh, György Tibor

    2016-11-30

    The linkage between the central nervous system availability and neuropharmacological activity of the constituents of Ginkgo biloba L. extracts (GBE) is still incomplete. In this study, the in vitro blood-brain barrier (BBB) permeability profile of the standardised GBE was investigated by the parallel artificial membrane permeability assay (PAMPA). Biomarkers, such as terpene trilactones, flavonoid aglycones and ginkgotoxin exerted moderate or good BBB-permeability potential (BBB+), while glycosides and biflavones were predicted as unable to pass the BBB. N-methyltyramine (NMT) and N,N-dimethyltyramine or hordenine (Hor) were identified among BBB+ compounds, while subsequent direct HRMS analysis revealed tyramine (Tyr) and N,N,N-trimethyltyramine or candicine (Can) in GBE as trace constituents. Distribution of Tyr, NMT, Hor and Can was determined by a validated ion-exchange mechanism-based liquid chromatography-electrospray ionisation-mass spectrometry (LC-ESI-MS) method in G. biloba samples, such as herbal drugs and dietary supplements. The total content of the four tyramine derivatives in various GBEs ranged from 7.3 up to 6357μg/g dry extract with NMT and Hor as most abundant ones. Considering the pharmacological activities and the revealed fluctuation in the concentration of the analysed adrenergic protoalkaloids, the presented rapid LC-ESI-MS method is proposed for monitoring of the levels of Tyr, NMT, Hor and Can in G. biloba products. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Cerebrovascular dysfunction and blood-brain barrier permeability induced by oxidized LDL are prevented by apocynin and magnesium sulfate in female rats.

    Science.gov (United States)

    Schreurs, Malou P H; Cipolla, Marilyn J

    2014-01-01

    Oxidized low-density lipoprotein (oxLDL) is elevated during several neurologic conditions that involve cerebral edema formation, including severe preeclampsia and eclampsia; however, our understanding of its effect on the cerebral vasculature is limited. We hypothesized that oxLDL induced blood-brain barrier (BBB) disruption and changes in cerebrovascular reactivity occur through NADPH oxidase-derived superoxide. We also investigated the effect of MgSO₄ on oxLDL-induced changes in the cerebral vasculature as this is commonly used in preventing cerebral edema formation. Posterior cerebral arteries from female rats were perfused with 5 µg/mL oxLDL in rat serum with or without 50 µM apocynin or 16 mM MgSO₄ and BBB permeability and vascular reactivity were compared. oxLDL increased BBB permeability and decreased myogenic tone that were prevented by apocynin. oxLDL increased constriction to the nitric oxide synthase inhibitor nitro-L-arginine that was unaffected by apocynin. oxLDL enhanced dilation to the NO donor sodium nitroprusside that was prevented by apocynin. MgSO₄ prevented oxLDL-induced BBB permeability without affecting oxLDL-induced changes in myogenic tone. Thus, oxLDL seems to cause BBB disruption and vascular tone dysregulation through NADPH oxidase-derived superoxide. These results highlight oxLDL and NADPH oxidase as potentially important therapeutic targets in neurologic conditions that involve elevated oxLDL.

  2. In vivo EPR pharmacokinetic evaluation of the redox status and the blood brain barrier permeability in the SOD1(G93A) ALS rat model.

    Science.gov (United States)

    Stamenković, Stefan; Pavićević, Aleksandra; Mojović, Miloš; Popović-Bijelić, Ana; Selaković, Vesna; Andjus, Pavle; Bačić, Goran

    2017-07-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting the motor pathways of the central nervous system. Although a number of pathophysiological mechanisms have been described in the disease, post mortem and animal model studies indicate blood-brain barrier (BBB) disruption and elevated production of reactive oxygen species as major contributors to disease pathology. In this study, the BBB permeability and the brain tissue redox status of the SOD1(G93A) ALS rat model in the presymptomatic (preALS) and symptomatic (ALS) stages of the disease were investigated by in vivo EPR spectroscopy using three aminoxyl radicals with different cell membrane and BBB permeabilities, Tempol, 3-carbamoyl proxyl (3CP), and 3-carboxy proxyl (3CxP). Additionally, the redox status of the two brain regions previously implicated in disease pathology, brainstem and hippocampus, was investigated by spectrophotometric biochemical assays. The EPR results indicated that among the three spin probes, 3CP is the most suitable for reporting the intracellular redox status changes, as Tempol was reduced in vivo within minutes (t1/2 =2.0±0.5min), thus preventing reliable kinetic modeling, whereas 3CxP reduction kinetics gave divergent conclusions, most probably due to its membrane impermeability. It was observed that the reduction kinetics of 3CP in vivo, in the head of preALS and ALS SOD1(G93A) rats was altered compared to the controls. Pharmacokinetic modeling of 3CP reduction in vivo, revealed elevated tissue distribution and tissue reduction rate constants indicating an altered brain tissue redox status, and possibly BBB disruption in these animals. The preALS and ALS brain tissue homogenates also showed increased nitrilation, superoxide production, lipid peroxidation and manganese superoxide dismutase activity, and a decreased copper-zinc superoxide dismutase activity. The present study highlights in vivo EPR spectroscopy as a reliable tool for the investigation of

  3. Effects of losartan on the blood-brain barrier permeability in long-term nitric oxide blockade-induced hypertensive rats.

    Science.gov (United States)

    Kucuk, Mutlu; Kaya, Mehmet; Kalayci, Rivaze; Cimen, Vedat; Kudat, Hasan; Arican, Nadir; Elmas, Imdat; Korkut, Ferruh

    2002-07-12

    Hypertension is closely associated with vascular endothelial dysfunction. The aim of this study was to investigate the effects of Angiotensin II (ANG II) receptor antagonist losartan on the blood-brain barrier (BBB) permeability in L-NAME-induced hypertension and/or in ANG II-induced acute hypertension in normotensive and hypertensive rats. Systolic blood pressure was measured by tail cuff method before, during and following L-NAME treatment (1 g/L). Losartan (3 mg/kg) was given to the animal for five days. Acute hypertension was induced by ANG II (60 microg/kg). Arterial blood pressure was directly measured on the day of the experiment. BBB disruption was quantified according to the extravasation of the albumin-bound Evans blue dye. Losartan significantly reduced the mean arterial blood pressure from 169 +/- 3.9 mmHg to 82 +/- 2.9 mmHg in L-NAME and from 171 +/- 2.9 mmHg to 84 +/- 2.9 in L-NAME plus losartan plus ANG II groups (p cerebral cortex significantly increased in L-NAME (p microvascular Evans blue dye efflux to brain, and losartan treatment attenuates this protein-bound dye transport into brain tissue presumably due to its protective effect on endothelial cells of brain vessels.

  4. Transient and local increase in the permeability of the blood-brain barrier and the blood-retinal barrier by hyperthermia of magnetic nanoparticles in a rat model

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    Tabatabaei Shafie, Seyed Nasrollah

    After successfully propelling therapeutic agents encapsulated in magnetic micro-carriers to a specific location inside an animal model by the gradient magnetic field of a modified clinical Magnetic Resonance (MR) scanner, we are now aiming to perform local drug delivery in the region of the central nervous system (CNS). To achieve localized drug delivery and increase efficacy, this project advances the theme that the therapeutic agents must be administered by means no more invasive than an intravenous injection followed by remote propulsion, controlled tracking, and on-command actuation in the CNS. The demanding function of the CNS requires an extremely stable environment. In fact, any small change in the composition of the interstitial fluid in the CNS plays a predominant role in regulating its microenvironment and neuronal activity. Therefore, the CNS is conceived to protect itself from frequent fluctuations of extracellular concentration of hormones, amino acids, and ion levels that occur after meals, exercise, or stress - as well as from toxic pathogens that may be circulating in the blood stream. This preventive barrier consists mainly of tightly interconnected endothelial cells that carpet the inner surface of most blood vessels in the CNS. While it provides a stable neuronal environment, more than 98% of all drug molecules are not able to cross this barrier and the extent to which a molecule enters is determined only by the permeability characteristics of the barrier. Therefore, while pharmaceutical research progresses for drug delivery to the CNS, it is limited by its pharmacokinetics through physiological barriers. Successful transient and local opening of the barrier for diffusion of therapeutics could strongly support the feasibility of treating a variety of neurological disorders. A recent effort presented in this dissertation provides evidence for the emergence of a novel approach to overcome this problem. This technique uses magnetic nanoparticles

  5. [The influence of acute hypercapnia on the permeability of the blood-brain barrier for gentamycin under conditions of general anesthesia in rabbits].

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    Pakulski, C

    1998-01-01

    The aim of the work was to demonstrate whether acute hypercapnia (paCO2 > 65 mm Hg) influenced the permeability of blood-brain barrier (BBB). Twelve Chinchilla rabbits which underwent general anaesthesia were randomly divided into 2 groups. The animals were sedated with intravenous administration of pentobarbital, then were subjected to endotracheal intubation and connected to volume-controlled respirator (Zimmermann pump). Artificial ventilation using air/oxygen mixture was applied. Auricular artery, inferior caval vein and aorta were catheterized with a catheter being also placed in the lateral ventricle of the brain. General anaesthesia was supported with continuous intravenous administration of pentobarbital. To maintain normal paCO2 values, the investigation was performed under normal ventilation in control group (5 rabbits). Controlled hypoventilation was applied to achieve an increase of paCO2 in the shortest possible time in the investigated group (7 rabbits). Heart rate (HR), systolic (SAP), diastolic (DAP) and mean (MAP) arterial blood pressure, intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were continuously recorded. Gentamycin was applied as the marker of function of BBB, because it couldn't penetrate into the cerebrospinal fluid after intravenous administration under physiological conditions. BBB function in normal and significantly increased paCO2 was evaluated using gentamycin permeability indexes (QG), defined as gentamycin concentration ratio in the cerebrospinal fluid to serum gentamycin concentration in the same moment of trial. Comparative analysis of the QG index for both groups according to values achieved before the trial and after 1 and 3 hours of experiment indicates the degree of BBB damage. Non-parametric differences significance test according to Kolmogorow-Smirnow was applied for statistical verification of the results. Significance level for the trial was alpha = 0.05. None of the monitored parameters has changed in

  6. Enhancement of Blood–Brain Barrier Permeability and Delivery of Antisense Oligonucleotides or Plasmid DNA to the Brain by the Combination of Bubble Liposomes and High-Intensity Focused Ultrasound

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    Yoichi Negishi

    2015-09-01

    Full Text Available The blood–brain barrier (BBB is a major obstacle that prevents therapeutic drugs or genes from being delivered to the central nervous system. Therefore, it is important to develop methods to enhance the permeability of the BBB. We have developed echo-contrast gas (C3F8 entrapping liposomes (Bubble liposomes, BLs that can work as a gene delivery tool in combination with ultrasound (US exposure. Here, we studied whether the permeability of the BBB can be enhanced by the combination of BLs and high-intensity focused ultrasound (HIFU. Mice were intravenously injected with Evans blue (EB. BLs were subsequently injected, and the right hemispheres were exposed to HIFU. As a result, the accumulation of EB in the HIFU-exposed brain hemispheres was increased over that observed in the non-HIFU-exposed hemispheres, depending on the intensity and the duration of the HIFU. Similarly, the combination of BLs and HIFU allowed fluorescent-labeled antisense oligonucleotides to be delivered into the HIFU-exposed left hemispheres of the treated mice. Furthermore, a firefly luciferase-expressing plasmid DNA was delivered to the brain by the combination method of BLs and HIFU, which resulted in the increased gene expression in the brain at the focused-US exposure site. These results suggest that the method of combining BLs and HIFU together serves as a useful means for accelerating the permeability of BBB and thereby enabling antisense oligonucleotides or genes to be delivered to the focused brain site.

  7. Studies on the potential neurotoxic and convulsant effects of increased blood levels of quinolinic acid in rats with altered blood-brain barrier permeability

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    Vezzani, A.; Stasi, M.A.; Wu, H.Q.; Castiglioni, M.; Weckermann, B.; Samanin, R. (Istituto di Ricerche Farmacologiche Mario Negri, Milano (Italy))

    1989-10-01

    Intravenous injection of 450 mg/kg quinolinic acid (Quin), an endogenous kynurenine metabolite with excitotoxic properties, induced only minor electroencephalographic (EEG) modifications and no neurotoxicity in rats with a mature blood-brain barrier (BBB). BBB permeability was altered in rats by focal unilateral irradiation of the cortex (7 mm in diameter and 5 mm in depth) with protons (60 Gy, 9 Gy/min). Three days after irradiation, Evans blue dye staining showed BBB breakdown in the dorsal hippocampus of the irradiated hemisphere. No neurotoxic or convulsant effects were observed as a consequence of the radiation itself. When BBB-lesioned rats were challenged with 225 mg/kg Quin iv, epileptiform activity was observed on EEG analysis. Tonic-clonic seizures were induced by 225-450 mg/kg Quin. Light microscopic analysis showed a dose-related excitotoxic type of lesion restricted to the hippocampus ipsilateral to the irradiated side. Neuro-degeneration was prevented by local injection of 120 nmol D(-)2-amino-7-phosphonoheptanoic acid, a selective N-methyl-D-aspartate receptor antagonist. No lesions or EEG or behavioral modifications occurred after 450 mg/kg nicotinic acid, an inactive analog of Quin. The potential neurotoxic and convulsant effects of increased blood levels of Quin under conditions of altered BBB permeability are discussed.

  8. The proton permeability of self-assembled polymersomes and their neuroprotection by enhancing a neuroprotective peptide across the blood-brain barrier after modification with lactoferrin

    Science.gov (United States)

    Yu, Yuan; Jiang, Xinguo; Gong, Shuyu; Feng, Liang; Zhong, Yanqiang; Pang, Zhiqing

    2014-02-01

    Biotherapeutics such as peptides possess strong potential for the treatment of intractable neurological disorders. However, because of their low stability and the impermeability of the blood-brain barrier (BBB), biotherapeutics are difficult to transport into brain parenchyma via intravenous injection. Herein, we present a novel poly(ethylene glycol)-poly(d,l-lactic-co-glycolic acid) polymersome-based nanomedicine with self-assembled bilayers, which was functionalized with lactoferrin (Lf-POS) to facilitate the transport of a neuroprotective peptide into the brain. The apparent diffusion coefficient (D*) of H+ through the polymersome membrane was 5.659 × 10-26 cm2 s-1, while that of liposomes was 1.017 × 10-24 cm2 s-1. The stability of the polymersome membrane was much higher than that of liposomes. The uptake of polymersomes by mouse brain capillary endothelial cells proved that the optimal density of lactoferrin was 101 molecules per polymersome. Fluorescence imaging indicated that Lf101-POS was effectively transferred into the brain. In pharmacokinetics, compared with transferrin-modified polymersomes and cationic bovine serum albumin-modified polymersomes, Lf-POS obtained the greatest BBB permeability surface area and percentage of injected dose per gram (%ID per g). Furthermore, Lf-POS holding S14G-humanin protected against learning and memory impairment induced by amyloid-β25-35 in rats. Western blotting revealed that the nanomedicine provided neuroprotection against over-expression of apoptotic proteins exhibiting neurofibrillary tangle pathology in neurons. The results indicated that polymersomes can be exploited as a promising non-invasive nanomedicine capable of mediating peptide therapeutic delivery and controlling the release of drugs to the central nervous system.

  9. Influence of blood-brain barrier permeability on O-(2-{sup 18}F-fluoroethyl)-L-tyrosine uptake in rat gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Stegmayr, Carina; Bandelow, Ulrike; Oliveira, Dennis; Lohmann, Philipp; Willuweit, Antje; Galldiks, Norbert; Luebke, Joachim H.R. [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); Filss, Christian; Ermert, Johannes; Langen, Karl-Josef [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); RWTH/University Hospital Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Shah, N. Jon [Institute of Neuroscience and Medicine, Forschungszentrum Juelich, Juelich (Germany); RWTH/University Hospital Aachen, Department of Nuclear Medicine and Neurology, Aachen (Germany); Juelich-Aachen Research Alliance (JARA) - Section JARA-Brain, Aachen (Germany)

    2017-03-15

    O-(2-{sup 18}F-fluoroethyl)-L-tyrosine ({sup 18}F-FET) is an established tracer for the diagnosis of brain tumors with PET. This study investigates the influence of blood-brain barrier (BBB) permeability on {sup 18}F-FET uptake in two rat glioma models and one human xenograft model. F98 glioma, 9L gliosarcoma or human U87 glioblastoma cells were implanted into the striatum of 56 Fischer or RNU rats. Thereafter, animals were divided into a control group and a group receiving injections of the glucocorticoid dexamethasone (Dex). After 12-13 days of tumor growth animals received injection of Evans blue dye (EBD) to visualize BBB disturbance and underwent {sup 18}F-FET PET followed by autoradiography. Time activity curves, standardized uptake values (SUV) and Tumor-to-brain ratios (TBR) of {sup 18}F-FET uptake [18-61 min post injection (p.i.)] were evaluated using a volume-of-Interest (VOI) analysis. BBB disturbance was quantitatively evaluated by EBD fluorescence. The membrane gaps of blood vessel endothelial tight junctions were measured using electron microscopy to visualize ultrastructural BBB alterations in one untreated and one Dex treated F98 glioma. Data were analyzed by two-way ANOVAs. In Dex treated animals EBD extravasation was significantly reduced in 9L (P < 0.001) and U87 (P = 0.008) models and showed a trend in F98 models (P = 0.053). In contrast, no significant differences of {sup 18}F-FET uptake were observed between Dex treated animals and control group except a decrease of the TBR in the 9L tumor model in PET (P < 0.01). Ultrastructural evaluation of tumor blood vessel endothelia revealed significant reduction of the cleft diameter between endothelial cells after Dex treatment in F98 model (P = 0.010). Despite a considerable reduction of BBB permeability in rat gliomas after Dex treatment, no relevant changes of {sup 18}F-FET uptake were noted in this experimental study. Thus, {sup 18}F-FET uptake in gliomas appears to be widely independent of the

  10. Increase in blood-brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury.

    Science.gov (United States)

    Readnower, Ryan D; Chavko, Mikulas; Adeeb, Saleena; Conroy, Michael D; Pauly, James R; McCarron, Richard M; Sullivan, Patrick G

    2010-12-01

    Traumatic brain injury (TBI) as a consequence of exposure to blast is increasingly prevalent in military populations, with the underlying pathophysiological mechanisms mostly unknown. In the present study, we utilized an air-driven shock tube to investigate the effects of blast exposure (120 kPa) on rat brains. Immediately following exposure to blast, neurological function was reduced. BBB permeability was measured using IgG antibody and evaluating its immunoreactivity in the brain. At 3 and 24 hr postexposure, there was a transient significant increase in IgG staining in the cortex. At 3 days postexposure, IgG immunoreactivity returned to control levels. Quantitative immunostaining was employed to determine the temporal course of brain oxidative stress following exposure to blast. Levels of 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT) were significantly increased at 3 hr postexposure and returned to control levels at 24 hr postexposure. The response of microglia to blast exposure was determined by autoradiographic localization of (3) H-PK11195 binding. At 5 days postexposure, increased binding was observed in the contralateral and ipsilateral dentate gyrus. These regions also displayed increased binding at 10 days postexposure; in addition to these regions there was increased binding in the contralateral ventral hippocampus and substantia nigra at this time point. By using antibodies against CD11b/c, microglia morphology characteristic of activated microglia was observed in the hippocampus and substantia nigra of animals exposed to blast. These results indicate that BBB breakdown, oxidative stress, and microglia activation likely play a role in the neuropathology associated with TBI as a result of blast exposure. Copyright © 2010 Wiley-Liss, Inc.

  11. Interrelations between blood-brain barrier permeability and matrix metalloproteinases are differently affected by tissue plasminogen activator and hyperoxia in a rat model of embolic stroke

    Directory of Open Access Journals (Sweden)

    Michalski Dominik

    2012-01-01

    Full Text Available Abstract Background In ischemic stroke, blood-brain barrier (BBB regulations, typically involving matrix metalloproteinases (MMPs and inhibitors (TIMPs as mediators, became interesting since tissue plasminogen activator (tPA-related BBB breakdown with risk of secondary hemorrhage was considered to involve these mediators too. Despite high clinical relevance, detailed interactions are purely understood. After a pilot study addressing hyperoxia as potential neuroprotective co-treatment to tPA, we analyzed interrelations between BBB permeability (BBB-P, MMPs and TIMPs. Findings Rats underwent embolic middle cerebral artery occlusion (eMCAO and treatment with normobaric (NBO or hyperbaric oxygen (HBO, tPA, tPA+HBO, or no treatment. BBB-P was assessed by intravenously applied FITC-albumin at 4 or 24 hours. MMP-2/-9 and TIMP-1/-2 serum levels were determined at 5 or 25 hours. Time point-corrected partial correlations were used to explore interrelations of BBB-P in ischemic regions (extra-/intravasal FITC-albumin ratio and related serum markers. BBB-P correlated positively with MMP-2 and MMP-9 in controls, whereas hyperoxia led to an inverse association, most pronounced for HBO/MMP-9 (r = -0.606; P Conclusions HBO was found to reverse the positively directed interrelation of BBB-P and MMPs after eMCAO, but this effect failed to sustain in the expected amount when HBO and tPA were given simultaneously.

  12. Ablation of CD11c(hi) dendritic cells exacerbates Japanese encephalitis by regulating blood-brain barrier permeability and altering tight junction/adhesion molecules.

    Science.gov (United States)

    Kim, Jin Hyoung; Hossain, Ferdaus Mohd Altaf; Patil, Ajit Mahadev; Choi, Jin Young; Kim, Seong Bum; Uyangaa, Erdenebelig; Park, Sang-Youel; Lee, John-Hwa; Kim, Bumseok; Kim, Koanhoi; Eo, Seong Kug

    2016-10-01

    Japanese encephalitis (JE), characterized by extensive neuroinflammation following infection with neurotropic JE virus (JEV), is becoming a leading cause of viral encephalitis due to rapid changes in climate and demography. The blood-brain barrier (BBB) plays an important role in restricting neuroinvasion of peripheral leukocytes and virus, thereby regulating the progression of viral encephalitis. In this study, we explored the role of CD11c(hi) dendritic cells (DCs) in regulating BBB integrity and JE progression using a conditional depletion model of CD11c(hi) DCs. Transient ablation of CD11c(hi) DCs resulted in markedly increased susceptibility to JE progression along with highly increased neuro-invasion of JEV. In addition, exacerbated JE progression in CD11c(hi) DC-ablated hosts was closely associated with increased expression of proinflammatory cytokines (IFN-β, IL-6, and TNF-α) and CC chemokines (CCL2, CCL3, CXCL2) in the brain. Moreover, our results revealed that the exacerbation of JE progression in CD11c(hi) DC-ablated hosts was correlated with enhanced BBB permeability and reduced expression of tight junction and adhesion molecules (claudin-5, ZO-1, occluding, JAMs). Ultimately, our data conclude that the ablation of CD11c(hi) DCs provided a subsidiary impact on BBB integrity and the expression of tight junction/adhesion molecules, thereby leading to exacerbated JE progression. These findings provide insight into the secondary role of CD11c(hi) DCs in JE progression through regulation of BBB integrity and the expression of tight junction/adhesion molecules. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Clamshell excavation of a permeable reactive barrier

    Science.gov (United States)

    Molfetta, Antonio Di; Sethi, Rajandrea

    2006-06-01

    Nowadays, permeable reactive barriers (PRB) are one of the most widespread techniques for the remediation of contaminated aquifers. Over the past 10 years, the use of iron-based PRBs has evolved from innovative to accepted standard practice for the treatment of a variety of groundwater contaminants (ITRC in: Permeable reactive barriers: lessons learned/new directions. The Interstate Technology and Regulatory Council, Permeable Reactive Barriers Team 2005). Although, a variety of excavation methods have been developed, backhoe excavators are often used for the construction of PRBs. The aim of this study is to describe the emplacement of a full-scale PRB and the benefits deriving from the use of a crawler crane equipped with a hydraulic grab (also known as clamshell excavator) in the excavation phases. The studied PRB was designed to remediate a chlorinated hydrocarbons plume at an old industrial landfill site, in Avigliana, near the city of Torino, in Italy. The continuous reactive barrier was designed to be 120 m long, 13 m deep, and 0.6 m thick. The installation of the barrier was accomplished using a clamshell for the excavation of the trench and a guar-gum slurry to support the walls. The performance of this technique was outstanding and allowed the installation of the PRB in 7 days. The degree of precision of the excavation was very high because of the intrinsic characteristics of this excavation tool and of the use of a concrete curb to guide the hydraulic grab. Moreover, the adopted technique permitted a saving of bioslurry thus minimizing the amount of biocide required.

  14. In vitro porcine blood-brain barrier model for permeability studies: pCEL-X software pKa(FLUX) method for aqueous boundary layer correction and detailed data analysis.

    Science.gov (United States)

    Yusof, Siti R; Avdeef, Alex; Abbott, N Joan

    2014-12-18

    In vitro blood-brain barrier (BBB) models from primary brain endothelial cells can closely resemble the in vivo BBB, offering valuable models to assay BBB functions and to screen potential central nervous system drugs. We have recently developed an in vitro BBB model using primary porcine brain endothelial cells. The model shows expression of tight junction proteins and high transendothelial electrical resistance, evidence for a restrictive paracellular pathway. Validation studies using small drug-like compounds demonstrated functional uptake and efflux transporters, showing the suitability of the model to assay drug permeability. However, one limitation of in vitro model permeability measurement is the presence of the aqueous boundary layer (ABL) resulting from inefficient stirring during the permeability assay. The ABL can be a rate-limiting step in permeation, particularly for lipophilic compounds, causing underestimation of the permeability. If the ABL effect is ignored, the permeability measured in vitro will not reflect the permeability in vivo. To address the issue, we explored the combination of in vitro permeability measurement using our porcine model with the pKa(FLUX) method in pCEL-X software to correct for the ABL effect and allow a detailed analysis of in vitro (transendothelial) permeability data, Papp. Published Papp using porcine models generated by our group and other groups are also analyzed. From the Papp, intrinsic transcellular permeability (P0) is derived by simultaneous refinement using a weighted nonlinear regression, taking into account permeability through the ABL, paracellular permeability and filter restrictions on permeation. The in vitro P0 derived for 22 compounds (35 measurements) showed good correlation with P0 derived from in situ brain perfusion data (r(2)=0.61). The analysis also gave evidence for carrier-mediated uptake of naloxone, propranolol and vinblastine. The combination of the in vitro porcine model and the software

  15. Therapeutic benefits of enhancing permeability barrier for atopic eczema

    Directory of Open Access Journals (Sweden)

    George Man

    2015-06-01

    Full Text Available The regulatory role of epidermal permeability barrier function in cutaneous inflammation has been well appreciated. While barrier disruption induces cutaneous inflammation, improvement of permeability barrier function alleviates inflammation. Studies have demonstrated that improvement of epidermal permeability barrier function not only prevents the development of atopic eczema, but also delays the relapse of these diseases. Moreover, enhancing the epidermal permeability barrier also alleviates atopic eczema. Furthermore, co-applications of barrier enhancing products with glucocorticoids can increase the therapeutic efficacy and reduce the adverse effects of glucocorticoids in the treatment of atopic eczema. Therefore, utilization of permeability barrier enhancing products alone or in combination with glucocorticoids could be a valuable approach in the treatment of atopic eczema. In this review, we discuss the benefits of improving the epidermal permeability barrier in the management of atopic eczema.

  16. Herbal medicines that benefit epidermal permeability barrier function

    Directory of Open Access Journals (Sweden)

    Lizhi Hu

    2015-06-01

    Full Text Available Epidermal permeability barrier function plays a critical role in regulating cutaneous functions. Hence, researchers have been searching for effective and affordable regimens to enhance epidermal permeability barrier function. In addition to topical stratum corneum lipids, peroxisome proliferator-activated receptor, and liver X receptor ligands, herbal medicines have been proven to benefit epidermal permeability barrier function in both normal and diseased skin, including atopic dermatitis, glucocorticoid-induced skin damage, and UVB-damaged skin. The potential mechanisms by which herbal medicines improve the permeability barrier include stimulation of epidermal differentiation, lipid production, antimicrobial peptide expression, and antioxidation. Therefore, utilization of herbal medicines could be a valuable alternative approach to enhance epidermal permeability barrier function in order to prevent and/or treat skin disorders associated with permeability barrier abnormalities.

  17. Enhancement of blood-brain barrier permeability is required for intravenously administered virus neutralizing antibodies to clear an established rabies virus infection from the brain and prevent the development of rabies in mice.

    Science.gov (United States)

    Huang, Chien-Tsun; Li, Zhenguang; Huang, Ying; Zhang, Guoqing; Zhou, Ming; Chai, Qingqing; Wu, Hua; Fu, Zhen F

    2014-10-01

    Rabies virus (RABV) is a neurotropic virus that causes fatal disease in humans and animals. Currently there is no cure for rabies once clinical signs appear. It is believed that once RABV enters the central nervous system (CNS), virus neutralizing antibodies (VNAs) in the periphery cannot pass through the blood-brain barrier (BBB) and into the CNS. Furthermore, it has been hypothesized that VNAs produced in the CNS by invading B cells, rather than those produced in the periphery and then transported into the CNS, are important in clearing RABV from the CNS. In the present study, mouse serum containing VNA was administered intravenously into mice after infection with wild-type RABV. Our studies demonstrate that exogenous administration of VNAs is crucial in the clearance of RABV from the brain and prevent the development of rabies in both immunocompetent and immunocompromised mice as long as the BBB permeability remains enhanced. This present study therefore provides a foundation for the possibility of developing VNA therapy for clinical rabies in humans. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. West Nile virus-induced cell adhesion molecules on human brain microvascular endothelial cells regulate leukocyte adhesion and modulate permeability of the in vitro blood-brain barrier model.

    Directory of Open Access Journals (Sweden)

    Kelsey Roe

    Full Text Available Characterizing the mechanisms by which West Nile virus (WNV causes blood-brain barrier (BBB disruption, leukocyte infiltration into the brain and neuroinflammation is important to understand the pathogenesis of WNV encephalitis. Here, we examined the role of endothelial cell adhesion molecules (CAMs in mediating the adhesion and transendothelial migration of leukocytes across human brain microvascular endothelial cells (HBMVE. Infection with WNV (NY99 strain significantly induced ICAM-1, VCAM-1, and E-selectin in human endothelial cells and infected mice brain, although the levels of their ligands on leukocytes (VLA-4, LFA-1and MAC-1 did not alter. The permeability of the in vitro BBB model increased dramatically following the transmigration of monocytes and lymphocytes across the models infected with WNV, which was reversed in the presence of a cocktail of blocking antibodies against ICAM-1, VCAM-1, and E-selectin. Further, WNV infection of HBMVE significantly increased leukocyte adhesion to the HBMVE monolayer and transmigration across the infected BBB model. The blockade of these CAMs reduced the adhesion and transmigration of leukocytes across the infected BBB model. Further, comparison of infection with highly neuroinvasive NY99 and non-lethal (Eg101 strain of WNV demonstrated similar level of virus replication and fold-increase of CAMs in HBMVE cells suggesting that the non-neuropathogenic response of Eg101 is not because of its inability to infect HBMVE cells. Collectively, these results suggest that increased expression of specific CAMs is a pathological event associated with WNV infection and may contribute to leukocyte infiltration and BBB disruption in vivo. Our data further implicate that strategies to block CAMs to reduce BBB disruption may limit neuroinflammation and virus-CNS entry via 'Trojan horse' route, and improve WNV disease outcome.

  19. West Nile virus-induced cell adhesion molecules on human brain microvascular endothelial cells regulate leukocyte adhesion and modulate permeability of the in vitro blood-brain barrier model.

    Science.gov (United States)

    Roe, Kelsey; Orillo, Beverly; Verma, Saguna

    2014-01-01

    Characterizing the mechanisms by which West Nile virus (WNV) causes blood-brain barrier (BBB) disruption, leukocyte infiltration into the brain and neuroinflammation is important to understand the pathogenesis of WNV encephalitis. Here, we examined the role of endothelial cell adhesion molecules (CAMs) in mediating the adhesion and transendothelial migration of leukocytes across human brain microvascular endothelial cells (HBMVE). Infection with WNV (NY99 strain) significantly induced ICAM-1, VCAM-1, and E-selectin in human endothelial cells and infected mice brain, although the levels of their ligands on leukocytes (VLA-4, LFA-1and MAC-1) did not alter. The permeability of the in vitro BBB model increased dramatically following the transmigration of monocytes and lymphocytes across the models infected with WNV, which was reversed in the presence of a cocktail of blocking antibodies against ICAM-1, VCAM-1, and E-selectin. Further, WNV infection of HBMVE significantly increased leukocyte adhesion to the HBMVE monolayer and transmigration across the infected BBB model. The blockade of these CAMs reduced the adhesion and transmigration of leukocytes across the infected BBB model. Further, comparison of infection with highly neuroinvasive NY99 and non-lethal (Eg101) strain of WNV demonstrated similar level of virus replication and fold-increase of CAMs in HBMVE cells suggesting that the non-neuropathogenic response of Eg101 is not because of its inability to infect HBMVE cells. Collectively, these results suggest that increased expression of specific CAMs is a pathological event associated with WNV infection and may contribute to leukocyte infiltration and BBB disruption in vivo. Our data further implicate that strategies to block CAMs to reduce BBB disruption may limit neuroinflammation and virus-CNS entry via 'Trojan horse' route, and improve WNV disease outcome.

  20. The diffusion-active permeable reactive barrier.

    Science.gov (United States)

    Schwarz, Alex O; Rittmann, Bruce E

    2010-03-01

    Using the biogeochemical model CCBATCH, which we expanded to include transport processes, we study a novel approach for the treatment of aquifers contaminated with toxic concentrations of metals, the diffusion-active permeable reactive barrier (DAPRB), which is based on generation of sulfide by Sulfate Reducing Bacteria (SRB) as the groundwater moves through a layered treatment zone. In the DAPRB, layers of low conductivity (low-K) containing reactive materials are intercalated between layers of high conductivity (high-K) that transport the groundwater across the barrier. Because diffusion dominates transport in the reactive layers, microbial communities can take advantage there of the chemical-gradient mechanism for protection from toxicants. The ideal sulfidic DAPRB design includes particulate organic matter (POM) and solid sulfate mineral inside the reactive (low-K) layer. This leads to sulfate reduction and the formation of sulfide ligands that complex with toxic metals, such as Zn(2+) in the high-K layer. We perform a theoretical biogeochemical analysis of the ideal configuration of a DAPRB for treatment of Zn-contaminated groundwater. Our analysis using the expanded CCBATCH confirms the gradient-resistance mechanism for bio-protection, with the ZnS bio-sink forming at the intersection of the Zn and sulfide plumes inside the high-K layers of the DAPRB. The detailed DAPRB analysis also shows that total alkalinity and pH distributions are representative footprints of the two key biogeochemical processes taking place, sulfidogenesis and Zn immobilization as sulfide mineral. This is so because these two reactions consume or produce acidic hydrogen and alkalinity. Additionally, because Zn immobilization is due to ZnS mineral precipitation, the ZnS mineral distribution is a good indicator for the bio-sink. Bio-sinks are located for the most part within the high-K layers, and their exact position depends on the relative magnitude of metal and sulfide fluxes. Finally

  1. Dabigatran abrogates brain endothelial cell permeability in response to thrombin.

    Science.gov (United States)

    Hawkins, Brian Thomas; Gu, Yu-Huan; Izawa, Yoshikane; del Zoppo, Gregory John

    2015-06-01

    Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge.

  2. Mechanisms of microbial traversal of the blood-brain barrier.

    Science.gov (United States)

    Kim, Kwang Sik

    2008-08-01

    Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality. Microbial invasion and traversal of the blood-brain barrier is a prerequisite for CNS infections. Pathogens can cross the blood-brain barrier transcellularly, paracellularly and/or in infected phagocytes (the so-called Trojan-horse mechanism). Consequently, pathogens can cause blood-brain barrier dysfunction, including increased permeability, pleocytosis and encephalopathy. A more complete understanding of the microbial-host interactions that are involved in microbial traversal of the blood-brain barrier and the associated barrier dysfunction should help to develop new strategies to prevent CNS infections.

  3. The blood-retinal barrier permeability in diabetic patients

    DEFF Research Database (Denmark)

    Krogsaa, B; Lund-Andersen, H; Mehlsen, J

    1981-01-01

    By the of aid an extended corpus vitreum fluorophotometric technique, the blood-retinal barrier permeability for fluorescein was studied in diabetologically well characterized patients with insulin dependent diabetes mellitus. The method, which involves simultaneous determination of the fluoresce...

  4. Topical tranexamic acid improves the permeability barrier in rosacea

    Directory of Open Access Journals (Sweden)

    Shaomin Zhong

    2015-06-01

    Conclusion: Topical tranexamic acid could improve the epidermal permeability barrier function and clinical signs of rosacea, likely resulting from inhibition of PAR-2 activation and consequent calcium influx. Thus, tranexamic acid could serve as an adjuvant therapy for rosacea.

  5. Altered permeability barrier structure in cholesteatoma matrix

    DEFF Research Database (Denmark)

    Svane-Knudsen, Viggo; Halkier-Sørensen, Lars; Rasmussen, Gurli

    2002-01-01

    lipid structures filling the intercellular spaces mainly control the barrier function. The barrier in cholesteatoma epithelium is several times thicker than in unaffected skin but presents distinctive features of a defective barrier as seen in other scaling skin diseases. The intercellular spaces appear...... frequently occur. The corneocytes are shed in clusters, not as single cells. Further, lipid droplets and intracellular membranous material are occasionally seen. In spite of these clear signs of barrier dysfunction, it is unknown whether the thickness of the barrier compensates for the defect in barrier...

  6. Test device for measuring permeability of a barrier material

    Science.gov (United States)

    Reese, Matthew; Dameron, Arrelaine; Kempe, Michael

    2014-03-04

    A test device for measuring permeability of a barrier material. An exemplary device comprises a test card having a thin-film conductor-pattern formed thereon and an edge seal which seals the test card to the barrier material. Another exemplary embodiment is an electrical calcium test device comprising: a test card an impermeable spacer, an edge seal which seals the test card to the spacer and an edge seal which seals the spacer to the barrier material.

  7. Permeable bio-reactive barriers for hydrocarbon remediation in Antarctica

    Energy Technology Data Exchange (ETDEWEB)

    Mumford, K.A.; Stevens, G.W.; Gore, D.B. [Melbourne Univ., Victoria (Australia). Dept. of Chemical and Biomoleculuar Engineering, Particulate Fluids Processing Centre; Snape, I.; Rayner, J.L. [Australian Antarctic Div., Kingston, Tasmania (Australia); Gore, D.B. [Macquarie Univ., Sydney, NSW (Australia). Dept. of Environmental Science

    2010-07-01

    This study assessed the performance of a permeable bio-reactive barrier designed to treat contaminated water. The bio-reactive barrier was installed at a fuel spill site located in the Windmill Islands, Antarctica. A funnel and gate design was used to prevent contaminant migration beyond the barrier location as well as to ensure controlled nutrient delivery. The study also investigated the performance of the bio-reactive barrier in regions with freeze-thaw conditions. The 4-year project was also conducted to assess optimal conditions for enhancing the barrier's ability to degrade hydrocarbons.

  8. Blood-brain barrier (BBB) toxicity and permeability assessment after L-(4-¹⁰Boronophenyl)alanine, a conventional B-containing drug for boron neutron capture therapy, using an in vitro BBB model.

    Science.gov (United States)

    Roda, E; Nion, S; Bernocchi, G; Coccini, T

    2014-10-02

    Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood-brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e., L-(4-(10)Boronophenyl)alanine, L-(10)BPA), already used in medicine but still not fully characterized regarding its CNS interactions, as well as (ii) the effects of the L-(10)BPA on the BBB integrity using an in vitro model, consisting of brain capillary endothelial cells co-cultured with glial cells, closely mimicking the in vivo conditions. The multi-step experimental strategy (i.e. Integrity test, Filter study, Transport assay) checked L-(10)BPA toxicity at 80 µg Boron equivalent/ml, and its ability to cross the BBB, additionally by characterizing the cytoskeletal and TJ's proteins by immunocytochemistry and immunoblotting. In conclusion, a lack of toxic effects of L-(10)BPA was demonstrated, nevertheless accompanied by cellular stress phenomena (e.g. vimentin expression modification), paralleled by a low permeability coefficient (0.39 ± 0.01 × 10(-3)cm min(-1)), corroborating the scarce probability that L-(10)BPA would reach therapeutically effective cerebral concentration. These findings emphasized the need for novel strategies aimed at optimizing boron delivery to brain tumours, trying to ameliorate the compound uptake or developing new targeted products suitable to safely and effectively treat head cancer. Thus, the use of in vitro BBB model for screening studies may provide a useful early safety assessment for new effective compounds. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. One-week exposure to a free-choice high-fat high-sugar diet does not disrupt blood-brain barrier permeability in fed or overnight fasted rats

    NARCIS (Netherlands)

    Rijnsburger, M.; Unmehopa, U A; Eggels, L.; Serlie, Mireille J; la Fleur, S E

    2018-01-01

    OBJECTIVES: The hypothalamus lies adjacent to the third ventricle and is in close proximity with the median eminence (ME), a circumventricular organ with an incomplete blood-brain barrier (BBB) which controls direct entry of nutrients into the brain. The blood-CSF barrier of the hypothalamus shows

  10. One-week exposure to a free-choice high-fat high-sugar diet does not disrupt blood-brain barrier permeability in fed or overnight fasted rats

    NARCIS (Netherlands)

    Rijnsburger, M.; Unmehopa, U. A.; Eggels, L.; Serlie, M. J.; La Fleur, S. E.

    2017-01-01

    The hypothalamus lies adjacent to the third ventricle and is in close proximity with the median eminence (ME), a circumventricular organ with an incomplete blood-brain barrier (BBB) which controls direct entry of nutrients into the brain. The blood-CSF barrier of the hypothalamus shows dynamic

  11. Melt Focusing Along Permeability Barriers in Various Tectonic Settings

    Science.gov (United States)

    Montesi, L. G.; Hebert, L. B.

    2012-12-01

    The lithosphere, cold and rigid, acts as a barrier to the migration of melt from sources in the convecting mantle to the surface. In mid-ocean ridge settings in particular, the contrast between the width of the melt production zone at depths, reaching tens to hundreds of kilometer from the ridge axis, and the zone of crustal accretion, only one or two kilometers wide, points to the presence of an efficient focusing mechanism. The development of a zone impermeable to melt, or permeability barrier, at the base of the thermal boundary layer, and transport of melt in a high porosity channel at the base of this barrier provides a reasonable explanation for this focusing. Applied to various segmented and non-segmented mid-ocean ridges like the ultraslow Southwest Indian Ridge and the ultrafast East Pacific Rise at the Siqueiros transform, this process predicts along-strike variations in crustal thickness that compare favorably with observations. Although the concept of permeability barriers has been discussed mainly in the context of mid-ocean ridges, it may apply to other locations where melting in the upper mantle occurs. Permeability barriers form when ascending melt cools and crystallizes as it enters the thermal boundary layer at the base of the lithosphere. Such a setup is present at subduction zones as melts ascending from the mantle wedge interact with the overriding plate. Convection in the wedge introduces thermal gradients that may focus melt roughly to a point above the transition from a coupled to decoupled slab interface. This location is close to where volcanic arcs are observed. Above mantle plumes, a permeability barrier may develop coincident with the lithosphere-asthenosphere boundary, allowing low-degree melts to stall and form a low-velocity layer that has been observed seismically. To date, the hypothesis of a permeability barrier has been thoroughly tested only in the context of mid-ocean ridges. Whether crystallization would be rapid enough in

  12. Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.

    Science.gov (United States)

    Phoenix, Timothy N; Patmore, Deanna M; Boop, Scott; Boulos, Nidal; Jacus, Megan O; Patel, Yogesh T; Roussel, Martine F; Finkelstein, David; Goumnerova, Liliana; Perreault, Sebastien; Wadhwa, Elizabeth; Cho, Yoon-Jae; Stewart, Clinton F; Gilbertson, Richard J

    2016-04-11

    The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Development in NMR spiral imaging and application to the assessment of the permeability of the blood-brain barrier on 2 models of brain tumors; Developpements en imagerie RMN spirale et application a la caracterisation de la permeabilite de la barriere hemato-encephalique sur deux modeles de tumeurs intracerebrales

    Energy Technology Data Exchange (ETDEWEB)

    Beaumont, M

    2007-12-15

    The results presented in this work were obtained as part of methodological developments in magnetic resonance imaging. First of all, the setting of the rapid imaging technique using a k-space sampling scheme along a variable density spiral is described. Numerical simulations were used to optimize the acquisitions parameters and to compare different reconstruction techniques. An original approach to calibrate the k-space trajectory was proposed. Then, spiral imaging was used to implement a method to measure the blood brain barrier permeability to Gd-DOTA. This protocol was combined to blood volume and vessel size index measurements using Sinerem. The results obtained highlighted differences between the microvascular parameters measured on C6 and RG2 tumor models. The presence of Sinerem induces a mean decrease of the transfer constant across the vascular wall (Ktrans), in the tumor, of 24 per cent. This study also showed extravasation of the Sinerem, during the first two hours after the product injection, only in the RG2 tumors. (author)

  14. Barrier Functionality of Porcine and Bovine Brain Capillary Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Ailar Nakhlband

    2011-09-01

    Full Text Available Introduction: To date, isolated cell based blood-brain barrier (BBB models have been widely used for brain drug delivery and targeting, due to their relatively proper bioelectrical and permeability properties. However, primary cultures of brain capillary endothelial cells (BCECs isolated from different species vary in terms of bioelectrical and permeability properties. Methods: To pursue this, in the current investigation, primary porcine and bovine BCECs (PBCECs and BBCECs, respectively were isolated and used as an in vitro BBB model. The bioelectrical and permeability properties were assessed in BCECs co-cultured with C6 cells with/without hydrocortisone (550 nM. The bioelectrical properties were further validated by means of the permeability coefficients of transcellular and paracellular markers. Results: The primary PBCECs displayed significantly higher trans-endothelial electrical resistance (~900 W.cm2 than BBCECs (~700 W.cm2 - both co-cultured with C6 cells in presence of hydrocortisone. Permeability coefficients of propranolol/diazepam and mannitol/sucrose in PBCECs were ~21 and ~2 (×10-6 cm.sec-1, where these values for BBCECs were ~25 and ~5 (×10-6 cm.sec-1. Conclusion: Upon our bioelectrical and permeability findings, both models display discriminative barrier functionality but porcine BCECs seem to provide a better platform than bovine BCECs for drug screening and brain targeting.

  15. Hormones and the blood-brain barrier.

    Science.gov (United States)

    Hampl, Richard; Bičíková, Marie; Sosvorová, Lucie

    2015-03-01

    Hormones 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.

  16. Tesmilifene modifies brain endothelial functions and opens the blood-brain/blood-glioma barrier.

    Science.gov (United States)

    Walter, Fruzsina R; Veszelka, Szilvia; Pásztói, Mária; Péterfi, Zoltán A; Tóth, András; Rákhely, Gábor; Cervenak, László; Ábrahám, Csongor S; Deli, Mária A

    2015-09-01

    Tesmilifene, a tamoxifen analog with antihistamine action, has chemopotentiating properties in experimental and clinical cancer studies. In our previous works, tesmilifene increased the permeability of the blood-brain barrier (BBB) in animal and culture models. Our aim was to investigate the effects of tesmilifene on brain microvessel permeability in the rat RG2 glioma model and to reveal its mode of action in brain endothelial cells. Tesmilifene significantly increased fluorescein extravasation in the glioma. Short-term treatment with tesmilifene reduced the resistance and increased the permeability for marker molecules in a rat triple co-culture BBB model. Tesmilifene also affected the barrier integrity in brain endothelial cells co-cultured with RG2 glioblastoma cells. Tesmilifene inhibited the activity of P-glycoprotein and multidrug resistance-associated protein-1 efflux pumps and down-regulated the mRNA expression of tight junction proteins, efflux pumps, solute carriers, and metabolic enzymes important for BBB functions. Among the possible signaling pathways that regulate BBB permeability, tesmilifene activated the early nuclear translocation of NFκB. The MAPK/ERK and PI3K/Akt kinase pathways were also involved. We demonstrate for the first time that tesmilifene increases permeability marker molecule extravasation in glioma and inhibits efflux pump activity in brain endothelial cells, which may have therapeutic relevance. Tesmilifene, a chemopotentiator in experimental and clinical cancer studies increases vascular permeability in RG2 glioma in rats and permeability for marker molecules in a culture model of the blood-brain barrier. Tesmilifene inhibits the activity of efflux pumps and down-regulates the mRNA expression of tight junction proteins, transporters, and metabolic enzymes important for the blood-brain barrier functions, which may have therapeutic relevance. © 2015 International Society for Neurochemistry.

  17. The Blood-Brain Barrier: An Engineering Perspective

    Directory of Open Access Journals (Sweden)

    Andrew eWong

    2013-08-01

    Full Text Available It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich’s first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and it remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore advances in our understanding of the structure and function of the blood-brain barrier are key to advances in treatment of a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.

  18. Immune responses at brain barriers and implications for brain development and neurological function in later life

    Directory of Open Access Journals (Sweden)

    Helen B. Stolp

    2013-08-01

    Full Text Available For a long time the brain has been considered an immune-privileged site due to a muted inflammatory response and the presence of protective brain barriers. It is now recognised that neuroinflammation may play an important role in almost all neurological disorders and that the brain barriers may be contributing through either normal immune signalling, or disruption of their basic physiological mechanisms. The distinction between normal function and dysfunction at the barriers is difficult to dissect, partly due to a lack of understanding of normal barrier function and partly because of physiological changes that occur as part of normal development and ageing. Brain barriers consist of a number of interacting structural and physiological elements including tight junctions between adjacent barrier cells and an array of influx and efflux transporters. Despite these protective mechanisms, the capacity for immune-surveillance of the brain is maintained, and there is evidence of inflammatory signalling at the brain barriers that may be an important part of the body’s response to damage or infection. This signalling system appears to change both with normal ageing, and during disease. Changes may affect diapedesis of immune cells and active molecular transfer, or cause rearrangement of the tight junctions and an increase in passive permeability across barrier interfaces. Here we review the many elements that contribute to brain barrier functions and how they respond to inflammation, particularly during development and aging. The implications of inflammation–induced barrier dysfunction for brain development and subsequent neurological function are also discussed.

  19. Breaking down the barriers: the gut microbiome, intestinal permeability and stress-related psychiatric disorders

    Science.gov (United States)

    Kelly, John R.; Kennedy, Paul J.; Cryan, John F.; Dinan, Timothy G.; Clarke, Gerard; Hyland, Niall P.

    2015-01-01

    The emerging links between our gut microbiome and the central nervous system (CNS) are regarded as a paradigm shift in neuroscience with possible implications for not only understanding the pathophysiology of stress-related psychiatric disorders, but also their treatment. Thus the gut microbiome and its influence on host barrier function is positioned to be a critical node within the brain-gut axis. Mounting preclinical evidence broadly suggests that the gut microbiota can modulate brain development, function and behavior by immune, endocrine and neural pathways of the brain-gut-microbiota axis. Detailed mechanistic insights explaining these specific interactions are currently underdeveloped. However, the concept that a “leaky gut” may facilitate communication between the microbiota and these key signaling pathways has gained traction. Deficits in intestinal permeability may underpin the chronic low-grade inflammation observed in disorders such as depression and the gut microbiome plays a critical role in regulating intestinal permeability. In this review we will discuss the possible role played by the gut microbiota in maintaining intestinal barrier function and the CNS consequences when it becomes disrupted. We will draw on both clinical and preclinical evidence to support this concept as well as the key features of the gut microbiota which are necessary for normal intestinal barrier function. PMID:26528128

  20. Long-Term Monitoring of Permeable Reactive Barriers - Progress Report

    Energy Technology Data Exchange (ETDEWEB)

    Liang, L.

    2001-04-12

    The purpose of this project is to conduct collaborative research to evaluate and maximize the effectiveness of permeable reactive barriers (PRBs) with a broad-based working group including representatives from the U.S. Department of Energy (DOE), U.S. Department of Defense (DoD), and the U.S. Environmental Protection Agency (EPA). The Naval Facilities Engineering Service Center (NFESC) and its project partner, Battelle, are leading the DoD effort with funding from DoD's Environmental Security Technology Certification Program (ESTCP) and Strategic Environmental Research and Development Program (SERDP). Oak Ridge National Laboratory (ORNL) is coordinating the DOE effort with support from Subsurface Contaminant Focus Area (SCFA), a research program under DOEs Office of Science and Technology. The National Risk Management Research Laboratory's Subsurface Protection and Remediation Division is leading EPA's effort. The combined effort of these three agencies allows the evaluation of a large number of sites. Documents generated by this joint project will be reviewed by the participating agencies' principal investigators, the Permeable Barriers Group of the Remediation Technologies Development Forum (RTDF), and the Interstate Technology and Regulatory Cooperation (ITRC). The technical objectives of this project are to collect and review existing field data at selected PRB sites, identify data gaps, conduct additional measurements, and provide recommendations to DOE users on suitable long-term monitoring strategies. The specific objectives are to (1) evaluate geochemical and hydraulic performance of PRBs, (2) develop guidelines for hydraulic and geochemical characterization/monitoring, and (3) devise and implement long-term monitoring strategies through the use of hydrological and geochemical models. Accomplishing these objectives will provide valuable information regarding the optimum configuration and lifetime of barriers at specific sites. It will

  1. Anatomy and physiology of the blood-brain barrier.

    Science.gov (United States)

    Serlin, Yonatan; Shelef, Ilan; Knyazer, Boris; Friedman, Alon

    2015-02-01

    Essential requisite for the preservation of normal brain activity is to maintain a narrow and stable homeostatic control in the neuronal environment of the CNS. Blood flow alterations and altered vessel permeability are considered key determinants in the pathophysiology of brain injuries. We will review the present-day literature on the anatomy, development and physiological mechanisms of the blood-brain barrier, a distinctive and tightly regulated interface between the CNS and the peripheral circulation, playing a crucial role in the maintenance of the strict environment required for normal brain function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Blood-brain barrier permeability of normal-appearing white matter in patients with vestibular schwannoma: A new hybrid approach for analysis of T1 -W DCE-MRI.

    Science.gov (United States)

    Li, Ka-Loh; Zhu, Xiaoping; Zhao, Sha; Jackson, Alan

    2017-07-01

    To develop and assess a "hybrid" method that combines a first-pass analytical approach and the Patlak plot (PP) to improve assessment of low blood-brain barrier permeability from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) data. Seven patients with vestibular schwannoma were enrolled. T1 -W DCE imaging was acquired on a 1.5T scanner. Normal-appearing white matter (NAWM) was divided into four regions of interest (ROIs) based on the magnitude of changes in longitudinal relaxation rate (ΔR1) after gadolinium administration. Kinetic analysis of ROI-averaged contrast agent concentration curves was performed using both the conventional PP and the hybrid method. Computer simulated uptake curves that resemble those from NAWM were analyzed with both methods. Percent deviations (PD) of the "measured" values from the "true" values were calculated to evaluate accuracy and precision of the two methods. The simulation showed that, at a noise level of 4% (a noise level similar to the in vivo data) and using a signal intensity (SI) averaging scheme, the new hybrid method achieved a PD of 0.9 ± 2.7% for vp , and a PD of -5.4 ± 5.9% for Ktrans . In comparison, the PP method obtained a PD of 3.6 ± 11.3% for vp , and -8.3 ± 12.8% for Ktrans . One-way analyses of variance (ANOVAs) showed significant variations from the four WM regions (P < 10-15 for ΔR1; P < 10-6 for Ktrans ; P < 10-4 for vp ). Both computer simulation and in vivo studies demonstrate improved reliability in vp and Ktrans estimates with the hybrid method. 3 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:79-93. © 2017 The Authors Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.

  3. Barrier mechanisms in the Drosophila blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Samantha Jane Hindle

    2014-12-01

    Full Text Available The invertebrate blood-brain barrier field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through GPCR signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate blood-brain barrier has recently been shown to require coordinated function of all layers of the compound barrier structure, analogous to signaling between the layers of the vertebrate neurovascular unit. These findings strengthen the notion that many blood-brain barrier mechanisms are conserved between vertebrates and invertebrates, and suggest that novel findings in invertebrate model organisms will have a significant impact on the understanding of vertebrate BBB functions. In this vein, important roles in coordinating localized and systemic signaling to dictate organism development and growth are beginning to show how the blood-brain barrier can govern whole animal physiologies. This includes novel functions of blood-brain barrier gap junctions in orchestrating synchronized neuroblast proliferation, and of blood-brain barrier secreted antagonists of insulin receptor signaling. These advancements and others are pushing the field forward in exciting new directions. In this review, we provide a synopsis of invertebrate blood-brain barrier anatomy and physiology, with a focus on insights from the past 5 years, and highlight important areas for future study.

  4. Permeability of skin and oral mucosa to water and horseradish peroxidase as related to the thickness of the permeability barrier

    Energy Technology Data Exchange (ETDEWEB)

    Squier, C.A.; Hall, B.K.

    1985-03-01

    The permeability of porcine skin and keratinized and nonkeratinized oral mucosa to tritium-labeled water and horseradish peroxidase (HRPO) was determined using perfusion chambers. Small blocks from each tissue were also incubated with HRPO and the extent of penetration visualized microscopically; this enabled measurements to be made of the thickness of the permeability barrier to this water-soluble tracer. Results obtained after inverting the oral mucosa in the chambers or adding metabolic inhibitors indicated that both compounds diffuse across the tissue. The permeability constants derived directly in the study showed that skin was less permeable than oral mucosa and that the floor of the mouth was significantly more permeable than all other regions. When these constants were normalized in terms of a standard permeability barrier thickness and the different tissues compared, the values obtained for skin were again less than those of the oral regions but, of these, the buccal mucosa was significantly higher. The difference in permeability between epidermis and keratinized oral epithelium may be due to differences in the volume density of membrane-coating granules known to exist between the tissues; differences between the oral mucosal regions may reflect differences in the nature of the intercellular barrier material.

  5. The blood-brain barrier and glutamate.

    Science.gov (United States)

    Hawkins, Richard A

    2009-09-01

    Glutamate concentrations in plasma are 50-100 micromol/L; in whole brain, they are 10,000-12,000 micromol/L but only 0.5-2 micromol/L in extracellular fluids (ECFs). The low ECF concentrations, which are essential for optimal brain function, are maintained by neurons, astrocytes, and the blood-brain barrier (BBB). Cerebral capillary endothelial cells form the BBB that surrounds the entire central nervous system. Tight junctions connect endothelial cells and separate the BBB into luminal and abluminal domains. Molecules entering or leaving the brain thus must pass 2 membranes, and each membrane has distinct properties. Facilitative carriers exist only in luminal membranes, and Na(+)-dependent glutamate cotransporters (excitatory amino acid transporters; EAATs) exist exclusively in abluminal membranes. The EAATs are secondary transporters that couple the Na(+) gradient between the ECF and the endothelial cell to move glutamate against the existing electrochemical gradient. Thus, the EAATs in the abluminal membrane shift glutamate from the ECF to the endothelial cell where glutamate is free to diffuse into blood on facilitative carriers. This organization does not allow net glutamate entry to the brain; rather, it promotes the removal of glutamate and the maintenance of low glutamate concentrations in the ECF. This explains studies that show that the BBB is impermeable to glutamate, even at high concentrations, except in a few small areas that have fenestrated capillaries (circumventricular organs). Recently, the question of whether the BBB becomes permeable in diabetes has arisen. This issue was tested in rats with diet-induced obesity and insulin resistance or with streptozotocin-induced diabetes. Neither condition produced any detectable effect on BBB glutamate transport.

  6. SURFACE-ALTERED ZEOLITES AS PERMEABLE BARRIERS FOR IN SITU TREATMENT OF CONTAMINATED GROUNDWATER

    Energy Technology Data Exchange (ETDEWEB)

    Robert S. Bowman; Zhaohui Li; Stephen J. Roy; Todd Burt; Timothy L. Johnson; Richard L. Johnson

    1999-08-30

    The overall objective of this effort is to develop and test a zeolite-based permeable barrier system for containing and remediating contaminated groundwater. The projected product is an engineered and tested permeable barrier system that can be adopted by the commercial sector.

  7. Pathological changes in the structures of the blood-brain barrier in acute cerebral circulatory disorders

    Directory of Open Access Journals (Sweden)

    S. І. Tertyshny

    2012-04-01

    Full Text Available Morphological changes of the blood-brain barrier were investigated in case of an acute brain disturbed circulation. Autocontrol of vessels with their dilatation and formation of aggregation from formal elements were shown from the onset of the disease. Distructive changes of the endothelium, basement membranes, pericytes, asrtocytosal processes are marked in the microvessels with formation of the perivascular edema. Increase permeability of the blood-brain barrier promotes hemorrhagic transformation and lymphomicrophagical infi ltration of the perivascular zones.

  8. Blood-retinal barrier permeability versus diabetes duration and retinal morphology in insulin dependent diabetic patients

    DEFF Research Database (Denmark)

    Krogsaa, B; Lund-Andersen, H; Mehlsen, J

    1987-01-01

    The blood-retinal barrier permeability to fluorescein was quantitated in 54 patients (22 females and 32 males) with insulin dependent diabetes mellitus (IDDM) of different duration. Correlation was demonstrated between permeability and diabetes duration. A normal permeability was measured...... in patients with up to ten years diabetes duration. A pathologically increased permeability was measured with ten to 15 years diabetes duration and during the next decade the permeability increased rapidly to 5-10 times the normal value. Onset of diabetes in the decade before and after puberty did not change...... the pattern. However, the pathologically increased permeability after ten years duration of the disease could not be demonstrated in diabetics with onset of the disease after the age of 30 years. The permeability of the blood-retinal barrier correlated well with changes in retinal morphology as seen...

  9. Permeability of Brain Tumor Vessels Induced by Uniform or Spatially Microfractionated Synchrotron Radiation Therapies.

    Science.gov (United States)

    Bouchet, Audrey; Potez, Marine; Coquery, Nicolas; Rome, Claire; Lemasson, Benjamin; Bräuer-Krisch, Elke; Rémy, Chantal; Laissue, Jean; Barbier, Emmanuel L; Djonov, Valentin; Serduc, Raphael

    2017-08-01

    To compare the blood-brain barrier permeability changes induced by synchrotron microbeam radiation therapy (MRT, which relies on spatial fractionation of the incident x-ray beam into parallel micron-wide beams) with changes induced by a spatially uniform synchrotron x-ray radiation therapy. Male rats bearing malignant intracranial F98 gliomas were randomized into 3 groups: untreated, exposed to MRT (peak and valley dose: 241 and 10.5 Gy, respectively), or exposed to broad beam irradiation (BB) delivered at comparable doses (ie, equivalent to MRT valley dose); both applied by 2 arrays, intersecting orthogonally the tumor region. Vessel permeability was monitored in vivo by magnetic resonance imaging 1 day before (T-1) and 1, 2, 7, and 14 days after treatment start. To determine whether physiologic parameters influence vascular permeability, we evaluated vessel integrity in the tumor area with different values for cerebral blood flow, blood volume, edema, and tissue oxygenation. Microbeam radiation therapy does not modify the vascular permeability of normal brain tissue. Microbeam radiation therapy-induced increase of tumor vascular permeability was detectable from T2 with a maximum at T7 after exposure, whereas BB enhanced vessel permeability only at T7. At this stage MRT was more efficient at increasing tumor vessel permeability (BB vs untreated: +19.1%; P=.0467; MRT vs untreated: +44.8%; Ptumor than BB. Microbeam radiation therapy-induced increased tumor vascular permeability is: (1) significantly greater; (2) earlier and more prolonged than that induced by BB irradiation, especially in highly proliferative tumor areas; and (3) targets all tumor areas discriminated by physiologic characteristics, including those not damaged by homogeneous irradiation. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Magnetic Nanoparticles Cross the Blood-Brain Barrier: When Physics Rises to a Challenge

    Directory of Open Access Journals (Sweden)

    Maria Antònia Busquets

    2015-12-01

    Full Text Available The blood-brain barrier is a physical and physiological barrier that protects the brain from toxic substances within the bloodstream and helps maintain brain homeostasis. It also represents the main obstacle in the treatment of many diseases of the central nervous system. Among the different approaches employed to overcome this barrier, the use of nanoparticles as a tool to enhance delivery of therapeutic molecules to the brain is particularly promising. There is special interest in the use of magnetic nanoparticles, as their physical characteristics endow them with additional potentially useful properties. Following systemic administration, a magnetic field applied externally can mediate the capacity of magnetic nanoparticles to permeate the blood-brain barrier. Meanwhile, thermal energy released by magnetic nanoparticles under the influence of radiofrequency radiation can modulate blood-brain barrier integrity, increasing its permeability. In this review, we present the strategies that use magnetic nanoparticles, specifically iron oxide nanoparticles, to enhance drug delivery to the brain.

  11. Characterization of a novel brain barrier ex vivo insect-based P-glycoprotein screening model

    DEFF Research Database (Denmark)

    Andersson, O.; Badisco, L.; Hansen, A. H.

    2014-01-01

    In earlier studies insects were proposed as suitable models for vertebrate blood–brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain....... As in vertebrates, the locust brain–barrier function is morphologically confined to one specific cell layer and by using a whole-brain ex vivo drug exposure technique our locust model may retain the major cues that maintain and modulate the physiological function of the brain barrier. We show that the locust model...

  12. Markers for blood-brain barrier integrity

    DEFF Research Database (Denmark)

    Saunders, Norman R; Dziegielewska, Katarzyna M; Møllgård, Kjeld

    2015-01-01

    known when first introduced, but seem to have been forgotten since. Understanding these limitations is important because Evans blue is still the most commonly used marker of brain barrier integrity and those using it seem oblivious to problems arising from its in vivo application. The introduction......In recent years there has been a resurgence of interest in brain barriers and various roles their intrinsic mechanisms may play in neurological disorders. Such studies require suitable models and markers to demonstrate integrity and functional changes at the interfaces between blood, brain......, and cerebrospinal fluid. Studies of brain barrier mechanisms and measurements of plasma volume using dyes have a long-standing history, dating back to the late nineteenth-century. Their use in blood-brain barrier studies continues in spite of their known serious limitations in in vivo applications. These were well...

  13. Usefulness of Permeability Map by Perfusion MRI of Brain Tumor the Grade Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Sung Jin [Dept. of Radiology, Dongsan Hospital, Keimyung University, Daegu (Korea, Republic of); Lee, Joo Young [GE Healthcare, Seoul (Korea, Republic of); Chang, Hyuk Won [Dept. of Radiology, Keimyung University College of Medicine, Daegu (Korea, Republic of)

    2009-09-15

    This study was conducted to assess how effective the permeability ratio and relative cerebral blood volume ratio are to tumor through perfusion MRI by measuring and reflecting the grade assessment and differential diagnosis and the permeability and relative cerebral blood volume of contrast media plunged from blood vessel into organ due to breakdown of blood-brain barrier in cerebral. Subject and Method : Subject of study was 29 patients whose diagnosis were confirmed by biopsy after surgery and 550 (11 slice x 50 image) perfusion MRI were used to make image of relative cerebral blood volume with the program furnished on instrument. The other method was to transmit to private computer and the image analysis was made additionally by making image of relative cerebral blood volume-reformulated singular value decomposition, rCBV-rSVD and permeability using IDL.6.2. In addition, Kruskal-wallis test tonggyein non numerical average by a comparative analysis of brain tumors Results : The rCBV ratio (Functool PF; GE Medical Systems and IDL 6.2 program by analysis) and permeability ratio of tumors were as follows; high grade glioma(n=4), (14.75, 19.25) 13.13. low grade astrocytoma(n=5) (14.80, 15.90) 11.60, glioblastoma(n=5) (10.90, 18.60), 22.00, metastasis(n=6) (11.00, 15.08). 22.33. meningioma(n=6) (18.58, 7.67), 5.58. oliogodendroglioma(n=3) (23.33, 16.33, 15.67. Conclusion : It was not easy to classify the grade with the relative cerebral blood volume ratio measured by using the relative cerebral blood image by type of tumors, however, permeability ratio measured by permeability image revealed that the higher the grade of tumor, the higher the measured permeability ratio, showing the assessment of tumor grade is more effective to differential diagnosis.

  14. Effect of cryoprotectants for maintaining drug permeability barriers in porcine buccal mucosa

    DEFF Research Database (Denmark)

    Marxen, Eva; Axelsen, Mary Carlos; Pedersen, Anne Marie Lynge

    2016-01-01

    if permeability barriers for small molecules (nicotine and diazepam) were maintained after freezing porcine buccal mucosa with cryoprotectants to -80°C. Combinations of dimethyl sulfoxide, bovine serum albumin, glycerol and sucrose were used as cryoprotectants. The permeability of nicotine and diazepam across...... tissue. Freezing with or without cryoprotectants did not significantly affect the flux of diazepam compared to fresh tissue. Only minor histological changes were seen in frozen/thawed porcine buccal mucosa compared to fresh tissue. In conclusion, permeability barriers for nicotine and diazepam were...

  15. Polyunsaturated fatty acids support epithelial barrier integrity and reduce IL-4 mediated permeability in vitro.

    Science.gov (United States)

    Willemsen, Linette E M; Koetsier, Marleen A; Balvers, Martin; Beermann, Christopher; Stahl, Bernd; van Tol, Eric A F

    2008-06-01

    The intestinal mucosa functions as a barrier against harmful dietary and microbial antigens. An intact gut barrier forms a prerequisite for protection against infection and allergy. Both allergic and inflammatory mediators (e.g. IL-4, IFN-gamma) are known to compromise the epithelial barrier integrity by enhancing permeability. Breast milk provides protection against infection and allergy and contains polyunsaturated fatty acids (PUFA). Although PUFA are commonly used in infant formulas their effect on intestinal barrier is still poorly understood. Therefore the effects of distinct PUFA (n-6: LA, GLA, DGLA, AA; n-3: ALA, EPA, DHA) and a fat blend with PUFA composition similar to that of the human breast milk fat fraction, on barrier integrity were investigated. Human intestinal epithelial cells (T84) were pre-incubated with individual PUFA or a lipase treated fat blend, with or without subsequent IL-4 exposure. Barrier integrity was evaluated by measuring transepithelial resistance and permeability. Membrane phospholipid composition was determined by capillary gas chromatography. DGLA, AA, EPA, DHA and to a lesser extend GLA enhanced basal TER and strongly reduced IL-4 mediated permeability, while LA and ALA were ineffective. Furthermore, the lipase treated fat blend effectively supported barrier function. PUFA were incorporated in the membrane phospholipid fraction of T84 cells. Long chain PUFA DGLA, AA, EPA and DHA were particularly effective in supporting barrier integrity by improving resistance and reducing IL-4 mediated permeability. Fat blends that release specific PUFA upon digestion in the gastrointestinal tract may support natural resistance.

  16. Nanotechnologies: a strategy to overcome blood-brain barrier.

    Science.gov (United States)

    De Rosa, Giuseppe; Salzano, Giuseppina; Caraglia, Michele; Abbruzzese, Alberto

    2012-01-01

    The possibility to treat central nervous system (CNS) disorders is strongly limited by the poor access of many therapeutic agent to the target tissues. This is mainly due to the presence of the blood-brain barrier (BBB), formed by a complex interplay of endothelial cells, astrocyte and pericytes, through which only selected molecules can passively diffuse to reach CNS. Drug pharmacokinetics and biodistribution can be changed by using nanotechnology, in order to improve drug accumulation into the action site and to limit the drug release in the healthy tissues. When the CNS diseases are characterised by BBB altered permeability, an enhanced drug delivery into the brain can be achieved by using nanocarriers. Moreover, modification of nanocarrier surface with specific endogenous or exogenous ligands can promote enhanced BBB crossing, also in case of unaltered endothelium. This review summarizes the most meaningful advances in the field of nanotechnology for brain delivery of therapeutics.

  17. Fragility of the permeability barrier of Escherichia coli

    NARCIS (Netherlands)

    Haest, C.W.M.; Gier, J. de; Es, G.A. van; Verkleij, A.J.; Deenen, L.L.M. van

    1972-01-01

    An unsaturated fatty acid requiring auxotroph of Escherichia coli was grown with addition of various unsaturated fatty acids. The permeability of the cells for erythritol appeared to be strongly dependent on the fatty acid incorporated in the membrane lipid. Below certain temperatures, depending on

  18. The biological significance of brain barrier mechanisms

    DEFF Research Database (Denmark)

    Saunders, Norman R; Habgood, Mark D; Møllgård, Kjeld

    2016-01-01

    Barrier mechanisms in the brain are important for its normal functioning and development. Stability of the brain's internal environment, particularly with respect to its ionic composition, is a prerequisite for the fundamental basis of its function, namely transmission of nerve impulses....... In addition, the appropriate and controlled supply of a wide range of nutrients such as glucose, amino acids, monocarboxylates, and vitamins is also essential for normal development and function. These are all cellular functions across the interfaces that separate the brain from the rest of the internal...... environment of the body. An essential morphological component of all but one of the barriers is the presence of specialized intercellular tight junctions between the cells comprising the interface: endothelial cells in the blood-brain barrier itself, cells of the arachnoid membrane, choroid plexus epithelial...

  19. Blood-Brain Barrier Effects of the Fusarium Mycotoxins Deoxynivalenol, 3 Acetyldeoxynivalenol, and Moniliformin and Their Transfer to the Brain.

    Directory of Open Access Journals (Sweden)

    Matthias Behrens

    Full Text Available Secondary metabolites produced by Fusarium fungi frequently contaminate food and feed and have adverse effects on human and animal health. Fusarium mycotoxins exhibit a wide structural and biosynthetic diversity leading to different toxicokinetics and toxicodynamics. Several studies investigated the toxicity of mycotoxins, focusing on very specific targets, like the brain. However, it still remains unclear how fast mycotoxins reach the brain and if they impair the integrity of the blood-brain barrier. This study investigated and compared the effects of the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and moniliformin on the blood-brain barrier. Furthermore, the transfer properties to the brain were analyzed, which are required for risk assessment, including potential neurotoxic effects.Primary porcine brain capillary endothelial cells were cultivated to study the effects of the examined mycotoxins on the blood-brain barrier in vitro. The barrier integrity was monitored by cellular impedance spectroscopy and 14C radiolabeled sucrose permeability measurements. The distribution of the applied toxins between blood and brain compartments of the cell monolayer was analyzed by high performance liquid chromatography-mass spectrometry to calculate transfer rates and permeability coefficients.Deoxynivalenol reduced the barrier integrity and caused cytotoxic effects at 10 μM concentrations. Slight alterations of the barrier integrity were also detected for 3-acetyldeoxynivalenol. The latter was transferred very quickly across the barrier and additionally cleaved to deoxynivalenol. The transfer of deoxynivalenol and moniliformin was slower, but clearly exceeded the permeability of the negative control. None of the compounds was enriched in one of the compartments, indicating that no efflux transport protein is involved in their transport.

  20. Permeability barrier properties of oral keratinocyte cultures: a model of intact human oral mucosa.

    Science.gov (United States)

    Selvaratnam, L; Cruchley, A T; Navsaria, H; Wertz, P W; Hagi-Pavli, E P; Leigh, I M; Squier, C A; Williams, D M

    2001-07-01

    The aim of this study was to establish whether an in vitro model of human oral mucosa had similar permeability characteristics to normal oral mucosa. Such a model would have considerable value as an alternative to the use of mucosal biopsies in studies of transmucosal drug delivery. Keratinocytes obtained from buccal mucosa, hard palate and abdominal skin were seeded onto inert collagen membranes (Cellagen Discs) or dead de-epidermised dermis (DDED) and grown either as submerged or air-liquid interface cultures. Subsequently the ultrastructural characteristics, permeability to water and barrier lipid content of the epithelial cultures were assessed and compared with samples of intact mucosa and skin. All the cultures stratified into multilayered epithelia and displayed features of differentiation including tonofilaments, desmosomes and membrane coating granules. The permeability characteristics and barrier lipid content of the oral mucosal cultures resembled those of intact mucosa. By contrast, epidermal keratinocytes failed to produce a permeability barrier comparable with that of skin and had low levels of barrier associated lipids. Cultures of human oral mucosal keratinocytes obtained from healthy adults develop similar permeability properties and barrier lipid composition to their site of origin. This model system may be useful for the evaluation of local and systemic oral mucosal drug delivery.

  1. Blood-brain barrier transport and protein binding of flumazenil and iomazenil in the rat: implications for neuroreceptor studies

    DEFF Research Database (Denmark)

    Videbaek, C; Ott, P; Paulson, O B

    1999-01-01

    of blood-brain barrier permeability for two benzodiazepine antagonists were performed in 44 rats by the double-indicator technique. Cerebral blood flow was measured by intracarotid Xe-injection. The apparent permeability-surface product (PSapp) was measured while CBF or bolus composition was changed...

  2. Effects of beta-hydroxybutyrate on brain vascular permeability in rats with traumatic brain injury.

    Science.gov (United States)

    Orhan, Nurcan; Ugur Yilmaz, Canan; Ekizoglu, Oguzhan; Ahishali, Bulent; Kucuk, Mutlu; Arican, Nadir; Elmas, Imdat; Gürses, Candan; Kaya, Mehmet

    2016-01-15

    This study investigates the effect of beta-hydroxybutyrate (BHB) on blood-brain barrier (BBB) integrity during traumatic brain injury (TBI) in rats. Evans blue (EB) and horseradish peroxidase (HRP) were used as determinants of BBB permeability. Glutathione (GSH) and malondialdehyde (MDA) levels were estimated in the right (injury side) cerebral cortex of animals. The gene expression levels for occludin, glucose transporter (Glut)-1, aquaporin4 (AQP4) and nuclear factor-kappaB (NF-κB) were performed, and Glut-1 and NF-κB activities were analyzed. BHB treatment decreased GSH and MDA levels in intact animals and in those exposed to TBI (P<0.05). Glut-1 protein levels decreased in sham, BHB and TBI plus BHB groups (P<0.05). NF-κB protein levels increased in animals treated with BHB and/or exposed to TBI (P<0.05). The expression levels of occludin and AQP4 did not significantly change among experimental groups. Glut-1 expression levels increased in BHB treated and untreated animals exposed to TBI (P<0.05). While NF-κB expression levels increased in animals in TBI (P<0.01), a decrease was noticed in these animals upon BHB treatment (P<0.01). In animals exposed to TBI, EB extravasation was observed in the ipsilateral cortex regardless of BHB treatment. Ultrastructurally, BHB attenuated but did not prevent the presence of HRP in brain capillary endothelial cells of animals with TBI; moreover, the drug also led to the observation of the tracer when used in intact rats (P<0.01). Altogether, these results showed that BHB not only failed to provide overall protective effects on BBB in TBI but also led to BBB disruption in healthy animals. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Sleep restriction impairs blood-brain barrier function.

    Science.gov (United States)

    He, Junyun; Hsuchou, Hung; He, Yi; Kastin, Abba J; Wang, Yuping; Pan, Weihong

    2014-10-29

    The blood-brain barrier (BBB) is a large regulatory and exchange interface between the brain and peripheral circulation. We propose that changes of the BBB contribute to many pathophysiological processes in the brain of subjects with chronic sleep restriction (CSR). To achieve CSR that mimics a common pattern of human sleep loss, we quantified a new procedure of sleep disruption in mice by a week of consecutive sleep recording. We then tested the hypothesis that CSR compromises microvascular function. CSR not only diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of the BBB, but it also decreased 2-deoxy-glucose uptake by the brain. The expression of several tight junction proteins also was decreased, whereas the level of cyclooxygenase-2 increased. This coincided with an increase of paracellular permeability of the BBB to the small tracers sodium fluorescein and biotin. CSR for 6 d was sufficient to impair BBB structure and function, although the increase of paracellular permeability returned to baseline after 24 h of recovery sleep. This merits attention not only in neuroscience research but also in public health policy and clinical practice. Copyright © 2014 the authors 0270-6474/14/3414697-10$15.00/0.

  4. Cardiotoxic drugs Herceptin and doxorubicin inhibit cardiac microvascular endothelial cell barrier formation resulting in increased drug permeability

    Directory of Open Access Journals (Sweden)

    Emma L. Wilkinson

    2016-10-01

    Full Text Available Cardiotoxicity induced by anti-cancer therapeutics is a severe, and potentially fatal, adverse reaction of the heart in response to certain drugs. Current in vitro approaches to assess cardiotoxicity have focused on analysing cardiomyocytes. More recently it has become apparent that non-cardiomyocyte cells of the heart can potentially contribute to cardiotoxicity. Herceptin and doxorubicin are known to induce cardiotoxicity in the clinic. The effect of these drugs on the endothelial tight junction barrier was tested by analysing tight junction formation and zona occludens-1 (ZO-1 levels, revealing that Herceptin and doxorubicin are able to induce barrier perturbment and decrease barrier function in human cardiac microvascular endothelial cells (HCMECs leading to increased permeability. Herceptin treatment had no effect on the tight junction barrier function in human dermal and human brain microvascular endothelial cells. HCMECs showed detectable levels of HER2 compared with the other endothelial cells suggesting that Herceptin binding to HER2 in these cells may interfere with tight junction formation. Our data suggests that doxorubicin and Herceptin can affect tight junction formation in the cardiac microvasculature leading to increased drug permeability and adverse effects on the cardiac myocytes.

  5. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

    Directory of Open Access Journals (Sweden)

    Gabriela Hurtado-Alvarado

    Full Text Available Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261 in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1, adherens junction protein (E-cadherin, A2A adenosine receptor, adenosine-synthesizing enzyme (CD73, and neuroinflammatory markers (Iba-1 and GFAP in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent

  6. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction.

    Science.gov (United States)

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier; Gómez-González, Beatriz

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  7. A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

    Science.gov (United States)

    Hurtado-Alvarado, Gabriela; Domínguez-Salazar, Emilio; Velázquez-Moctezuma, Javier

    2016-01-01

    Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and

  8. Low extracellular Ca2+ conditions induce an increase in brain endothelial permeability that involves intercellular Ca2+ waves.

    Science.gov (United States)

    De Bock, Marijke; Culot, Maxime; Wang, Nan; da Costa, Anaelle; Decrock, Elke; Bol, Mélissa; Bultynck, Geert; Cecchelli, Romeo; Leybaert, Luc

    2012-12-03

    The intracellular calcium concentration ([Ca(2+)](i)) is an important factor determining the permeability of endothelial barriers including the blood-brain barrier (BBB). However, nothing is known concerning the effect of spatially propagated intercellular Ca(2+) waves (ICWs). The propagation of ICWs relies in large part on channels formed by connexins that are present in endothelia. We hypothesized that ICWs may result in a strong disturbance of endothelial function, because the [Ca(2+)](i) changes are coordinated and involve multiple cells. Thus, we aimed to investigate the effect of ICWs on endothelial permeability. ICW activity was triggered in immortalized and primary brain endothelial cells by lowering the extracellular Ca(2+) concentration. Low extracellular Ca(2+) increased the endothelial permeability and this was significantly suppressed by buffering [Ca(2+)](i) with BAPTA-AM, indicating a central role of [Ca(2+)](i) changes. The endothelial permeability increase was furthermore inhibited by the connexin channel blocking peptide Gap27, which also blocked the ICWs, and by inhibiting protein kinase C (PKC), Ca(2+)/calmodulin-dependent kinase II (CaMKII) and actomyosin contraction. We compared these observations with the [Ca(2+)](i) changes and permeability alterations provoked by the inflammatory agent bradykinin (BK), which triggers oscillatory [Ca(2+)](i) changes without wave activity. BK-associated [Ca(2+)](i) changes and the endothelial permeability increase were significantly smaller than those associated with ICWs, and the permeability increase was not influenced by inhibition of PKC, CaMKII or actomyosin contraction. We conclude that ICWs significantly increase endothelial permeability and therefore, the connexins that underlie wave propagation form an interesting target to limit BBB alterations. This article is part of a Special Issue entitled Electrical Synapses. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Intact blood-brain barrier during spontaneous attacks of migraine without aura

    DEFF Research Database (Denmark)

    Amin, F M; Hougaard, A; Cramer, S P

    2017-01-01

    BACKGROUND AND PURPOSE: The integrity of the blood-brain barrier (BBB) has been questioned in migraine, but BBB permeability has never been investigated during spontaneous migraine attacks. In the present study, BBB permeability during spontaneous attacks of migraine without aura was investigated...... compared to an interictal state. METHODS: Seventy-four patients suffering from migraine without aura were recruited to participate in this cross-sectional dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) study. The patients were instructed to report at the hospital for DCE-MRI scan during...... that the BBB permeability during spontaneous migraine attacks without aura was unchanged....

  10. Mapping the Fluid Pathways and Permeability Barriers of a Large Gas Hydrate Reservoir

    Science.gov (United States)

    Campbell, A.; Zhang, Y. L.; Sun, L. F.; Saleh, R.; Pun, W.; Bellefleur, G.; Milkereit, B.

    2012-12-01

    An understanding of the relationship between the physical properties of gas hydrate saturated sedimentary basins aids in the detection, exploration and monitoring one of the world's upcoming energy resources. A large gas hydrate reservoir is located in the MacKenzie Delta of the Canadian Arctic and geophysical logs from the Mallik test site are available for the gas hydrate stability zone (GHSZ) between depths of approximately 850 m to 1100 m. The geophysical data sets from two neighboring boreholes at the Mallik test site are analyzed. Commonly used porosity logs, as well as nuclear magnetic resonance, compressional and Stoneley wave velocity dispersion logs are used to map zones of elevated and severely reduced porosity and permeability respectively. The lateral continuity of horizontal permeability barriers can be further understood with the aid of surface seismic modeling studies. In this integrated study, the behavior of compressional and Stoneley wave velocity dispersion and surface seismic modeling studies are used to identify the fluid pathways and permeability barriers of the gas hydrate reservoir. The results are compared with known nuclear magnetic resonance-derived permeability values. The aim of investigating this heterogeneous medium is to map the fluid pathways and the associated permeability barriers throughout the gas hydrate stability zone. This provides a framework for an understanding of the long-term dissociation of gas hydrates along vertical and horizontal pathways, and will improve the knowledge pertaining to the production of such a promising energy source.

  11. Pathogenesis of permeability barrier abnormalities in the ichthyoses: inherited disorders of lipid metabolism

    Science.gov (United States)

    Elias, Peter M.; Williams, Mary L.; Holleran, Walter M.; Jiang, Yan J.; Schmuth, Matthias

    2010-01-01

    Many of the ichthyoses are associated with inherited disorders of lipid metabolism. These disorders have provided unique models to dissect physiologic processes in normal epidermis and the pathophysiology of more common scaling conditions. In most of these disorders, a permeability barrier abnormality “drives” pathophysiology through stimulation of epidermal hyperplasia. Among primary abnormalities of nonpolar lipid metabolism, triglyceride accumulation in neutral lipid storage disease as a result of a lipase mutation provokes a barrier abnormality via lamellar/nonlamellar phase separation within the extracellular matrix of the stratum corneum (SC). Similar mechanisms account for the barrier abnormalities (and subsequent ichthyosis) in inherited disorders of polar lipid metabolism. For example, in recessive X-linked ichthyosis (RXLI), cholesterol sulfate (CSO4) accumulation also produces a permeability barrier defect through lamellar/nonlamellar phase separation. However, in RXLI, the desquamation abnormality is in part attributable to the plurifunctional roles of CSO4 as a regulator of both epidermal differentiation and corneodesmosome degradation. Phase separation also occurs in type II Gaucher disease (GD; from accumulation of glucosylceramides as a result of to β-glucocerebrosidase deficiency). Finally, failure to assemble both lipids and desquamatory enzymes into nascent epidermal lamellar bodies (LBs) accounts for both the permeability barrier and desquamation abnormalities in Harlequin ichthyosis (HI). The barrier abnormality provokes the clinical phenotype in these disorders not only by stimulating epidermal proliferation, but also by inducing inflammation. PMID:18245815

  12. Treatment of fue diesel with a permeable reactive barrier technology

    Directory of Open Access Journals (Sweden)

    SANTIAGO ALONSO CARDONA GALLO

    2007-01-01

    Full Text Available La investigación estudió el tratamiento de diesel combustibles de producción mexicana contenidos en agua con un sistema de barrera reactiva permeables a escala de laboratorio (siete columnas. Se uso un suelo agrícola como medio reactivo. Se aplico peroxido de hidrógeno al 50% industrial como fuente de oxigeno y nitrógeno en urea al 46% como nutriente. Se caracterizo el medio reactivo con los principales parámetros de interés (humedad, materia orgánica, pH, nitrógeno total, fósforo disponible, clasificación del suelo, conductividad eléctrica, sólidos suspendidos volátiles, densidad real y aparente, porosidad, textura, color, salinidad, conductividad hidráulica, capacidad de campo y densidad de bacterias. Se determinaron las cinéticas de degradación y la capacidad de adsorción del diesel en el medio reactivo. Las barreras reactivas permeables se diseñaron con los resultados cinéticos obtenidos en los reactores por lotes. Las columnas tenían dimensiones de 30 cm de longitud y 10 cm de diámetro. Las cinéticas de determinaron durante 18 días y las columnas se corrieron durante 70 días presentando remociones arriba del 80%. Se usaron concentraciones iniciales de diesel de 15,000 mg/L. Para la modelación de la adsorción se aplicaron las ecuaciones de Freundlich y Langmuir, donde esta ultima presentó un mejor ajuste a los datos a los datos experimentales y una mayor capacidad de adsorción. Para el suministro de los nutrientes y oxigeno se aplico el modelo propuesto por McCarty y la ecuación media para diesel propuesta por Jackson. Se determinó una velocidad de degradación de 0.0908 d-1, un coeficiente de distribución del diesel en el medio reactivo de 0.8 ml/g, una capacidad de adsorción de diesel en el medio reactivo de 13.50 mg/L y un factor de retardo de 3.69

  13. A framework for understanding semi-permeable barrier effects on migratory ungulates

    Science.gov (United States)

    Sawyer, Hall; Kauffman, Matthew J.; Middleton, Arthur D.; Morrison, Thomas A.; Nielson, Ryan M.; Wyckoff, Teal B.

    2013-01-01

    1. Impermeable barriers to migration can greatly constrain the set of possible routes and ranges used by migrating animals. For ungulates, however, many forms of development are semi-permeable, and making informed management decisions about their potential impacts to the persistence of migration routes is difficult because our knowledge of how semi-permeable barriers affect migratory behaviour and function is limited. 2. Here, we propose a general framework to advance the understanding of barrier effects on ungulate migration by emphasizing the need to (i) quantify potential barriers in terms that allow behavioural thresholds to be considered, (ii) identify and measure behavioural responses to semi-permeable barriers and (iii) consider the functional attributes of the migratory landscape (e.g. stopovers) and how the benefits of migration might be reduced by behavioural changes. 3. We used global position system (GPS) data collected from two subpopulations of mule deer Odocoileus hemionus to evaluate how different levels of gas development influenced migratory behaviour, including movement rates and stopover use at the individual level, and intensity of use and width of migration route at the population level. We then characterized the functional landscape of migration routes as either stopover habitat or movement corridors and examined how the observed behavioural changes affected the functionality of the migration route in terms of stopover use. 4. We found migratory behaviour to vary with development intensity. Our results suggest that mule deer can migrate through moderate levels of development without any noticeable effects on migratory behaviour. However, in areas with more intensive development, animals often detoured from established routes, increased their rate of movement and reduced stopover use, while the overall use and width of migration routes decreased. 5. Synthesis and applications. In contrast to impermeable barriers that impede animal movement

  14. Permeability barriers to embryo cryopreservation of Pectinophora gossypiella (Lepidoptera: Gelechiidae).

    Science.gov (United States)

    Rajamohan, Arun; Rinehart, Joseph P; Foster, Stephen P; Leopold, Roger A

    2013-04-01

    The aim of this study was to develop a method to cryopreserve the embryos of the pink bollworm moth, Pectinophora gossypiella (Saunders). Previously developed dipteran cryopreservation protocols were not directly adaptable to use with the embryos of this lepidopteran species. Physiochemical and electron microscope observations revealed substantial differences in the structure of the chorion, wax layer, and vitelline membrane complex when comparing the cryopreservable embryonic stages of P. gossypiella and dipteran embryos. Thus, the initial steps dealing with dechorionation and permeabilization were ineffective and had to be altered. Exposure to the sodium hypochlorite-based chorion removal step decreased P. gossypiella embryo viability to a very low level. Survival increased and permeability was evident when an alkane wash was used as the first step in the procedure. After the alkane treatment with a surfactant yielded the maximum exchange of cryoprotectant with water as evidenced by a significant lowering of the supercooling point of the cryoprotectant-loaded embryos. The remainder of the cryopreservation and storage recovery protocol for P. gossypiella was similar to those developed for dipteran embryos. Survival of recovered, hatched embryos to adulthood was approximately 7%.

  15. A clay permeable reactive barrier to remove Cs-137 from groundwater: Column experiments.

    Science.gov (United States)

    De Pourcq, K; Ayora, C; García-Gutiérrez, M; Missana, T; Carrera, J

    2015-11-01

    Clay minerals are reputed sorbents for Cs-137 and can be used as a low-permeability material to prevent groundwater flow. Therefore, clay barriers are employed to seal Cs-137 polluted areas and nuclear waste repositories. This work is motivated by cases where groundwater flow cannot be impeded. A permeable and reactive barrier to retain Cs-137 was tested. The trapping mechanism is based on the sorption of cesium on illite-containing clay. The permeability of the reactive material is provided by mixing clay on a matrix of wood shavings. Column tests combined with reactive transport modeling were performed to check both reactivity and permeability. Hydraulic conductivity of the mixture (10(-4) m/s) was sufficient to ensure an adequate hydraulic performance of an eventual barrier excavated in most aquifers. A number of column experiments confirmed Cs retention under different flow rates and inflow solutions. A 1D reactive transport model based on a cation-exchange mechanism was built. It was calibrated with batch experiments for high concentrations of NH4+ and K+ (the main competitors of Cs in the exchange positions). The model predicted satisfactorily the results of the column experiments. Once validated, it was used to investigate the performance and duration of a 2 m thick barrier under different scenarios (flow, clay content, Cs-137 and K concentration). Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Dexou low pH plume baseline permeable reactive barrier options

    Energy Technology Data Exchange (ETDEWEB)

    Phifer, M.A.

    2000-06-20

    The current Environmental Restoration Department (ERD) Permeable Reactive Barrier (PRB) baseline configuration consists of a limestone trench and a granular cast iron trench in series. This report provides information relative to the use of PRB technology for the remediation of the D-Area low pH groundwater plumes.

  17. Topical Hesperidin Improves Epidermal Permeability Barrier Function and Epidermal Differentiation in Normal Murine Skin

    Science.gov (United States)

    Hou, Maihua; Man, Mona; Man, Wenyan; Zhu, Wenyuan; Hupe, Melanie; Park, Kyungho; Crumrine, Debra; Elias, Peter M.; Man, Mao-Qiang

    2012-01-01

    Orange peel extract appears to exhibit beneficial effects on skin whitening, inflammation, UVB protection, as well as keratinocyte proliferation. In the present study, we determine whether topical hesperidin influences epidermal permeability barrier function and its underlying mechanisms. Hairless mice were treated topically with 2% hesperidin or 70% ethanol alone twice daily for 6 days. At the end of treatment, basal barrier function as well as transepidermal water loss (TEWL) was measured 2 and 4 hours post barrier disruption. Epidermal proliferation and differentiation were evaluated by immunohistochemical staining and Western blot analysis. Additionally, lamellar body density and secretion were assessed by electron microscopy. Although there were no significant differences in basal barrier function, in comparison to control animals, topical hesperidin significantly accelerated barrier recovery at both 2 and 4 hours after acute barrier abrogation. Enhanced barrier function in hesperidin-treated skin correlated with stimulation of both epidermal proliferation and differentiation, as well as enhanced lamellar body secretion. These results indicate that topical hesperidin enhances epidermal permeability barrier homeostasis at least in part due to stimulation of epidermal proliferation, differentiation, as well as lamellar body secretion. PMID:22509829

  18. Redox-active media for permeable reactive barriers

    Energy Technology Data Exchange (ETDEWEB)

    Sivavec, T.M. [General Electric Corp. Research and Development Center, Schenectady, NY (United States); Mackenzie, P.D.; Horney, D.P.; Baghel, S.S.

    1997-12-31

    In this paper, three classes of redox-active media are described and evaluated in terms of their long-term effectiveness in treating TCE-contaminated groundwater in permeable reactive zones. Zero-valent iron, in the form of recycled cast iron filings, the first class, has received considerable attention as a reactive media and has been used in about a dozen pilot- and full-scale subsurface wall installations. Criteria used in selecting commercial sources of granular iron, will be discussed. Two other classes of redox-active media that have not yet seen wide use in pilot- or full-scale installations will also be described: Fe(II) minerals and bimetallic systems. Fe(II) minerals, including magnetite (Fe{sub 3}O{sub 4}), and ferrous sulfide (troilite, FeS), are redox-active and afford TCE reduction rates and product distributions that suggest that they react via a reductive mechanism similar to that which operates in the FeO system. Fe(II) species within the passive oxide layer coating the iron metal may act as electron transfer mediators, with FeO serving as the bulk reductant. Bimetallic systems, the third class of redox-active media, are commonly prepared by plating a second metal onto zero-valent iron (e.g., Ni/Fe and Pd/Fe) and have been shown to accelerate solvent degradation rates relative to untreated iron metal. The long-term effectiveness of this approach, however, has not yet been determined in groundwater treatability tests. The results of a Ni-plated iron column study using site groundwater indicate that a change in reduction mechanism (to catalytic dehydrohalogenation/hydrogenation) accounts for the observed rate enhancement. A significant loss in media reactivity was observed over time, attributable to Ni catalyst deactivation or poisoning. Zero-valent iron systems have not shown similar losses in reactivity in long-term laboratory, pilot or field investigations.

  19. Direct visualization of the arterial wall water permeability barrier using CARS microscopy.

    Science.gov (United States)

    Lucotte, Bertrand M; Powell, Chloe; Knutson, Jay R; Combs, Christian A; Malide, Daniela; Yu, Zu-Xi; Knepper, Mark; Patel, Keval D; Pielach, Anna; Johnson, Errin; Borysova, Lyudmyla; Dora, Kim A; Balaban, Robert S

    2017-05-02

    The artery wall is equipped with a water permeation barrier that allows blood to flow at high pressure without significant water leak. The precise location of this barrier is unknown despite its importance in vascular function and its contribution to many vascular complications when it is compromised. Herein we map the water permeability in intact arteries, using coherent anti-Stokes Raman scattering (CARS) microscopy and isotopic perfusion experiments. Generation of the CARS signal is optimized for water imaging with broadband excitation. We identify the water permeation barrier as the endothelial basolateral membrane and show that the apical membrane is highly permeable. This is confirmed by the distribution of the AQP1 water channel within endothelial membranes. These results indicate that arterial pressure equilibrates within the endothelium and is transmitted to the supporting basement membrane and internal elastic lamina macromolecules with minimal deformation of the sensitive endothelial cell. Disruption of this pressure transmission could contribute to endothelial cell dysfunction in various pathologies.

  20. Inflammation at the Blood–Brain Barrier in Multiple Sclerosis

    NARCIS (Netherlands)

    Mizee, M.R.; van Doorn, R.P.; Prat, A.; de Vries, H.E.; Fricker, G.; Ott, M.; Mahringer, A.

    2014-01-01

    The blood–brain barrier is specialized to function as a barrier to protect the central nervous system (CNS) by restricting entry of unwanted molecules and immune cells into the brain and inversely, to prevent CNS-born agents from reaching the systemic circulation. The blood–brain barrier

  1. Use of jet grouting to create a low permeability horizontal barrier below an incinerator ash landfill

    Energy Technology Data Exchange (ETDEWEB)

    Furth, A.J.; Burke, G.K. [Hayward Baker Inc., Odenton, MD (United States); Deutsch, W.L. Jr. [Roy F. Weston, Inc., West Chester, PA (United States)

    1997-12-31

    The City of Philadelphia`s Division of Aviation (DOA) has begun construction of a new commuter runway, designated as Runway 8-26, at the Philadelphia International Airport. A portion of this runway will be constructed over a former Superfund site known as the Enterprise Avenue Landfill, which for many years was used to dispose of solid waste incinerator ash and other hazardous materials. The site was clay capped in the 1980`s, but in order for the DOA to use the site, additional remediation was needed to meet US EPA final closure requirements. One component of the closure plan included installation of a low permeability horizontal barrier above a very thin (approximately 0.61 to 0.91 meters) natural clay stratum which underlies an approximately 1020 m{sup 2} area of the landfill footprint so as to insure that a minimum 1.52 meter thick low permeability barrier exists beneath the entire 150,000 m{sup 2} landfill. The new barrier was constructed using jet grouting techniques to achieve remote excavation and replacement of the bottom 0.91 meters of the waste mass with a low permeability grout. The grout was formulated to meet the low permeability, low elastic modulus and compressive strength requirements of the project design. This paper will discuss the advantages of using jet grouting for the work and details the development of the grout mixture, modeling of the grout zone under load, field construction techniques, performance monitoring and verification testing.

  2. Endothelial calcium dynamics, connexin channels and blood-brain barrier function.

    Science.gov (United States)

    De Bock, Marijke; Wang, Nan; Decrock, Elke; Bol, Mélissa; Gadicherla, Ashish K; Culot, Maxime; Cecchelli, Romeo; Bultynck, Geert; Leybaert, Luc

    2013-09-01

    Situated between the circulation and the brain, the blood-brain barrier (BBB) protects the brain from circulating toxins while securing a specialized environment for neuro-glial signaling. BBB capillary endothelial cells exhibit low transcytotic activity and a tight, junctional network that, aided by the cytoskeleton, restricts paracellular permeability. The latter is subject of extensive research as it relates to neuropathology, edema and inflammation. A key determinant in regulating paracellular permeability is the endothelial cytoplasmic Ca(2+) concentration ([Ca(2+)]i) that affects junctional and cytoskeletal proteins. Ca(2+) signals are not one-time events restricted to a single cell but often appear as oscillatory [Ca(2+)]i changes that may propagate between cells as intercellular Ca(2+) waves. The effect of Ca(2+) oscillations/waves on BBB function is largely unknown and we here review current evidence on how [Ca(2+)]i dynamics influence BBB permeability. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Potential Retinal Benefits of Dietary Polyphenols Based on Their Permeability across the Blood-Retinal Barrier.

    Science.gov (United States)

    Liu, Yixiang; Liu, Guang-Ming; Cao, Min-Jie; Chen, Qingchou; Sun, Lechang; Ji, Baoping

    2017-04-19

    Whether all dietary polyphenols nourish the eyes via oral supplementation is controversial. Given that passage of dietary polyphenols across the blood-retina barrier (BRB) is the precondition for polyphenols to exhibit ocular benefits, the BRB permeability of polyphenols was assessed in this study. Being common dietary polyphenols in fruits and vegetables, nonanthocyanin flavonoids, anthocyanins, and phenolic acids were investigated. BRB was simulated in vitro by using a differentiated retinal pigment epithelial cell monolayer cultivated on a Transwell culture system. Penetration rate was calculated by quantitatively analyzing the polyphenols in basolateral media. The BRB permeability of different polyphenols obviously (p nonanthocyanin flavonoids > anthocyanins. Glycosylation and methylation improved the BRB permeability of nonanthocyanin flavonoids and anthocyanins. However, instability and carbonylation at the C-4 position severely suppressed the BRB permeability of anthocyanins and nonanthocyanin flavonoids. Moreover, a new metabolite was discovered during penetration of anthocyanins into the BRB. However, hydrophilic phenolic acids exhibited better BRB permeability than hydrophobic ones. Data demonstrate that BRB permeability of polyphenols was determined based on structural characteristics, hydrophilicity, stability, and metabolic changes.

  4. Modulation of p-glycoprotein transport function at the blood-brain barrier.

    Science.gov (United States)

    Bauer, Björn; Hartz, Anika M S; Fricker, Gert; Miller, David S

    2005-02-01

    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.

  5. Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors.

    Science.gov (United States)

    Dalvi, Siddhartha; Nguyen, Hieu H; On, Ngoc; Mitchell, Ryan W; Aukema, Harold M; Miller, Donald W; Hatch, Grant M

    2015-12-01

    The blood-brain barrier, formed by microvessel endothelial cells, is the restrictive barrier between the brain parenchyma and the circulating blood. Arachidonic acid (ARA; 5,8,11,14-cis-eicosatetraenoic acid) is a conditionally essential polyunsaturated fatty acid [20:4(n-6)] and is a major constituent of brain lipids. The current study examined the transport processes for ARA in confluent monolayers of human brain microvascular endothelial cells (HBMEC). Addition of radioactive ARA to the apical compartment of HBMEC cultured on Transwell(®) inserts resulted in rapid incorporation of radioactivity into the basolateral medium. Knock down of fatty acid transport proteins did not alter ARA passage into the basolateral medium as a result of the rapid generation of prostaglandin E2 (PGE2 ), an eicosanoid known to facilitate opening of the blood-brain barrier. Permeability following ARA or PGE2 exposure was confirmed by an increased movement of fluorescein-labeled dextran from apical to basolateral medium. ARA-mediated permeability was attenuated by specific cyclooxygenase-2 inhibitors. EP3 and EP4 receptor antagonists attenuated the ARA-mediated permeability of HBMEC. The results indicate that ARA increases permeability of HBMEC monolayers likely via increased production of PGE2 which acts upon EP3 and EP4 receptors to mediate permeability. These observations may explain the rapid influx of ARA into the brain previously observed upon plasma infusion with ARA. The blood-brain barrier, formed by microvessel endothelial cells, is a restrictive barrier between the brain parenchyma and the circulating blood. Radiolabeled arachidonic acid (ARA) movement across, and monolayer permeability in the presence of ARA, was examined in confluent monolayers of primary human brain microvessel endothelial cells (HBMECs) cultured on Transwell(®) plates. Incubation of HBMECs with ARA resulted in a rapid increase in HBMEC monolayer permeability. The mechanism was mediated, in part

  6. Peptide Transport through the Blood-Brain Barrier

    Science.gov (United States)

    1991-01-01

    cause glomerular nephropathies , (c) the potential antigenicity of the vector, i.e., some cationized heterologous proteins are highly immunogenic, (d...I diabetes . N. Enctl. J. Med. 312:1078-1084. 12. Pardridge, W.M. (1988): Recent advances in blood-brain barrier transport. Ann. Rev. Pharmacol...barrier. In: Pathophysiology of the Blood-Brain Barrier: Long Term Consequences of Barrier Dysfunction for the Brain (B.B. Johansson, C. Owman, and H

  7. New treatments for restoring impaired epidermal barrier permeability: skin barrier repair creams.

    Science.gov (United States)

    Draelos, Zoe Diana

    2012-01-01

    Skin health depends on an intact barrier composed of protein-rich corneocytes surrounded by the lamellar intercellular lipids. This barrier provides waterproof protection for the body, preventing infection, regulating electrolyte balance, maintaining body temperature, and providing a mechanism for sensation. Damage to the skin barrier results in skin disease that can be treated by a variety of externally applied substances, such as ceramides, hyaluronic acid, licorice extracts, dimethicone, petrolatum, and paraffin wax. These substances are found in moisturizers that are sold as cosmetics and in prescriptions as 510(k) devices. This contribution examines the formulation and effect of skin barrier creams. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Oxidation of trichloroethylene, toluene, and ethanol vapors by a partially saturated permeable reactive barrier

    Science.gov (United States)

    Mahmoodlu, Mojtaba G.; Hassanizadeh, S. Majid; Hartog, Niels; Raoof, Amir

    2014-08-01

    The mitigation of volatile organic compound (VOC) vapors in the unsaturated zone largely relies on the active removal of vapor by ventilation. In this study we considered an alternative method involving the use of solid potassium permanganate to create a horizontal permeable reactive barrier for oxidizing VOC vapors. Column experiments were carried out to investigate the oxidation of trichloroethylene (TCE), toluene, and ethanol vapors using a partially saturated mixture of potassium permanganate and sand grains. Results showed a significant removal of VOC vapors due to the oxidation. We found that water saturation has a major effect on the removal capacity of the permeable reactive layer. We observed a high removal efficiency and reactivity of potassium permanganate for all target compounds at the highest water saturation (Sw = 0.6). A change in pH within the reactive layer reduced oxidation rate of VOCs. The use of carbonate minerals increased the reactivity of potassium permanganate during the oxidation of TCE vapor by buffering the pH. Reactive transport of VOC vapors diffusing through the permeable reactive layer was modeled, including the pH effect on the oxidation rates. The model accurately described the observed breakthrough curve of TCE and toluene vapors in the headspace of the column. However, miscibility of ethanol in water in combination with produced water during oxidation made the modeling results less accurate for ethanol. A linear relationship was found between total oxidized mass of VOC vapors per unit volume of permeable reactive layer and initial water saturation. This behavior indicates that pH changes control the overall reactivity and longevity of the permeable reactive layer during oxidation of VOCs. The results suggest that field application of a horizontal permeable reactive barrier can be a viable technology against upward migration of VOC vapors through the unsaturated zone.

  9. Surfactant-modified zeolites as permeable barriers to organic and inorganic groundwater contaminants

    Energy Technology Data Exchange (ETDEWEB)

    Bowman, R.S.; Sullivan, E.J. [New Mexico Institute of Mining and Technology, Socorro, NM (United States)

    1995-10-01

    We have shown in laboratory experiments that natural zeolites treated with hexadecyltrimethylammonium (HDTMA) are effective sorbents for nonpolar organics, inorganic cations, and inorganic anions. Due to their low cost ({approximately}$0.75/kg) and granular nature, HDTMA-zeolites appear ideal candidates for reactive, permeable subsurface barriers. The HDTMA-zeolites are stable over a wide range of pH (3-13), ionic strength (1 M Cs{sup +} or Ca{sup 2+}), and in organic solvents. Surfactant-modified zeolites sorb nonpolar organics (benzene, toluene, xylene, chlorinated aliphatics) via a partitioning mechanism, inorganic cations (Pb{sup 2+}) via ion exchange and surface complexation, and inorganic anions (CrO{sub 4}{sup 2-}, SeO{sub 4}{sup 2-}, SO{sub 4}{sup 2-}) via surface precipitation.The goal of this work is to demonstrate the use of surfactant-modified zeolite as a permeable barrier to ground water contaminants.

  10. The nuclear pore complex core scaffold and permeability barrier: variations of a common theme.

    Science.gov (United States)

    Hayama, Ryo; Rout, Michael P; Fernandez-Martinez, Javier

    2017-06-01

    The study of the nuclear pore complex (NPC) is a fascinating endeavor, as it not only implies uncovering the 'engineering marvel' of its architecture and function, but also provides a key window into a significant evolutionary event: the origin of the eukaryotic cell. The combined efforts of many groups in the field, with the help of novel methodologies and new model organisms, are facilitating a much deeper understanding of this complex assembly. Here we cover recent advances on the characterization of the structure of the NPC scaffold and of the biophysical mechanisms that define the permeability barrier. We identify common architectural and functional principles between those two NPC compartments, expanding the previous protocoatomer hypothesis to suggest possible evolutionary origins for the FG nucleoporins and the NPC permeability barrier. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. A calcite permeable reactive barrier for the remediation of Fluoride from spent potliner (SPL) contaminated groundwater

    DEFF Research Database (Denmark)

    Turner, B.D.; Binning, Philip John; Sloan, S.W.

    2008-01-01

    . The paper focuses on two issues in the implementation of calcite permeable reactive barriers for remediating fluoride contaminated water: the impact of the groundwater chemical matrix and CO2 addition on fluoride removal. Column tests comparing pure NaF solutions, synthetic SPL solutions, and actual SPL......The use of calcite (CaCO3) as a substrate for a permeable reactive barrier (PRB) for removing fluoride from contaminated groundwater is proposed and is illustrated by application to groundwater contaminated by spent potliner leachate (SPL), a waste derived from the aluminium smelting process...... leachate indicate that the complex chemical matrix of the SPL leachate can impact fluoride removal significantly. For SPL contaminant mixtures, fluoride removal is initially less than expected from idealized, pure, solutions. However, with time, the effect of other contaminants on fluoride removal...

  12. Gas permeability of bentonite barriers: development, construction and testing of a measurement system

    Directory of Open Access Journals (Sweden)

    Heraldo Nunes Pitanga

    Full Text Available Abstract This article proposes a testing device to quickly and reliably estimate the gas permeability of bentonite-based clay barriers used in landfill cover systems. The testing methodology is based on a transient gas flow regime that passes through the barrier, therefore not requiring the use of sophisticated equipment that aim to maintain constant differential pressure and measure the gas flow, common requirements for testing methods under a permanent flow regime. To confirm the feasibility of the proposed technique, tests were performed on a pure hydrated bentonite layer, which subsequently encompassed samples of geosynthetic clay liner (GCL at different moisture contents. Geosynthetic clay liners are often selected as a part of the barrier layer for cover systems in solid waste landfills to prevent infiltration of rainfall and migration of biogas into the atmosphere. The results confirmed the equipment reliability and differentiate the different responses of the gas flow barriers studied, considering their different compositions and different moistures.

  13. Blood-brain barrier transport machineries and targeted therapy of brain diseases

    Directory of Open Access Journals (Sweden)

    Jaleh Barar

    2016-12-01

    Full Text Available Introduction: Desired clinical outcome of pharmacotherapy of brain diseases largely depends upon the safe drug delivery into the brain parenchyma. However, due to the robust blockade function of the blood-brain barrier (BBB, drug transport into the brain is selectively controlled by the BBB formed by brain capillary endothelial cells and supported by astrocytes and pericytes. Methods: In the current study, we have reviewed the most recent literature on the subject to provide an insight upon the role and impacts of BBB on brain drug delivery and targeting. Results: All drugs, either small molecules or macromolecules, designated to treat brain diseases must adequately cross the BBB to provide their therapeutic properties on biological targets within the central nervous system (CNS. However, most of these pharmaceuticals do not sufficiently penetrate into CNS, failing to meet the intended therapeutic outcomes. Most lipophilic drugs capable of penetrating BBB are prone to the efflux functionality of BBB. In contrast, all hydrophilic drugs are facing severe infiltration blockage imposed by the tight cellular junctions of the BBB. Hence, a number of strategies have been devised to improve the efficiency of brain drug delivery and targeted therapy of CNS disorders using multimodal nanosystems (NSs. Conclusion: In order to improve the therapeutic outcomes of CNS drug transfer and targeted delivery, the discriminatory permeability of BBB needs to be taken under control. The carrier-mediated transport machineries of brain capillary endothelial cells (BCECs can be exploited for the discovery, development and delivery of small molecules into the brain. Further, the receptor-mediated transport systems can be recruited for the delivery of macromolecular biologics and multimodal NSs into the brain.

  14. Removal of chromate in a permeable reactive barrier using zero-valent iron

    DEFF Research Database (Denmark)

    Kjeldsen, Peter; Locht, T

    2002-01-01

    Chromate is a commonly found groundwater contaminant. Permeable reactive barriers containing zero-valent iron as iron filings are able to remove the chromate by a combined reduction/precipitation reaction. However, due to the passivation of the reduction capability of the iron surfaces...... by the precipitation of chromate and other groundwater constituents, the barrier may have a limited capacity for chromate removal. By performing a column experiment with iron filings it was shown that the capacity was slightly lower at high chromate concentration (500 ppm) in comparison to low concentration (20 ppm...

  15. Design Guidance for Application of Permeable Barriers to Remediate Dissolved Chlorinated Solvents,

    Science.gov (United States)

    1997-02-01

    detector GC gas chromatography GC-FID gas chromatograph-flame ionization detector GE General Electric GX gum xanthan HDPE high-density polyethylene HFB...absence of air bubbles in the column. 44 SECTION 6.0 MODELING TO SUPPORT THE PERMEABLE BARRIER DESIGN Modeling enables an understanding of the...Construction and Quality Control, ASTMSTP 1129. American Society for Testing and Materials, Philadelphia, PA. 94 Chabra, R. P. 1993. Bubbles , Drops and Particles

  16. Aggressive Antioxidant Reductive Stress Impairs Brain Endothelial Cell Angiogenesis and Blood Brain Barrier Function.

    Science.gov (United States)

    Mentor, Shireen; Fisher, David

    2017-01-01

    Oxidative stress in the brain microvasculature is a common characteristic in models of cerebrovascular disease. Considering the effects of reactive oxygen species activity in vascular-derived insults, it is naturally prudent to hypothesize those interventions inhibiting reactive oxygen species activity, such as antioxidant supplementation, may be beneficial for cerebrovascular disease. Hyper doses of antioxidant supplements, and foods with high antioxidant concentrations, are commonly used as an ongoing remedial and 'over-the-counter' treatments for most seasonal ailments. For the first time, this study reports the adverse effects of excess antioxidants on angiogenic properties of the blood-brain barrier (BBB) which have clinical implications. A medicinal tea, known as Rooibos, commonly used in South Africa and marketed globally, for its prominent antioxidant profile, demonstrated its effects on brain endothelial cellular proliferation, toxicology, mitochondrial activity and permeability. Mouse brain endothelial cells were seeded at cell densities ranging from 103-106 cells/ml and were incubated at pre-determined time intervals of 24 to120 hours. Daily exposure of a selected concentration range of fermented Rooibos tea caused dose-related decreases in cellular proliferation, and unequivocally decreased permeability across our in vitro BBB model. Despite the negative effects on cellular proliferation, no toxicity was observed for all selected fermented Rooibos concentrations. Our data conclusively shows that the use of excess antioxidants perturbs BBB functionality and angiogenic properties, adversely implicating the homeostatic regulation of the brain microenvironment, while suppression in cellular proliferation impacts both the maintenance and repair function of brain capillaries. Our study indicates that excess antioxidants will lead to an impaired response to mechanical-induced injury and pathogenic infection of the BBB, compromising patient recovery. Copyright

  17. The blood-brain barrier in psychoneuroimmunology.

    Science.gov (United States)

    Banks, William A

    2009-05-01

    The term ''psychoneuroimmunology'' connotes separate compartments that interact. The blood-brain barrier (BBB) is both the dividing line, physical and physiologic, between the immune system and the central nervous system (CNS) and the locale for interaction. The BBB restricts unregulated mixing of immune substances in the blood with those in the CNS, directly transports neuroimmune-active substances between the blood and CNS, and itself secretes neuroimmune substances. These normal functions of the BBB can be altered by neuroimmune events. As such, the BBB is an important conduit in the communication between the immune system and the CNS.

  18. Strength and Numerical Analysis in the Design of Permeable Reactive Barriers

    Science.gov (United States)

    Pawluk, Katarzyna; Wrzesiński, Grzegorz; Lendo-Siwicka, Marzena

    2017-10-01

    Permeable reactive barriers are one of the most important in situ technologies in groundwater remediation. Most of the installed PRBs have tended to use singular reactive media, but there is an increasing number of applications using combined or sequenced media to treat mixtures of contaminants within a groundwater plume. The concept of a multi-layered permeable reactive barrier (MPRB) to prevent and protect groundwater along traffic routes, especially in ecologically and naturally valuable areas, was developed following several field and laboratory investigations conducted in the Department of Geotechnical Engineering of the Warsaw University of Life Sciences. In accordance with the guidelines of the Interstate Technology & Regulatory Council for the selection of reactive materials, numerous laboratory and field investigations should be performed to determine the environmental conditions, type and concentrations of the contaminants, and the physical-chemical and permeability properties of the reactive materials. However, the deformation and strength properties of the reactive materials should be also considered in the design and evaluation of the safety conditions. In this paper, strength and deformation properties of silica spongolite, zeolite, and activated carbon were investigated using direct shear and oedometer tests. The laboratory test results were used in numerical calculations with the application of the finite element method. The aim of this study was to define the impact of the installation stages of a multi-layered permeable reactive barrier on the stability of a road embankment. Numerical analysis may prevent, reduce or eliminate the risk in the case of a breakdown during the construction or/and exploitation of a PRB.

  19. Permeable bio-reactive barriers to address petroleum hydrocarbon contamination at subantarctic Macquarie Island.

    Science.gov (United States)

    Freidman, Benjamin L; Terry, Deborah; Wilkins, Dan; Spedding, Tim; Gras, Sally L; Snape, Ian; Stevens, Geoffrey W; Mumford, Kathryn A

    2017-05-01

    A reliance on diesel generated power and a history of imperfect fuel management have created a legacy of petroleum hydrocarbon contamination at subantarctic Macquarie Island. Increasing environmental awareness and advances in contaminant characterisation and remediation technology have fostered an impetus to reduce the environmental risk associated with legacy sites. A funnel and gate permeable bio-reactive barrier (PRB) was installed in 2014 to address the migration of Special Antarctic Blend diesel from a spill that occurred in 2002, as well as older spills and residual contaminants in the soil at the Main Power House. The PRB gate comprised of granular activated carbon and natural clinoptilolite zeolite. Petroleum hydrocarbons migrating in the soil water were successfully captured on the reactive materials, with concentrations at the outflow of the barrier recorded as being below reporting limits. The nutrient and iron concentrations delivered to the barrier demonstrated high temporal variability with significant iron precipitation observed across the bed. The surface of the granular activated carbon was largely free from cell attachment while natural zeolite demonstrated patchy biofilm formation after 15 months following PRB installation. This study illustrates the importance of informed material selection at field scale to ensure that adsorption and biodegradation processes are utilised to manage the environmental risk associated with petroleum hydrocarbon spills. This study reports the first installation of a permeable bio-reactive barrier in the subantarctic. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Reactive Transport Modeling for Mobilization of Arsenic in a Sediment Downgradient from an Iron Permeable Reactive Barrier

    National Research Council Canada - National Science Library

    Sung-Wook Jeen

    2017-01-01

    ... As. While granular iron permeable reactive barriers (PRBs) can be effective for the treatment of arsenic in groundwater, the mobilization of arsenic in the sediment downgradient of the PRB might be an issue due to the reduced geochemical conditions generated...

  1. Long-Term Groundwater Monitoring Optimization, Clare Water Supply Superfund Site, Permeable Reactive Barrier and Soil Remedy Areas, Clare, Michigan

    Science.gov (United States)

    This report contains a review of the long-term groundwater monitoring network for the Permeable Reactive Barrier (PRB) and Soil Remedy Areas at the Clare Water Supply Superfund Site in Clare, Michigan.

  2. Brain Extracellular Space as a Diffusion Barrier.

    Science.gov (United States)

    Nicholson, Charles; Kamali-Zare, Padideh; Tao, Lian

    2011-10-01

    The extracellular space (ECS) consists of the narrow channels between brain cells together with their geometrical configuration and contents. Despite being only 20-60 nm in width, the ECS typically occupies 20% of the brain volume. Numerous experiments over the last 50 years have established that molecules moving through the ECS obey the laws of diffusion but with an effective diffusion coefficient reduced by a factor of about 2.6 compared to free diffusion. This review considers the origins of the diffusion barrier arising from the ECS and its properties. The paper presents a brief overview of software for implementing two point-source paradigms for measurements of localized diffusion properties: the real-time iontophoresis or pressure method for small ions and the integrative optical imaging method for macromolecules. Selected results are presented. This is followed by a discussion of the application of the MCell Monte Carlo simulation program to determining the importance of geometrical constraints, especially dead-space microdomains, and the possible role of interaction with the extracellular matrix. It is concluded that we can predict the impediment to diffusion of many molecules of practical importance and also use studies of the diffusion of selected molecular probes to reveal the barrier properties of the ECS.

  3. The gut-blood barrier permeability - A new marker in cardiovascular and metabolic diseases?

    Science.gov (United States)

    Ufnal, Marcin; Pham, Kinga

    2017-01-01

    Recent studies suggest that blood-borne metabolites of gut microbiota, such as trimethylamine N-oxide (TMAO) are involved in the aetiology of cardiovascular diseases and may serve as markers of cardiovascular risk. To enter the bloodstream the microbiota-derived molecules need to pass the gut-blood barrier (GBB). The GBB plays an important role in maintaining organism homeostasis. It is a complex multi-layer system which determines the absorption of nutrients, water and many other substances. The integrity and permeability of the GBB may be impaired in numerous diseases including gastrointestinal, metabolic and cardiovascular diseases. Here, we propose that the evaluation of the GBB permeability may have a significant diagnostic potential in cardiovascular and metabolic diseases. Second, we suggest that the GBB permeability is a variable that confounds diagnostic value of new gut microbiota-derived biomarkers such as TMAO. Therefore, cardiovascular risk assessment requires the evaluation of both TMAO and the GBB permeability. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Revisiting blood-brain barrier: A chromatographic approach.

    Science.gov (United States)

    Subirats, Xavier; Muñoz-Pascual, Laura; Abraham, Michael H; Rosés, Martí

    2017-10-25

    Drugs designed to reach a pharmacological CNS target must be effectively transported across the blood-brain barrier (BBB), a thin monolayer of endothelial cells tightly attached together between the blood and the brain parenchyma. Because of the lipidic nature of the BBB, several physicochemical partition models have been studied as surrogates for the passive permeation of potential drug candidates across the BBB (octanol-water, alkane-water, PAMPA...). In the last years, biopartition chromatography is gaining importance as a noncellular system for the estimation of biological properties in early stages of drug development. Microemulsions (ME) are suitable mobile phases, because of their ease of formulation, stability and adjustability to a large number of compositions mimicking biological structures. In the present work, several microemulsion liquid chromatographic (MELC) systems have been characterized by means of the Abraham's solvation parameter model, in order to assess their suitability as BBB distribution or permeability surrogates. In terms of similarity between BBB and MELC systems (dispersion forces arising from solute non-bonded electrons, dipolarity/polarizability, hydrogen-bond acidity and basicity, and molecular volume), the passive permeability surface area product (log PS) for neutral (including zwitterions), fully and partially ionized drugs was found to be well correlated with the ME made of 3.3% SDS (w/v; surfactant) 0.8% heptane (w/v; oil phase) and 6.6% 1-butanol (w/v; co-surfactant) in 50mM aqueous phosphate buffer, pH 7.4. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura.

    Science.gov (United States)

    Hougaard, Anders; Amin, Faisal M; Christensen, Casper E; Younis, Samaira; Wolfram, Frauke; Cramer, Stig P; Larsson, Henrik B W; Ashina, Messoud

    2017-06-01

    See Moskowitz (doi:10.1093/brain/awx099) for a scientific commentary on this article.The migraine aura is characterized by transient focal cortical disturbances causing dramatic neurological symptoms that are usually followed by migraine headache. It is currently not understood how the aura symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood-brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood-brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas of the anterior, middle and posterior circulation during spontaneous attacks of migraine with aura. Patients reported to our institution to undergo magnetic resonance imaging during the headache phase after presenting with typical visual aura. Nineteen patients were scanned during attacks and on an attack-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood-brain barrier permeability in any of the investigated regions. There was no correlation between blood-brain barrier permeability, brain perfusion, and time from symptom onset to examination or pain intensity. Our findings demonstrate hyperperfusion in brainstem during the headache phase of migraine with aura, while the blood-brain barrier remains intact during attacks of migraine with aura. These data thus contradict the preclinical hypothesis of cortical spreading depression-induced blood-brain barrier

  6. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier.

    Science.gov (United States)

    Lazear, Helen M; Daniels, Brian P; Pinto, Amelia K; Huang, Albert C; Vick, Sarah C; Doyle, Sean E; Gale, Michael; Klein, Robyn S; Diamond, Michael S

    2015-04-22

    Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis. Copyright © 2015, American Association for the Advancement of Science.

  7. Magnetic resonance imaging-guided focused ultrasound to increase localized blood-spinal cord barrier permeability.

    Science.gov (United States)

    Payne, Allison H; Hawryluk, Gregory W; Anzai, Yoshimi; Odéen, Henrik; Ostlie, Megan A; Reichert, Ethan C; Stump, Amanda J; Minoshima, Satoshi; Cross, Donna J

    2017-12-01

    Spinal cord injury (SCI) affects thousands of people every year in the USA, and most patients are left with some permanent paralysis. Therapeutic options are limited and only modestly affect outcome. To address this issue, we used magnetic resonance imaging-guided focused ultrasound (MRgFUS) as a non-invasive approach to increase permeability in the blood-spinal cord barrier (BSCB). We hypothesize that localized, controlled sonoporation of the BSCB by MRgFUS will aid delivery of therapeutics to the injury. Here, we report our preliminary findings for the ability of MRgFUS to increase BSCB permeability in the thoracic spinal cord of a normal rat model. First, an excised portion of normal rat spinal column was used to characterize the acoustic field and to estimate the insertion losses that could be expected in an MRgFUS blood spinal cord barrier opening. Then, in normal rats, MRgFUS was applied in combination with intravenously administered microbubbles to the spinal cord region. Permeability of the BSCB was indicated as signal enhancement by contrast administered prior to T1-weighted magnetic resonance imaging and verified by Evans blue dye. Neurological testing using the Basso, Beattie, and Breshnahan scale and the ladder walk was normal in 8 of 10 rats tested. Two rats showed minor impairment indicating need for further refinement of parameters. No gross tissue damage was evident by histology. In this study, we have opened successfully the blood spinal cord barrier in the thoracic region of the normal rat spine using magnetic resonance-guided focused ultrasound combined with microbubbles.

  8. Microbial barrier permeability and thermophysiological and mechanical properties of static dissipative woven fabric system

    Science.gov (United States)

    Schwarz, I.; Rogina-Car, B.; Kopitar, D.

    2017-10-01

    Some of the most significant properties of static dissipative woven fabric systems, in applications where contact of textile material and human body is present, beside antistatic properties are definitely microbial barrier permeability and thermophysiological properties. Application of such materials with associated properties is of great importance in bedding upholstery and comfortable apparel. Based on the conducted relevant tests, according to standardized and newly developed methods, it can be concluded that the such static dissipative woven fabric fulfils all the highly set criteria’s, resulting in a system that can, with certainty, provide the necessary health protection and comfort.

  9. LONG-TERM GEOCHEMICAL BEHAVIOR OF A ZEROVALENT IRON PERMEABLE REACTIVE BARRIER FOR THE TREATMENT OF HEXAVALENT CHROMIUM IN GROUNDWATER

    Science.gov (United States)

    Passive, in-situ reactive barriers have proven to be viable, cost-effective systems for the remediation of Cr-contaminated groundwater at some sites. Permeable reactive barriers (PRBs) are installed in the flow-path of groundwater, most typically as vertical treatment walls. Re...

  10. Blood-brain barrier disruption by continuous-wave radio frequency radiation.

    Science.gov (United States)

    Sirav, Bahriye; Seyhan, Nesrin

    2009-01-01

    The increasing use of cellular phones and the increasing number of associated base stations are becoming a widespread source of non ionizing electromagnetic radiation. Some biological effects are likely to occur even at low-level EM fields. This study was designed to investigate the effects of 900 and 1,800 MHz Continuous Wave Radio Frequency Radiation (CW RFR) on the permeability of Blood Brain Barrier (BBB) of rats. Results have shown that 20 min RFR exposure of 900 and 1,800 MHz induces an effect and increases the permeability of BBB of male rats. There was no change in female rats. The scientific evidence on RFR safety or harm remains inconclusive. More studies are needed to demonstrate the effects of RFR on the permeability of BBB and the mechanisms of that breakdown.

  11. Discontinuous permeable adsorptive barrier design and cost analysis: a methodological approach to optimisation.

    Science.gov (United States)

    Santonastaso, Giovanni Francesco; Bortone, Immacolata; Chianese, Simeone; Di Nardo, Armando; Di Natale, Michele; Erto, Alessandro; Karatza, Despina; Musmarra, Dino

    2017-09-19

    The following paper presents a method to optimise a discontinuous permeable adsorptive barrier (PAB-D). This method is based on the comparison of different PAB-D configurations obtained by changing some of the main PAB-D design parameters. In particular, the well diameters, the distance between two consecutive passive wells and the distance between two consecutive well lines were varied, and a cost analysis for each configuration was carried out in order to define the best performing and most cost-effective PAB-D configuration. As a case study, a benzene-contaminated aquifer located in an urban area in the north of Naples (Italy) was considered. The PAB-D configuration with a well diameter of 0.8 m resulted the best optimised layout in terms of performance and cost-effectiveness. Moreover, in order to identify the best configuration for the remediation of the aquifer studied, a comparison with a continuous permeable adsorptive barrier (PAB-C) was added. In particular, this showed a 40% reduction of the total remediation costs by using the optimised PAB-D.

  12. Outer brain barriers in rat and human development

    DEFF Research Database (Denmark)

    Brøchner, Christian B; Holst, Camilla Bjørnbak; Møllgård, Kjeld

    2015-01-01

    Complex barriers at the brain's surface, particularly in development, are poorly defined. In the adult, arachnoid blood-cerebrospinal fluid (CSF) barrier separates the fenestrated dural vessels from the CSF by means of a cell layer joined by tight junctions. Outer CSF-brain barrier provides...... diffusion restriction between brain and subarachnoid CSF through an initial radial glial end feet layer covered with a pial surface layer. To further characterize these interfaces we examined embryonic rat brains from E10 to P0 and forebrains from human embryos and fetuses (6-21st weeks post...

  13. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction.

    Science.gov (United States)

    Wardill, Hannah R; Mander, Kimberley A; Van Sebille, Ysabella Z A; Gibson, Rachel J; Logan, Richard M; Bowen, Joanne M; Sonis, Stephen T

    2016-12-15

    Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity. © 2016 UICC.

  14. Effects of Soybean Agglutinin on Intestinal Barrier Permeability and Tight Junction Protein Expression in Weaned Piglets

    Directory of Open Access Journals (Sweden)

    Xiaodong Zhang

    2011-11-01

    Full Text Available This study was developed to provide further information on the intestinal barrier permeability and the tight junction protein expression in weaned piglets fed with different levels of soybean agglutinin (SBA. Twenty-five weaned crossbred barrows (Duroc × Landrace × Yorkshire were selected and randomly allotted to five groups, each group with five replicates. The piglets in the control group were not fed with leguminous products. 0.05, 0.1, 0.15 and 0.2% SBA was added to the control diet to form four experimental diets, respectively. After the experimental period of 7 days (for each group, all the piglets were anesthetized with excess procaine and slaughtered. The D-lactic acid in plasma and the Ileal mucosa diamine oxidase (DAO was analyzed to observe the change in the intestinal permeability. The tight junction proteins occludin and ZO-1 in the jejunum tissue distribution and relative expression were detected by immunohistochemistry and Western Blot. The results illustrated that a high dose of SBA (0.1–0.2% could increase the intestinal permeability and reduce piglet intestinal epithelial tight junction protein occludin or ZO-1 expression, while low dose of SBA (0.05% of total diet had no significant affects. The contents of DAO, D-lactic acid, occludin or ZO-1, had a linear relationship with the SBA levels (0–0.2% in diets. The high dose SBA (0.1–0.2% could increase the intestinal permeability and reduce piglet intestinal epithelial tight junction protein occludin or ZO-1 expression, while low dose of SBA (0.05% of total diet had no affects.

  15. Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function.

    Science.gov (United States)

    Lin, Tzu-Kai; Man, Mao-Qiang; Santiago, Juan-Luis; Park, Kyungho; Roelandt, Truus; Oda, Yuko; Hupe, Melanie; Crumrine, Debra; Lee, Hae-Jin; Gschwandtner, Maria; Thyssen, Jacob P; Trullas, Carles; Tschachler, Erwin; Feingold, Kenneth R; Elias, Peter M

    2013-02-01

    Systemic antagonists of the histamine type 1 and 2 receptors (H1/2r) are widely used as anti-pruritics and central sedatives, but demonstrate only modest anti-inflammatory activity. Because many inflammatory dermatoses result from defects in cutaneous barrier function, and because keratinocytes express both Hr1 and Hr2, we hypothesized that H1/2r antagonists might be more effective if they were used topically to treat inflammatory dermatoses. Topical H1/2r antagonists additively enhanced permeability barrier homeostasis in normal mouse skin by the following mechanisms: (i) stimulation of epidermal differentiation, leading to thickened cornified envelopes; and (ii) enhanced epidermal lipid synthesis and secretion. As barrier homeostasis was enhanced to a comparable extent in mast cell-deficient mice, with no further improvement following application of topical H1/2r antagonists, H1/2r antagonists likely oppose mast cell-derived histamines. In four immunologically diverse, murine disease models, characterized by either inflammation alone (acute irritant contact dermatitis, acute allergic contact dermatitis) or by prominent barrier abnormalities (subacute allergic contact dermatitis, atopic dermatitis), topical H1/2r agonists aggravated, whereas H1/2r antagonists improved, inflammation and/or barrier function. The apparent ability of topical H1r/2r antagonists to target epidermal H1/2r could translate into increased efficacy in the treatment of inflammatory dermatoses, likely due to decreased inflammation and enhanced barrier function. These results could shift current paradigms of antihistamine utilization from a predominantly systemic to a topical approach.

  16. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

    Directory of Open Access Journals (Sweden)

    Murrin L Charles

    2011-03-01

    Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

  17. Modelling the endothelial blood-CNS barriers: a method for the production of robust in vitro models of the rat blood-brain barrier and blood-spinal cord barrier.

    Science.gov (United States)

    Watson, P Marc D; Paterson, Judy C; Thom, George; Ginman, Ulrika; Lundquist, Stefan; Webster, Carl I

    2013-06-18

    Modelling the blood-CNS barriers of the brain and spinal cord in vitro continues to provide a considerable challenge for research studying the passage of large and small molecules in and out of the central nervous system, both within the context of basic biology and for pharmaceutical drug discovery. Although there has been considerable success over the previous two decades in establishing useful in vitro primary endothelial cell cultures from the blood-CNS barriers, no model fully mimics the high electrical resistance, low paracellular permeability and selective influx/efflux characteristics of the in vivo situation. Furthermore, such primary-derived cultures are typically labour-intensive and generate low yields of cells, limiting scope for experimental work. We thus aimed to establish protocols for the high yield isolation and culture of endothelial cells from both rat brain and spinal cord. Our aim was to optimise in vitro conditions for inducing phenotypic characteristics in these cells that were reminiscent of the in vivo situation, such that they developed into tight endothelial barriers suitable for performing investigative biology and permeability studies. Brain and spinal cord tissue was taken from the same rats and used to specifically isolate endothelial cells to reconstitute as in vitro blood-CNS barrier models. Isolated endothelial cells were cultured to expand the cellular yield and then passaged onto cell culture inserts for further investigation. Cell culture conditions were optimised using commercially available reagents and the resulting barrier-forming endothelial monolayers were characterised by functional permeability experiments and in vitro phenotyping by immunocytochemistry and western blotting. Using a combination of modified handling techniques and cell culture conditions, we have established and optimised a protocol for the in vitro culture of brain and, for the first time in rat, spinal cord endothelial cells. High yields of both CNS

  18. A quantitative MRI method for imaging blood-brain barrier leakage in experimental traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Blood-brain barrier (BBB disruption is common following traumatic brain injury (TBI. Dynamic contrast enhanced (DCE MRI can longitudinally measure the transport coefficient Ktrans which reflects BBB permeability. Ktrans measurements however are not widely used in TBI research because it is generally considered to be noisy and possesses low spatial resolution. We improved spatiotemporal resolution and signal sensitivity of Ktrans MRI in rats by using a high-sensitivity surface transceiver coil. To overcome the signal drop off profile of the surface coil, a pre-scan module was used to map the flip angle (B1 field and magnetization (M0 distributions. A series of T1-weighted gradient echo images were acquired and fitted to the extended Kety model with reversible or irreversible leakage, and the best model was selected using F-statistics. We applied this method to study the rat brain one hour following controlled cortical impact (mild to moderate TBI, and observed clear depiction of the BBB damage around the impact regions, which matched that outlined by Evans Blue extravasation. Unlike the relatively uniform T2 contrast showing cerebral edema, Ktrans shows a pronounced heterogeneous spatial profile in and around the impact regions, displaying a nonlinear relationship with T2. This improved Ktrans MRI method is also compatible with the use of high-sensitivity surface coil and the high-contrast two-coil arterial spin-labeling method for cerebral blood flow measurement, enabling more comprehensive investigation of the pathophysiology in TBI.

  19. Glutamate Transporters in the Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Helms, Hans Christian Cederberg; Nielsen, Carsten Uhd; Waagepetersen, Helle Sønderby

    2017-01-01

    concentration of L-glutamate causes excitotoxicity. A tight control of the brain interstitial fluid L-glutamate levels is therefore imperative, in order to maintain optimal neurotransmission and to avoid such excitotoxicity. The blood-brain barrier, i.e., the endothelial lining of the brain capillaries...... cells. The mechanisms underlying transendothelial L-glutamate transport are however still not well understood. The present chapter summarizes the current knowledge on blood-brain barrier L-glutamate transporters and the suggested pathways for the brain-to-blood L-glutamate efflux....

  20. Optimization Model for the Design of Multi-layered Permeable Reactive Barriers

    Science.gov (United States)

    Połoński, Mieczysław; Pawluk, Katarzyna; Rybka, Iwona

    2017-10-01

    Permeable reactive barriers (PRBs) are employed as in situ groundwater remediation technology. The installation of PRBs is usually a major investment, where one of the biggest cost drivers are material costs. PRBs are barriers against contaminants moving under the natural gradient, however not against groundwater contaminants. The most common construction of a PRB is a single barrier, but in the case of contaminant mixtures a multi-layered construction, i.e. a combination of different reactive materials and removal processes, is required. The most important parameters for PRB design are dimensions. The barrier must be long enough to treat the entire width of the plume (dimension perpendicular to groundwater flow) and should extend to and be keyed into an impermeable layer. The problem is to determine the optimal thickness of a PRB, which should provide a residence time appropriate for reducing the concentration of contaminants to the desired effluent concentration. In PRBs, design is accomplished using numerical methods or simulators, which are useful to predict the scenarios and evaluate the resulting groundwater flow systems to specific site conditions. On the other hand, numerical methods are complicated and may have significant errors if the discretization is too coarse or is incorrectly aligned. This paper deals with a simple, conceptual model of a one-approach optimization method for multi-layered PRB design. Based on literature and laboratory test results (residence time, density and hydraulic coefficient), a selection of layers of reactive materials was determined. Considering the lowest cost of the reactive materials, the required thicknesses of activated carbon, zeolite and zero valent iron were calculated using two different algorithms. The simple model may be used for preliminary barrier design and cost calculations. Using the optimization model in a preliminary design stage, it is possible to reject the PRB concept and avoid losing time for the

  1. Local burn injury impairs epithelial permeability and antimicrobial peptide barrier function in distal unburned skin.

    Science.gov (United States)

    Plichta, Jennifer K; Droho, Steve; Curtis, Brenda J; Patel, Parita; Gamelli, Richard L; Radek, Katherine A

    2014-06-01

    Our objective was to characterize the mechanisms by which local burn injury compromises epithelial barrier function in burn margin, containing the elements necessary for healing of the burn site, and in distal unburned skin, which serves as potential donor tissue. Experimental mouse scald burn injury. University Research Laboratory. C57/Bl6 Male mice, 8-12 weeks old. To confirm that dehydration was not contributing to our observed barrier defects, in some experiments mice received 1 mL of saline fluid immediately after burn, while a subgroup received an additional 0.5 mL at 4 hours and 1 mL at 24 hours following burn. We then assessed skin pH and transepidermal water loss every 12 hours on the burn wounds for 72 hours postburn. Burn margin exhibited increased epidermal barrier permeability indicated by higher pH, greater transepidermal water loss, and reduced lipid synthesis enzyme expression and structural protein production up to 96 hours postburn. By contrast, antimicrobial peptide production and protease activity were elevated in burn margin. Skin extracts from burn margin did not exhibit changes in the ability to inhibit bacterial growth. However, distal unburned skin from burned mice also demonstrated an impaired response to barrier disruption, indicated by elevated transepidermal water loss and reduced lipid synthesis enzyme and structural protein expression up to 96 hours postburn. Furthermore, skin extracts from distal unburned skin exhibited greater protease activity and a reduced capacity to inhibit bacterial growth of several skin pathogens. Finally, we established that antimicrobial peptide levels were also altered in the lung and bladder, which are common sites of secondary infection in burn-injured patients. These findings reveal several undefined deficiencies in epithelial barrier function at the burn margin, potential donor skin sites, and organs susceptible to secondary infection. These functional and biochemical data provide novel insights into

  2. PET studies on P-glycoprotein function in the blood-brain barrier : How it affects uptake and binding of drugs within the CNS

    NARCIS (Netherlands)

    Elsinga, PH; Hendrikse, Nelis; Bart, J; Vaalburg, W; van Waarde, A

    2004-01-01

    Permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of therapeutic drugs. The BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are

  3. Alteration of blood-brain barrier integrity by retroviral infection.

    Directory of Open Access Journals (Sweden)

    Philippe V Afonso

    2008-11-01

    Full Text Available The blood-brain barrier (BBB, which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans, both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies.

  4. Overcoming the blood-brain barrier for delivering drugs into the brain by using adenosine receptor nanoagonist.

    Science.gov (United States)

    Gao, Xihui; Qian, Jun; Zheng, Shuyan; Changyi, Yinzhi; Zhang, Jianping; Ju, Shenghong; Zhu, Jianhua; Li, Cong

    2014-04-22

    The extremely low permeability of the blood-brain barrier (BBB) poses the greatest impediment in the treatment of central nervous system (CNS) diseases. Recent work indicated that BBB permeability can be up-regulated by activating A2A adenosine receptor (AR), which temporarily increases intercellular spaces between the brain capillary endothelial cells. However, due to transient circulation lifetime of adenosine-based agonists, their capability to enhance brain delivery of drugs, especially macromolecular drugs, is limited. In this work, a series of nanoagonists (NAs) were developed by labeling different copies of A2A AR activating ligands on dendrimers. In vitro transendothelial electrical resistance measurements demonstrated that the NAs increased permeability of the endothelial cell monolayer by compromising the tightness of tight junctions, the key structure that restricts the entry of blood-borne molecules into the brain. In vivo imaging studies indicated the remarkably up-regulated brain uptake of a macromolecular model drug (45 kDa) after intravenous injection of NAs. Autoradiographic imaging showed that the BBB opening time-window can be tuned in a range of 0.5-2.0 h by the NAs labeled with different numbers of AR-activating ligands. By choosing a suitable NA, it is possible to maximize brain drug delivery and minimize the uncontrollable BBB leakage by matching the BBB opening time-window with the pharmacokinetics of a therapeutic agent. The NA-mediated brain drug delivery strategy holds promise for the treatment of CNS diseases with improved therapeutic efficiency and reduced side-effects.

  5. Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors

    DEFF Research Database (Denmark)

    Larsson, H B; Stubgaard, M; Frederiksen, J L

    1990-01-01

    In this study quantitation of the degree of deficiency of the blood-brain barrier (BBB) in patients with multiple sclerosis or brain tumors, by using MRI, is shown to be possible. As a measure of permeability of the BBB to Gadolinium-DTPA (Gd-DTPA) the flux per unit of distribution volume per unit...... of brain mass was used. This quantity was found by introducing the longitudinal relaxation rate (R1) as a measure of concentration of Gd-DTPA in the brain tissue in the mathematical model for the transcapillary transport over the BBB. High accordance between the observed data points and the model was found...

  6. Hierarchical assembly of the eggshell and permeability barrier in C. elegans

    Science.gov (United States)

    Olson, Sara K.; Greenan, Garrett; Desai, Arshad; Müller-Reichert, Thomas

    2012-01-01

    In metazoans, fertilization triggers the assembly of an extracellular coat that constitutes the interface between the embryo and its environment. In nematodes, this coat is the eggshell, which provides mechanical rigidity, prevents polyspermy, and is impermeable to small molecules. Using immunoelectron microscopy, we found that the Caenorhabditis elegans eggshell was composed of an outer vitelline layer, a middle chitin layer, and an inner layer containing chondroitin proteoglycans. The switch between the chitin and proteoglycan layers was achieved by internalization of chitin synthase coincident with exocytosis of proteoglycan-containing cortical granules. Inner layer assembly did not make the zygote impermeable as previously proposed. Instead, correlative light and electron microscopy demonstrated that the permeability barrier was a distinct envelope that formed in a separate step that required fatty acid synthesis, the sugar-modifying enzyme PERM-1, and the acyl chain transfer enzyme DGTR-1. These findings delineate the hierarchy of eggshell assembly and define key molecular mechanisms at each step. PMID:22908315

  7. AN IN-SITU PERMEABLE REACTIVE BARRIER FOR THE TREATMENT OF HEXAVALENT CHROMIUM AND TRICHLOROETHYLENE IN GROUNDWATER: VOLUME 3 MULTICOMPONENT REACTIVE TRANSPORT MODELING

    Science.gov (United States)

    Reactive transport modeling has been conducted to describe the performance of the permeable reactive barrier at the Coast Guard Support Center near Elizabeth City, NC. The reactive barrier was installed to treat groundwater contaminated by hexavalent chromium and chlorinated org...

  8. [Blood-brain barrier transport of opioid analgesics].

    Science.gov (United States)

    Suzuki, Toyofumi

    2011-01-01

    Opioid analgesics exhibit cationic properties under physiological conditions, and the mechanism underlying permeation of the blood-brain barrier thus cannot be fully explained by simple diffusion alone. Various types of transporters that exhibit substrate specificity are localized on the blood-brain barrier, and play a role in transporting substances from circulating blood and from brain interstitial fluid. Progress is being made in explaining the mechanisms, functions, and physiological roles of polyspecific organic cation transporters, but little evidence has indicated that these previously identified organic cation transporters are involved in the transport of opioid analgesics across the blood-brain barrier. Consequently, clarifying the role of transporters in the distribution of opioid analgesics into the brain and determining their transport molecule will not only provide clues to effective drug delivery to the brain, but will also contribute to optimizing pain relief treatment, and by extension play a role in drug discovery for analgesics. Currently there are enthusiastic discussions in the literature regarding the existence of putative transporters involved in the transport of opioid analgesics across the blood-brain barrier. This review article introduces the results of our research as well as recent findings on the involvement of transporters in the blood-brain barrier transport of opioid analgesics such as morphine, morphine metabolites, oxycodone, fentanyl, codeine, and pentazocine.

  9. [Effect of infrasound on ultrastructure and permeability of rat's blood-retinal barrier].

    Science.gov (United States)

    Qiu, Ping; Zhang, Zuoming; Jiang, Yong; Gou, Qun; Wang, Bing; Gou, Lin; Chen, Jingzao

    2002-08-01

    To investigate the possible effect of infrasound on the ultra-structure and permeability of rat's blood-retinal barrier (BRB). Ultra-structural changes of BRB were observed through the injection of lanthanum nitrate (La), which was used as a tracer to demonstrate the breakdown of the BRB, into blood vessels. Fifteen mature male rats divided into 5 groups were exposed to infrasound at a 8 Hz frequency, 130 dB sound pressure level in a pressure chamber especially designed for the experiment for 0, 1, 7, 14, 21 days, respectively. Under the action of infrasound, along with the prolongation of exposure, the damage of BRB was severer and severer. On the 1st day, there was no significant change in La leakage. On the 7th day, La diffused in the interphotoreceptor space at nuclear level. On the 14th day, La granules could be seen in the space of nervous cells. Finally, on the 21st day, La was found between synapses, synapses and nerve cells, as well as between the nerve cells and supporting cells, then sometimes reached vitreous body. Under the electron microscope, there were no significant morphological changes, but changes related to metabolism, such as edematous mitochondria, dilated rough endoplasmic reticula, precipitation of glycogen grandules, widening of perinuclear space, etc. The results thus suggest that the exposure to infrasound cause the breakdown of rat's blood-retinal barrier and visual impairment.

  10. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier.

    Science.gov (United States)

    Biancardi, Vinicia Campana; Son, Sook Jin; Ahmadi, Sahra; Filosa, Jessica A; Stern, Javier E

    2014-03-01

    Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood-brain barrier (BBB) integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether BBB permeability within critical hypothalamic and brain stem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification after intravascularly injected fluorescent dyes and immunohistochemistry, we found increased BBB permeability, along with altered key BBB protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. BBB disruption, including increased permeability and downregulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, colocalizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased BBB permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation.

  11. LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS USING ZERO-VALENT IRON: GEOCHEMICAL AND MICROBIOLOGICAL EFFECTS

    Science.gov (United States)

    Geochemical and microbiological factors that control long-term performance of subsurface permeable reactive barriers were evaluated at the Elizabeth City, NC and the Denver Federal Center, CO sites. These ground water treatment systems use zero-valent iron filings (Peerless Meta...

  12. Transfection of brain capillary endothelial cells in primary culture with defined blood-brain barrier properties.

    Science.gov (United States)

    Burkhart, Annette; Thomsen, Louiza Bohn; Thomsen, Maj Schneider; Lichota, Jacek; Fazakas, Csilla; Krizbai, István; Moos, Torben

    2015-08-07

    Primary brain capillary endothelial cells (BCECs) are a promising tool to study the blood-brain barrier (BBB) in vitro, as they maintain many important characteristics of the BBB in vivo, especially when co-cultured with pericytes and/or astrocytes. A novel strategy for drug delivery to the brain is to transform BCECs into protein factories by genetic modifications leading to secretion of otherwise BBB impermeable proteins into the central nervous system. However, a huge challenge underlying this strategy is to enable transfection of non-mitotic BCECs, taking a non-viral approach. We therefore aimed to study transfection in primary, non-mitotic BCECs cultured with defined BBB properties without disrupting the cells' integrity. Primary cultures of BCECs, pericytes and astrocytes were generated from rat brains and used in three different in vitro BBB experimental arrangements, which were characterised based on a their expression of tight junction proteins and other BBB specific proteins, high trans-endothelial electrical resistance (TEER), and low passive permeability to radiolabeled mannitol. Recombinant gene expression and protein synthesis were examined in primary BCECs. The BCECs were transfected using a commercially available transfection agent Turbofect™ to express the red fluorescent protein HcRed1-C1. The BCECs were transfected at different time points to monitor transfection in relation to mitotic or non-mitotic cells, as indicated by fluorescence-activated cell sorting analysis after 5-and 6-carboxylfluorescein diacetate succinidyl ester incorporation. The cell cultures exhibited important BBB characteristics judged from their expression of BBB specific proteins, high TEER values, and low passive permeability. Among the three in vitro BBB models, co-culturing with BCECs and astrocytes was well suited for the transfection studies. Transfection was independent of cell division and with equal efficacy between the mitotic and non-mitotic BCECs. Importantly

  13. Retinoic Acid Induces Blood-Brain Barrier Development

    NARCIS (Netherlands)

    Mizee, M.R.; Wooldrik, D.; Lakeman, K.A.M.; van het Hof, B.; Drexhage, J.A.R.; Geerts, D.; Bugiani, M.; Aronica, E.; Mebius, R.E.; Prat, A.; de Vries, H.E.; Reijerkerk, A.

    2013-01-01

    The blood- brain barrier (BBB) is crucial in the maintenance of a controlled environment within the brain to safeguard optimal neuronal function. The endothelial cells (ECs) of theBBBpossess specific properties that restrict the entry of cells and metabolites into the CNS. The specialized BBB

  14. Retinoic acid induces blood-brain barrier development

    NARCIS (Netherlands)

    Mizee, Mark R.; Wooldrik, Desiree; Lakeman, Kim A. M.; van het Hof, Bert; Drexhage, Joost A. R.; Geerts, Dirk; Bugiani, Marianna; Aronica, Eleonora; Mebius, Reina E.; Prat, Alexandre; de Vries, Helga E.; Reijerkerk, Arie

    2013-01-01

    The blood-brain barrier (BBB) is crucial in the maintenance of a controlled environment within the brain to safeguard optimal neuronal function. The endothelial cells (ECs) of the BBB possess specific properties that restrict the entry of cells and metabolites into the CNS. The specialized BBB

  15. Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Salter Michael W

    2010-11-01

    Full Text Available Abstract Background The blood-brain barrier (BBB plays the crucial role of limiting exposure of the central nervous system (CNS to damaging molecules and cells. Dysfunction of the BBB is critical in a broad range of CNS disorders including neurodegeneration, inflammatory or traumatic injury to the CNS, and stroke. In peripheral tissues, the vascular-tissue permeability is normally greater than BBB permeability, but vascular leakage can be induced by efferent discharge activity in primary sensory neurons leading to plasma extravasation into the extravascular space. Whether discharge activity of sensory afferents entering the CNS may open the BBB or blood-spinal cord barrier (BSCB remains an open question. Results Here we show that peripheral nerve injury (PNI produced by either sciatic nerve constriction or transecting two of its main branches causes an increase in BSCB permeability, as assessed by using Evans Blue dye or horseradish peroxidase. The increase in BSCB permeability was not observed 6 hours after the PNI but was apparent 24 hours after the injury. The increase in BSCB permeability was transient, peaking about 24-48 hrs after PNI with BSCB integrity returning to normal levels by 7 days. The increase in BSCB permeability was prevented by administering the local anaesthetic lidocaine at the site of the nerve injury. BSCB permeability was also increased 24 hours after electrical stimulation of the sciatic nerve at intensity sufficient to activate C-fibers, but not when A-fibers only were activated. Likewise, BSCB permeability increased following application of capsaicin to the nerve. The increase in permeability caused by C-fiber stimulation or by PNI was not anatomically limited to the site of central termination of primary afferents from the sciatic nerve in the lumbar cord, but rather extended throughout the spinal cord and into the brain. Conclusions We have discovered that injury to a peripheral nerve and electrical stimulation of C

  16. Understanding Heterogeneity and Permeability of Brain Metastases in Murine Models of HER2-Positive Breast Cancer Through Magnetic Resonance Imaging: Implications for Detection and Therapy

    Directory of Open Access Journals (Sweden)

    Donna H. Murrell

    2015-06-01

    Full Text Available OBJECTIVES: Brain metastases due to breast cancer are increasing, and the prognosis is poor. Lack of effective therapy is attributed to heterogeneity of breast cancers and their resulting metastases, as well as impermeability of the blood–brain barrier (BBB, which hinders delivery of therapeutics to the brain. This work investigates three experimental models of HER2+ breast cancer brain metastasis to better understand the inherent heterogeneity of the disease. We use magnetic resonance imaging (MRI to quantify brain metastatic growth and explore its relationship with BBB permeability. DESIGN: Brain metastases due to breast cancer cells (SUM190-BR3, JIMT-1-BR3, or MDA-MB-231-BR-HER2 were imaged at 3 T using balanced steady-state free precession and contrast-enhanced T1-weighted spin echo sequences. The histology and immunohistochemistry corresponding to MRI were also analyzed. RESULTS: There were differences in metastatic tumor appearance by MRI, histology, and immunohistochemistry (Ki67, CD31, CD105 across the three models. The mean volume of an MDA-MB-231-BR-HER2 tumor was significantly larger compared to other models (F2,12 = 5.845, P < .05; interestingly, this model also had a significantly higher proportion of Gd-impermeable tumors (F2,12 = 22.18, P < .0001. Ki67 staining indicated that Gd-impermeable tumors had significantly more proliferative nuclei compared to Gd-permeable tumors (t[24] = 2.389, P < .05 in the MDA-MB-231-BR-HER2 model. CD31 and CD105 staining suggested no difference in new vasculature patterns between permeable and impermeable tumors in any model. CONCLUSION: Significant heterogeneity is present in these models of brain metastases from HER2+ breast cancer. Understanding this heterogeneity, especially as it relates to BBB permeability, is important for improvement in brain metastasis detection and treatment delivery.

  17. Morphine induces expression of platelet-derived growth factor in human brain microvascular endothelial cells: implication for vascular permeability.

    Directory of Open Access Journals (Sweden)

    Hongxiu Wen

    Full Text Available Despite the advent of antiretroviral therapy, complications of HIV-1 infection with concurrent drug abuse are an emerging problem. Morphine, often abused by HIV-infected patients, is known to accelerate neuroinflammation associated with HIV-1 infection. Detailed molecular mechanisms of morphine action however, remain poorly understood. Platelet-derived growth factor (PDGF has been implicated in a number of pathological conditions, primarily due to its potent mitogenic and permeability effects. Whether morphine exposure results in enhanced vascular permeability in brain endothelial cells, likely via induction of PDGF, remains to be established. In the present study, we demonstrated morphine-mediated induction of PDGF-BB in human brain microvascular endothelial cells, an effect that was abrogated by the opioid receptor antagonist-naltrexone. Pharmacological blockade (cell signaling and loss-of-function (Egr-1 approaches demonstrated the role of mitogen-activated protein kinases (MAPKs, PI3K/Akt and the downstream transcription factor Egr-1 respectively, in morphine-mediated induction of PDGF-BB. Functional significance of increased PDGF-BB manifested as increased breach of the endothelial barrier as evidenced by decreased expression of the tight junction protein ZO-1 in an in vitro model system. Understanding the regulation of PDGF expression may provide insights into the development of potential therapeutic targets for intervention of morphine-mediated neuroinflammation.

  18. Impact of mineral fouling on hydraulic behavior of permeable reactive barriers.

    Science.gov (United States)

    Lin, Li; Benson, Craig H; Lawson, Elizabeth M

    2005-01-01

    This paper describes reactive transport simulations conducted to assess the impact of mineral fouling on the hydraulic behavior of continuous-wall permeable reactive barriers (PRBs) employing granular zero-valent iron (ZVI) in carbonate-rich alluvial aquifers. The reactive transport model included a geochemical algorithm for simulating corrosion and mineral precipitation reactions that have been observed in ZVI PRBs. Results of simulations show that porosity and hydraulic conductivity of the ZVI decrease over time and that flows are redistributed throughout the PRB in response to fouling of the pore space. Under typical conditions, only subtle changes occur within the first 10 years (i.e., duration of the current field experience record with PRBs), and the most significant changes do not occur until the PRB has operated for at least 30 years. However, changes can occur sooner (or later) if the rate at which mineral-forming ions are delivered to the PRB is higher (or lower) than that expected under typical conditions (i.e., due to higher/lower flow rate or inflowing ground water that has higher/lower ionic strength). When the PRB is more permeable than the aquifer, the median Darcy flux in the PRB does not change appreciably over time because the aquifer controls the rate of flow through the PRB. However, seepage velocities in the PRB increase, and residence times decrease, due to porosity reductions caused by accumulation of minerals in the pore space. When fouling becomes extensive, bypassing and reductions in flow rate in the PRB occur.

  19. Routes for drug translocation across the blood-brain barrier

    DEFF Research Database (Denmark)

    Kristensen, Mie; Brodin, Birger

    2017-01-01

    A number of potent drugs for the treatment of brain diseases are available. However, in order for them to reach their target site of action, they must pass the blood-brain barrier (BBB). The capillary endothelium comprises the major barrier of the BBB and allows only passive permeation of some...... small lipophilic molecules. Brain delivery of the larger biopharmaceuticals, which today includes an increasing number of novel drug entities, is therefore restricted; both due to their molecular size and their hydrophilic nature. Thus, the development of novel drug entities intended for the treatment...... of brain diseases such as neurodegenerative diseases or brain cancers, require a delivery strategy for overcoming the BBB before reaching its final target within the brain. Peptide-based delivery vectors is an emerging tool as shuttles for drug delivery across the BBB and one may explore receptor...

  20. The complementary membranes forming the blood-brain barrier.

    Science.gov (United States)

    Hawkins, Richard A; Peterson, Darryl R; Viña, Juan R

    2002-09-01

    Brain capillary endothelial cells form the blood-brain barrier. They are connected by extensive tight junctions, and are polarized into luminal (blood-facing) and abluminal (brain-facing) plasma membrane domains. The polar distribution of transport proteins allows for active regulation of brain extracellular fluid. Experiments on isolated membrane vesicles from capillary endothelial cells of bovine brain demonstrated the polar arrangement of amino acid and glucose transporters, and the utility of such arrangements have been proposed. For instance, passive carriers for glutamine and glutamate have been found only in the luminal membrane of blood-brain barrier cells, while Na-dependent secondary active transporters are at the abluminal membrane. This organization could promote the net removal of nitrogen-rich amino acids from brain, and account for the low level of glutamate penetration into the central nervous system. Furthermore, the presence of a gamma-glutamyl cycle at the luminal membrane and Na-dependent amino acid transporters at the abluminal membrane may serve to modulate movement of amino acids from blood-to-brain. Passive carriers facilitate amino acid transport into brain. However, activation of the gamma-glutamyl cycle by increased plasma amino acids is expected to generate oxoproline within the blood-brain barrier. Oxoproline stimulates secondary active amino acid transporters (Systems A and B(o)+) at the abluminal membrane, thereby reducing net influx of amino acids to brain. Finally, passive glucose transporters are present in both the luminal and abluminal membranes of the blood-brain barrier. Interestingly, a high affinity Na-dependent glucose carrier has been described only in the abluminal membrane. This raises the question whether glucose entry may be regulated to some extent. Immunoblotting studies suggest more than one type of passive glucose transporter exist in the blood-brain barrier, each with an asymmetrical distribution. In conclusion, it

  1. Monitoring Performance of a Dual Wall Permeable Reactive Barrier for Treating Perchlorate and TCE

    Science.gov (United States)

    Dowman, C. E.; Hashimoto, Y.; Warner, S.; Bennett, P.; Gandhi, D.; Szerdy, F.; Neville, S.; Fennessy, C.; Scow, K. M.

    2008-12-01

    AMEC Geomatrix, through collaboration with Aerojet General Corporation and the University of California, Davis (UCD), has performed work leading to the installation of a dual wall permeable reactive barrier (PRB) system capable of treating perchlorate and chlorinated aliphatic hydrocarbon compounds (CAHs), including trichloroethylene (TCE), at Aerojet's Area 40 site in Sacramento, California. This unique system consisted of an upgradient zero-valent iron (ZVI) permeable reactive barrier (PRB) that is intended to not only degrade CAHs, but also, provide hydrogen generated from the ZVI corrosion process, to a downgradient bio-effective PRB (carbohydrate solution circulated through a gravel-packed trench) for destroying perchlorate. The subsurface was characterized during a site investigation, and numerous logistical and site-specific challenges of installation were addressed. The site-specific challenges included installation of a passive remediation system in a remote location with no access to electricity. The selected remediation system was keyed into the undulating bedrock 20 to 25 feet below the ground surface without the use of shoring. Under a collaborative effort, UCD provided initial bench testing. AMEC Geomatrix designed and installed the dual wall system consisting of two approximately parallel 50-foot long by 2-foot thick by 25-foot deep PRB segments which are separated by about 8 feet perpendicular to the approximate direction of groundwater flow. AMEC Geomatrix performed the installation of performance monitoring network, which consisted of 21 wells, and monitored these points for a 6-month period. Monitoring and sampling techniques were designed to measure water levels and water quality parameters in the subsurface during sampling events, to better assess the hydrologic and chemical processes. The monitoring results indicate that the upgradient ZVI PRB effectively treats groundwater with TCE concentrations approaching 60 mg/L, and in addition, may

  2. Confounding parameters in preclinical assessment of blood-brain barrier permeation: an overview with emphasis on species differences and effect of disease states.

    Science.gov (United States)

    Deo, Anand K; Theil, Frank-Peter; Nicolas, Jean-Marie

    2013-05-06

    Drug delivery across the brain-blood interfaces is a complex process involving physicochemical drug properties, transporters, enzymes, and barrier dysfunction in diseased conditions. Intact blood-brain barrier (BBB) limits the entry of potentially harmful compounds into the brain but may also reduce the CNS permeability of therapeutic agents. BBB permeability is typically assessed by measuring brain-to-plasma ratio in rodents (referred to as B/P ratio, BB, or Kp, often calculated as logBB), an approach that suffers significant limitations as discussed in the present review. Kp is not a permeability measurement but a partition coefficient mainly driven by the relative binding to plasma and brain tissue components including lipids, phospholipids, and proteins. Compounds with high Kp are often lipophilic with low free fraction available to mediate CNS activities. Efforts should be more concentrated on measuring pharmacologically relevant free drug concentrations at the target site. Using healthy rodents to predict brain penetration in patients might be biased due to species differences in BBB-related parameters such as transporter expression and functional activities. In addition, pathophysiological conditions such as aging, multiple sclerosis, and Alzheimer's and Parkinson's diseases have been described to affect BBB permeability, with barrier leakage and altered transporter activity. The impact of these species differences and disease states on drug delivery to the brain is largely overlooked. More data are needed to better understand their clinical implication in order to design more appropriate screening strategies and ultimately better mitigate the risk for failure in late stage development.

  3. Azo dyes and the blood-brain barrier: Robert Aird's novel concept in chronic neurological disease (1903-2000).

    Science.gov (United States)

    Bladin, Peter F

    2014-01-01

    The well-established medical involvement of derivatives of the azo dye industry lent credibility to the 1935 announcement by Stanley Cobb of the use of vital brilliant red dye as an anticonvulsant. Although in the fullness of time clinical experience would discard this concept, nevertheless it was to give rise to Robert Aird who posited that the mechanism of action of this dye was due to its ability to decrease the permeability of the blood-brain barrier. In a very prolonged exploration of this concept, Aird concluded that blood-brain barrier permeability underlay the causation of a long list of chronic neurological conditions--a concept that was eventually abandoned. This article examines the details and the effects of this concept and its impact upon neurology. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Targeted liposomes for drug delivery across the blood-brain barrier

    NARCIS (Netherlands)

    van Rooy, I.|info:eu-repo/dai/nl/304823074

    2011-01-01

    Our brain is protected by the blood-brain barrier (BBB). This barrier is formed by specialized endothelial cells of the brain vasculature and prevents toxic substances from entering the brain. The downside of this barrier is that many drugs that have been developed to cure brain diseases cannot

  5. Permeable Reactive Barriers Designed To Mitigate Eutrophication Alter Bacterial Community Composition and Aquifer Redox Conditions

    Science.gov (United States)

    Hiller, Kenly A.; Foreman, Kenneth H.; Weisman, David

    2015-01-01

    Permeable reactive barriers (PRBs) consist of a labile carbon source that is positioned to intercept nitrate-laden groundwater to prevent eutrophication. Decomposition of carbon in the PRB drives groundwater anoxic, fostering microbial denitrification. Such PRBs are an ideal habitat to examine microbial community structure under high-nitrate, carbon-replete conditions in coastal aquifers. We examined a PRB installed at the Waquoit Bay National Estuarine Research Reserve in Falmouth, MA. Groundwater within and below the PRB was depleted in oxygen compared to groundwater at sites upgradient and at adjacent reference sites. Nitrate concentrations declined from a high of 25 μM upgradient and adjacent to the barrier to <0.1 μM within the PRB. We analyzed the total and active bacterial communities filtered from groundwater flowing through the PRB using amplicons of 16S rRNA and of the 16S rRNA genes. Analysis of the 16S rRNA genes collected from the PRB showed that the total bacterial community had high relative abundances of bacteria thought to have alternative metabolisms, such as fermentation, including candidate phyla OD1, OP3, TM7, and GN02. In contrast, the active bacteria had lower abundances of many of these bacteria, suggesting that the bacterial taxa that differentiate the PRB groundwater community were not actively growing. Among the environmental variables analyzed, dissolved oxygen concentration explained the largest proportion of total community structure. There was, however, no significant correlation between measured environmental parameters and the active microbial community, suggesting that controls on the active portion may differ from the community as a whole. PMID:26231655

  6. A claudin-9-based ion permeability barrier is essential for hearing.

    Directory of Open Access Journals (Sweden)

    Yoko Nakano

    2009-08-01

    Full Text Available Hereditary hearing loss is one of the most common birth defects, yet the majority of genes required for audition is thought to remain unidentified. Ethylnitrosourea (ENU-mutagenesis has been a valuable approach for generating new animal models of deafness and discovering previously unrecognized gene functions. Here we report on the characterization of a new ENU-induced mouse mutant (nmf329 that exhibits recessively inherited deafness. We found a widespread loss of sensory hair cells in the hearing organs of nmf329 mice after the second week of life. Positional cloning revealed that the nmf329 strain carries a missense mutation in the claudin-9 gene, which encodes a tight junction protein with unknown biological function. In an epithelial cell line, heterologous expression of wild-type claudin-9 reduced the paracellular permeability to Na+ and K+, and the nmf329 mutation eliminated this ion barrier function without affecting the plasma membrane localization of claudin-9. In the nmf329 mouse line, the perilymphatic K+ concentration was found to be elevated, suggesting that the cochlear tight junctions were dysfunctional. Furthermore, the hair-cell loss in the claudin-9-defective cochlea was rescued in vitro when the explanted hearing organs were cultured in a low-K+ milieu and in vivo when the endocochlear K+-driving force was diminished by deletion of the pou3f4 gene. Overall, our data indicate that claudin-9 is required for the preservation of sensory cells in the hearing organ because claudin-9-defective tight junctions fail to shield the basolateral side of hair cells from the K+-rich endolymph. In the tight-junction complexes of hair cells, claudin-9 is localized specifically to a subdomain that is underneath more apical tight-junction strands formed by other claudins. Thus, the analysis of claudin-9 mutant mice suggests that even the deeper (subapical tight-junction strands have biologically important ion barrier function.

  7. The blood-brain barrier in systemic lupus erythematosus.

    Science.gov (United States)

    Abbott, N J; Mendonça, L L F; Dolman, D E M

    2003-01-01

    Central nervous system (CNS) involvement may occur in 20-70% of systemic lupus erythematosus (SLE) patients where neurological symptoms are overt; this is termed neuropsychiatric lupus or NPSLE. This review summarizes evidence that damage to the brain endothelium forming the blood-brain barrier (BBB) is a contributory factor in NPSLE. The normal CNS is protected by blood-tissue barriers at three sites, the brain endothelium (BBB), the choroid plexus epithelium (blood-CSF barrier) and the arachnoid epithelium. The tight junctions of the barrier layers severely restrict entry of plasma constituents including proteins, so that the CSF and brain interstitial fluid contain low levels of protein. Methods for diagnosing BBB damage include imaging (CT, MRI) using contrast agents, and analysing protein content and profiles of CSF Changes in the albumin quotient Qalbumin show evidence for barrier damage, while changes in the immunoglobulin (Ig) index can indicate intrathecal antibody production. However, BBB damage may be transient, and hence undetected or underestimated. Few mechanistic studies exist, but the two main candidate mechanisms for BBB damage are microthrombi in cerebral vessels leading to ischaemia, and immune-mediated attack and activation of the endothelium leading to local cytokine production. Both can result in barrier breakdown. Neurological syndromes could then be secondary to damage to the BBB. The implications for treatment of NPSLE are discussed.

  8. Evaluation of five strategies to limit the impact of fouling in permeable reactive barriers.

    Science.gov (United States)

    Li, Lin; Benson, Craig H

    2010-09-15

    Ground water flow and geochemical reactive transport models were used to assess the effectiveness of five strategies used to limit fouling and to enhance the long-term hydraulic behavior of continuous-wall permeable reactive barriers (PRBs) employing granular zero valent iron (ZVI). The flow model accounted for geological heterogeneity and the reactive transport model included a geochemical algorithm for simulating iron corrosion and mineral precipitation reactions that have been observed in ZVI PRBs. The five strategies that were evaluated are pea gravel equalization zones, a sacrificial pre-treatment zone, pH adjustment, large ZVI particles, and mechanical treatment. Results of simulations show that installation of pea gravel equalization zones results in flow equalization and a more uniform distribution of residence times within the PRB. Residence times within the PRB are less affected by mineral precipitation when a pre-treatment zone is employed. pH adjustment limits the total amount of hydroxide ions in ground water to reduce porosity reduction and to retain larger residence times. Larger ZVI particles reduce porosity reduction as a result of the smaller iron surface area for iron corrosion, and retain longer residence time. Mechanical treatment redistributes the porosity uniformly throughout the PRB over time, which is effective in maintaining residence time. Copyright 2010 Elsevier B.V. All rights reserved.

  9. Investigating dominant processes in ZVI permeable reactive barriers using reactive transport modeling.

    Science.gov (United States)

    Weber, Anne; Ruhl, Aki S; Amos, Richard T

    2013-08-01

    The reactive and hydraulic efficacy of zero valent iron permeable reactive barriers (ZVI PRBs) is strongly affected by geochemical composition of the groundwater treated. An enhanced version of the geochemical simulation code MIN3P was applied to simulate dominating processes in chlorinated hydrocarbons (CHCs) treating ZVI PRBs including geochemical dependency of ZVI reactivity, gas phase formation and a basic formulation of degassing. Results of target oriented column experiments with distinct chemical conditions (carbonate, calcium, sulfate, CHCs) were simulated to parameterize the model. The simulations demonstrate the initial enhancement of anaerobic iron corrosion due to carbonate and long term inhibition by precipitates (chukanovite, siderite, iron sulfide). Calcium was shown to enhance long term corrosion due to competition for carbonate between siderite, chukanovite, and aragonite, with less inhibition of iron corrosion by the needle like aragonite crystals. Application of the parameterized model to a field site (Bernau, Germany) demonstrated that temporarily enhanced groundwater carbonate concentrations caused an increase in gas phase formation due to the acceleration of anaerobic iron corrosion. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. Solid phase studies and geochemical modelling of low-cost permeable reactive barriers.

    Science.gov (United States)

    Bartzas, Georgios; Komnitsas, Kostas

    2010-11-15

    A continuous column experiment was carried out under dynamic flow conditions in order to study the efficiency of low-cost permeable reactive barriers (PRBs) to remove several inorganic contaminants from acidic solutions. A 50:50 w/w waste iron/sand mixture was used as candidate reactive media in order to activate precipitation and promote sorption and reduction-oxidation mechanisms. Solid phase studies of the exhausted reactive products after column shutdown, using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD), confirmed that the principal Fe corrosion products identified in the reactive zone are amorphous iron (hydr)oxides (maghemite/magnetite and goethite), intermediate products (sulfate green rust), and amorphous metal sulfides such as amFeS and/or mackinawite. Geochemical modelling of the metal removal processes, including interactions between reactive media, heavy metal ions and sulfates, and interpretation of the ionic profiles was also carried out by using the speciation/mass transfer computer code PHREEQC-2 and the WATEQ4F database. Mineralogical characterization studies as well as geochemical modelling calculations also indicate that the effect of sulfate and silica sand on the efficiency of the reactive zone should be considered carefully during design and operation of low-cost field PRBs. Copyright © 2010 Elsevier B.V. All rights reserved.

  11. Uranium precipitation in a permeable reactive barrier by progressive irreversible dissolution of zerovalent iron.

    Science.gov (United States)

    Morrison, S J; Metzler, D R; Carpenter, C E

    2001-01-15

    A permeable reactive barrier (PRB) containing zerovalent iron [Fe(O)] was installed at a former uranium milling site in Monticello, UT. A large-scale column experiment was conducted at the site to test the feasibility of Fe(O) to treat U prior to installing the PRB. Effluents from the field column experiment had pH values near 7.34, moderate decreases in C(IV) and Ca concentrations, and an elevated Fe concentration (27.1 mg/L). In contrast, groundwater exiting the PRB had a pH value of 9.82, decreases in C(IV) and Ca concentrations, and a low concentration of Fe (0.17 mg/L). A geochemical model was used to explain the chemical changes that occurred in both the field column experiment and the PRB. The model simulated the systems by the progressive irreversible dissolution of Fe(O). Modeling results indicated that a longer residence time in the PRB compared with the shorter residence time in the column contributed to the disparate effluent qualities. Prior to modeling, a controlled laboratory column experiment was conducted to help evaluate the dominant chemical mechanisms by which Fe(O) removes U from aqueous solutions. Results of the laboratory column experiment indicated that only a small amount of U could be adsorbed to ferric minerals, and, therefore, this mechanism was not considered in the model.

  12. Assessment of a Hydroxyapatite Permeable Reactive Barrier to Remediate Uranium at the Old Rifle Site Colorado.

    Energy Technology Data Exchange (ETDEWEB)

    Moore, Robert C.; Szecsody, James (PNNL); Rigali, Mark J.; Vermuel, Vince (PNNL); Leullen, Jon (AECOM)

    2016-02-01

    We have performed an initial evaluation and testing program to assess the effectiveness of a hydroxyapatite (Ca10(PO4)6(OH)2) permeable reactive barrier and source area treatment to decrease uranium mobility at the Department of Energy (DOE) former Old Rifle uranium mill processing site in Rifle, western Colorado. Uranium ore was processed at the site from the 1940s to the 1970s. The mill facilities at the site as well as the uranium mill tailings previously stored there have all been removed. Groundwater in the alluvial aquifer beneath the site still contains elevated concentrations of uranium, and is currently used for field tests to study uranium behavior in groundwater and investigate potential uranium remediation technologies. The technology investigated in this work is based on in situ formation of apatite in sediment to create a subsurface apatite PRB and also for source area treatment. The process is based on injecting a solution containing calcium citrate and sodium into the subsurface for constructing the PRB within the uranium plume. As the indigenous sediment micro-organisms biodegrade the injected citrate, the calcium is released and reacts with the phosphate to form hydroxyapatite (precipitate). This paper reports on proof-of-principle column tests with Old Rifle sediment and synthetic groundwater.

  13. Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2.

    Directory of Open Access Journals (Sweden)

    Julie Dwyer

    Full Text Available Glioblastoma constitutes the most aggressive and deadly of brain tumors. As yet, both conventional and molecular-based therapies have met with limited success in treatment of this cancer. Among other explanations, the heterogeneity of glioblastoma and the associated microenvironment contribute to its development, as well as resistance and recurrence in response to treatments. Increased vascularity suggests that tumor angiogenesis plays an important role in glioblastoma progression. However, the molecular crosstalk between endothelial and glioblastoma cells requires further investigation. To examine the effects of glioblastoma-derived signals on endothelial homeostasis, glioblastoma cell secretions were collected and used to treat brain endothelial cells. Here, we present evidence that the glioblastoma secretome provides pro-angiogenic signals sufficient to disrupt VE-cadherin-mediated cell-cell junctions and promote endothelial permeability in brain microvascular endothelial cells. An unbiased angiogenesis-specific antibody array screen identified the chemokine, interleukin-8, which was further demonstrated to function as a key factor involved in glioblastoma-induced permeability, mediated through its receptor CXCR2 on brain endothelia. This underappreciated interface between glioblastoma cells and associated endothelium may inspire the development of novel therapeutic strategies to induce tumor regression by preventing vascular permeability and inhibiting angiogenesis.

  14. Design, installation, and performance of a multi-layered permeable reactive barrier, Los Alamos National Laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Kaszuba, J. P. (John P.); Longmire, P. A. (Patrick A.); Strietelmeier, E. A. (Elizabeth A.); Taylor, T. P. (Tammy P.); Den-Baars, P. S. (Peter S.)

    2004-01-01

    A multi-layered permeable reactive barrier (PRB) has been installed in Mortandad Canyon, on the Pajarito Plateau in the north-central part of LANL, to demonstrate in-situ treatment of a suite of contaminants with dissimilar geochemical properties. The PRB will also mitigate possible vulnerabilities from downgradient contaminant movement within alluvial and deeper perched groundwater. Mortandad Canyon was selected as the location for this demonstration project because the flow of alluvial groundwater is constrained by the geology of the canyon, a large network of monitoring wells already were installed along the canyon reach, and the hydrochemistry and contaminant history of the canyon is well-documented. The PRB uses a funnel-and-gate system with a series of four reactive media cells to immobilize or destroy contaminants present in alluvial groundwater, including strontium-90, plutonium-238,239,240, americium-241, perchlorate, and nitrate. The four cells, ordered by sequence of contact with the groundwater, consist of gravel-sized scoria (for colloid removal); phosphate rock containing apatite (for metals and radionuclides); pecan shells and cotton seed admixed with gravel (bio-barrier, to deplete dissolved oxygen and destroy potential RCRA organic compounds, nitrate and perchlorate); and limestone (pH buffering and anion adsorption). Design elements of the PRB are based on laboratory-scale treatability studies and on a field investigation of hydrologic, geochemical, and geotechnical parameters. The PRB was designed with the following criteria: 1-day residence time within the biobarrier, 10-year lifetime, minimization of surface water infiltration and erosion, optimization of hydraulic capture, and minimization of excavated material requiring disposal. Each layer has been equipped with monitoring wells or ports to allow sampling of groundwater and reactive media, and monitor wells are located immediately adjacent to the up- and down-gradient perimeter of the

  15. Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease

    Science.gov (United States)

    Cabezas, Ricardo; Ávila, Marcos; Gonzalez, Janneth; El-Bachá, Ramon Santos; Báez, Eliana; García-Segura, Luis Miguel; Jurado Coronel, Juan Camilo; Capani, Francisco; Cardona-Gomez, Gloria Patricia; Barreto, George E.

    2014-01-01

    The blood–brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson’s Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson’s disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions. PMID:25136294

  16. Astrocytic modulation of Blood Brain Barrier: Perspectives on Parkinson´s Disease

    Directory of Open Access Journals (Sweden)

    Ricardo eCabezas

    2014-08-01

    Full Text Available TThe blood–brain barrier (BBB is a tightly regulated interface in the Central Nervous System that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells, pericytes and astrocytes that create a neurovascular unit with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson´s Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the endothelial cells and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson´s disease and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions.

  17. Blood-brain barrier dysfunction after primary blast injury in vitro.

    Science.gov (United States)

    Hue, Christopher D; Cao, Siqi; Haider, Syed F; Vo, Kiet V; Effgen, Gwen B; Vogel, Edward; Panzer, Matthew B; Bass, Cameron R Dale; Meaney, David F; Morrison, Barclay

    2013-10-01

    The incidence of blast-induced traumatic brain injury (bTBI) has increased substantially in recent military conflicts. However, the consequences of bTBI on the blood-brain barrier (BBB), a specialized cerebrovascular structure essential for brain homeostasis, remain unknown. In this study, we utilized a shock tube driven by compressed gas to generate operationally relevant, ideal pressure profiles consistent with improvised explosive devices (IEDs). By multiple measures, the barrier function of an in vitro BBB model was disrupted following exposure to a range of controlled blast loading conditions. Trans-endothelial electrical resistance (TEER) decreased acutely in a dose-dependent manner that was most strongly correlated with impulse, as opposed to peak overpressure or duration. Significantly increased hydraulic conductivity and solute permeability post-injury further confirmed acute alterations in barrier function. Compromised ZO-1 immunostaining identified a structural basis for BBB breakdown. After blast exposure, TEER remained significantly depressed 2 days post-injury, followed by spontaneous recovery to pre-injury control levels at day 3. This study is the first to report immediate disruption of an in vitro BBB model following primary blast exposure, which may be important for the development of novel helmet designs to help mitigate the effects of blast on the BBB.

  18. Candesartan improves ischemia-induced impairment of the blood-brain barrier in vitro.

    Science.gov (United States)

    So, Gohei; Nakagawa, Shinsuke; Morofuji, Yoichi; Hiu, Takeshi; Hayashi, Kentaro; Tanaka, Kunihiko; Suyama, Kazuhiko; Deli, Maria A; Nagata, Izumi; Matsuo, Takayuki; Niwa, Masami

    2015-05-01

    Candesartan has been reported to have a protective effect on cerebral ischemia in vivo and in human ischemic stroke. We studied the direct effects of candesartan on blood-brain barrier (BBB) function with our in vitro monolayer model generated using rat brain capillary endothelial cells (RBECs). The in vitro BBB model was subjected to normoxia or 6-h oxygen glucose deprivation (OGD)/24-h reoxygenation, with or without candesartan. 6-h OGD/24-h reoxygenation decreased transendothelial electrical resistance and increased the endothelial permeability for sodium fluorescein in RBEC monolayers. Candesartan (10 nM) improved RBEC barrier dysfunction induced by 6-h OGD/24-h reoxygenation. Immunostaining and immunoblotting analysis indicated that the effect of candesartan on barrier function under 6-h OGD/24-h reoxygenation was not related to the expression levels of tight junction proteins. However, candesartan affected RBEC morphological changes induced by 6-h OGD/24-h reoxygenation. We analyzed oxidative stress and cell viability using chemical reagents. Candesartan improved cell viability following 6-h OGD/24-h reoxygenation, whereas candesartan had no effect on oxidative stress. These results show that candesartan directly improves cell function and viability of brain capillary endothelial cells under OGD/reoxygenation, suggesting that the protective effects of candesartan on ischemic stroke are related to protection of the BBB.

  19. The inner CSF-brain barrier

    DEFF Research Database (Denmark)

    Whish, Sophie; Dziegielewska, Katarzyna M; Møllgård, Kjeld

    2015-01-01

    In the adult the interface between the cerebrospinal fluid and the brain is lined by the ependymal cells, which are joined by gap junctions. These intercellular connections do not provide a diffusional restrain between the two compartments. However, during development this interface, initially...... of plasma proteins (70 kDa) diffuse freely. Transcriptomic analysis of junctional proteins present in the cerebrospinal fluid-brain interface showed expression of adherens junctional proteins, actins, cadherins and catenins changing in a development manner consistent with the observed changes...... outlining the inner CSF-brain interface from E16; most of these markers were not present in the adult ependyma. Claudin-5 was present in the apical-most part of radial glial cells and in endothelial cells in embryos, but only in endothelial cells including plexus endothelial cells in adults. Claudin-11...

  20. Reactive Transport Modeling for Mobilization of Arsenic in a Sediment Downgradient from an Iron Permeable Reactive Barrier

    OpenAIRE

    Sung-Wook Jeen

    2017-01-01

    Arsenic (As) can be naturally present in the native aquifer materials and can be released to groundwater through reduction dissolution of iron oxides containing As. While granular iron permeable reactive barriers (PRBs) can be effective for the treatment of arsenic in groundwater, the mobilization of arsenic in the sediment downgradient of the PRB might be an issue due to the reduced geochemical conditions generated by reactions in the PRB. The release of arsenic in the sediment downgradient ...

  1. Transfer of opiorphin through a blood-brain barrier culture model.

    Science.gov (United States)

    Bocsik, Alexandra; Darula, Zsuzsanna; Tóth, Géza; Deli, Mária A; Wollemann, Mária

    2015-08-01

    Opioid peptides are potent analgesics with therapeutic potential in the treatment of acute and chronic pain. Their efficacy is limited by peptidases (enkephalinases). Opiorphin pentapeptide (QRFSR) is the first characterized human endogenous inhibitor of enkephalinases. The peptide is able to increase the binding and affinity of endogenous opiates to mu opioid receptors; thus, the mechanism of opiorphin may provide a new therapeutic approach in pain management. The analgesic effect of opiorphin was proven in several earlier published in vitro and in vivo studies. Our aim was to test the transfer of opiorphin through a blood-brain barrier model for the first time. The flux of opiorphin was tested on a blood-brain barrier culture model consisting of rat brain endothelial, glial and pericyte cells. Brain endothelial cells in this triple co-culture model form tight monolayers characterized by transendothelial electrical resistance measurement. Relative quantity of the peptide was estimated by mass spectrometry. The transfer of opiorphin through the blood-brain barrier model was estimated to be ∼3%, whereas the permeability coefficient was 0.53 ± 1.36 × 10(-6) cm/s (n = 4). We also observed rapid conversion of N-terminal glutamine into pyroglutamic acid during the transfer experiments. Our results indicate that opiorphin crosses cultured brain endothelial cells in the absence of serum factors in a significant amount. This is in agreement with previous in vivo data showing potentiation of enkephalin-mediated antinociception. We suggest that opiorphin may have a potential as a centrally acting novel drug to treat pain. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

  2. Developmental changes of l-arginine transport at the blood-brain barrier in rats.

    Science.gov (United States)

    Tachikawa, Masanori; Hirose, Shirou; Akanuma, Shin-Ichi; Matsuyama, Ryo; Hosoya, Ken-Ichi

    2017-12-14

    l-Arginine is required for regulating synapse formation/patterning and angiogenesis in the developing brain. We hypothesized that this requirement would be met by increased transporter-mediated supply across the blood-brain barrier (BBB). Thus, the purpose of this work was to test the idea that elevation of blood-to-brain l-arginine transport across the BBB in the postnatal period coincides with up-regulation of cationic acid transporter 1 (CAT1) expression in developing brain capillaries. We found that the apparent brain-to-plasma concentration ratio (Kp, app) of l-arginine after intravenous administration during the first and second postnatal weeks was 2-fold greater than that at the adult stage. Kp, app of l-serine was also increased at the first postnatal week. In contrast, Kp, app of d-mannitol, a passively BBB-permeable molecule, did not change, indicating that increased transport of l-arginine and l-serine is not due to BBB immaturity. Double immunohistochemical staining of CAT1 and a marker protein, glucose transporter 1, revealed that CAT1 was localized on both luminal and abluminal membranes of brain capillary endothelial cells during the developmental and adult stages. A dramatic increase in CAT1 expression in the brain was seen at postnatal day 7 (P7) and day 14 (P14) and the expression subsequently decreased as the brain matured. In accordance with this, intense immunostaining of CAT1 was observed in brain capillaries at P7 and P14. These findings strongly support our hypothesis and suggest that the supply of blood-born l-arginine to the brain via CAT1 at the BBB plays a key role in meeting the elevated demand for l-arginine in postnatal brain. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Revisiting blood-brain barrier: a chromatographic approach

    OpenAIRE

    Subirats i Vila, Xavier; Muñoz-Pascual, Laura; Abraham, Michael H.; Rosés Pascual, Martí

    2017-01-01

    Drugs designed to reach a pharmacological CNS target must be effectively transported across the blood-brain barrier (BBB), a thin monolayer of endothelial cells tightly attached together between the blood and the brain parenchyma. Because of the lipidic nature of the BBB, several physicochemical partition models have been studied as surrogates for the passive permeation of potential drug candidates across the BBB (octanol-water, alkane-water, PAMPA...). In the last years, biopartition chromat...

  4. A mathematical approach for assessing the transport of large neutral amino acids across the blood-brain barrier in man.

    Science.gov (United States)

    Dahl, Rasmus Holmboe; Berg, Ronan M G

    2015-01-01

    Changes in the large neutral amino acid (LNAA) transport across the blood-brain barrier (BBB) is thought to contribute to brain dysfunction in a number of clinical conditions, including phenylketonuria, acute liver failure, and sepsis. Here, we present a novel approach for estimating BBB permeability and the LNAA concentrations in brain extracellular fluid, by demonstrating that they can be mathematically derived on the basis of kinetic constants of the BBB available from the literature, if cerebral blood flow and the arterial and jugular venous LNAA concentrations are known. While it is well known that the permeability surface area product of the BBB to a LNAA from blood to brain (PS1) can be calculated from the arterial LNAA concentrations and kinetic constants of the BBB, we demonstrate that the permeability surface area product from brain to blood (PS2) can be calculated by deriving the substrate activity of the saturable transporter from the kinetic constants and arterial and jugular venous LNAA concentrations, and that the concentration of the LNAA in brain extracellular fluid can then be determined. This approach is methodically simple, and may be useful for assessing the transcerebral exchange kinetics of LNAAs in future human-experimental and clinical studies.

  5. Iron uptake and transport at the blood-brain barrier

    DEFF Research Database (Denmark)

    Larsen, Annette Burkhart; Thomsen, Louiza Bohn; Moos, Torben

    The mechanism by which iron is transported across the blood-brain barrier (BBB) remains controversial, and in this study we aimed to further clarify mechanisms by which iron is transported into the brain. We analyzed and compared the mRNA and protein expression of a variety of proteins involved...... in the transport of iron (transferrin receptor, divalent metal transporter I (DMT1), steap 2, steap 3, ceruloplasmin, hephaestin and ferroportin) in both primary rat brain capillary endothelial cells (BCEC) and immortalized rat brain capillary endothelial cell line (RBE4) grown in co-culture with defined polarity....... The mRNA expression of the iron-related molecules was also investigated in isolated brain capillaries from iron deficiency, iron reversible and normal rats. We also performed iron transport studies to analyze the routes by which iron is transported through the brain capillary endothelial cells: i) We...

  6. Modeling porosity reductions caused by mineral fouling in continuous-wall permeable reactive barriers.

    Science.gov (United States)

    Li, Lin; Benson, Craig H; Lawson, Elizabeth M

    2006-02-01

    A study was conducted to assess key factors to include when modeling porosity reductions caused by mineral fouling in permeable reactive barriers (PRBs) containing granular zero valent iron. The public domain codes MODFLOW and RT3D were used and a geochemical algorithm was developed for RT3D to simulate geochemical reactions occurring in PRBs. Results of simulations conducted with the model show that the largest porosity reductions occur between the entrance and mid-plane of the PRB as a result of precipitation of carbonate minerals and that smaller porosity reductions occur between the mid-plane and exit face due to precipitation of ferrous hydroxide. These findings are consistent with field and laboratory observations, as well as modeling predictions made by others. Parametric studies were conducted to identify the most important variables to include in a model evaluating porosity reduction. These studies showed that three minerals (CaCO3, FeCO3, and Fe(OH)2 (am)) account for more than 99% of the porosity reductions that were predicted. The porosity reduction is sensitive to influent concentrations of HCO3-, Ca2+, CO3(2-), and dissolved oxygen, the anaerobic iron corrosion rate, and the rates of CaCO3 and FeCO3 formation. The predictions also show that porosity reductions in PRBs can be spatially variable and mineral forming ions penetrate deeper into the PRB as a result of flow heterogeneities, which reflects the balance between the rate of mass transport and geochemical reaction rates. Level of aquifer heterogeneity and the contrast in hydraulic conductivity between the aquifer and PRB are the most important hydraulic variables affecting porosity reduction. Spatial continuity of aquifer hydraulic conductivity is less significant.

  7. Delivery of siRNA silencing P-gp in peptide-functionalized nanoparticles causes efflux modulation at the blood-brain barrier

    DEFF Research Database (Denmark)

    Gomes, Maria João; Kennedy, Patrick J; Martins, Susana

    2017-01-01

    AIM: Explore the use of transferrin-receptor peptide-functionalized nanoparticles (NPs) targeting blood-brain barrier (BBB) as siRNA carriers to silence P-glycoprotein (P-gp). MATERIALS & METHODS: Permeability experiments were assessed through a developed BBB cell-based model; P-gp mRNA expression...... was evaluated in vitro; rhodamine 123 permeability was assessed after cell monolayer treatment with siRNA NPs. RESULTS: Beyond their ability to improve siRNA permeability through the BBB by twofold, 96-h post-transfection, functionalized polymeric NPs successfully reduced P-gp mRNA expression up to 52...

  8. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases.

    Science.gov (United States)

    Gabathuler, Reinhard

    2010-01-01

    The central nervous system is protected by barriers which control the entry of compounds into the brain, thereby regulating brain homeostasis. The blood-brain barrier, formed by the endothelial cells of the brain capillaries, restricts access to brain cells of blood-borne compounds and facilitates nutrients essential for normal metabolism to reach brain cells. This very tight regulation of the brain homeostasis results in the inability of some small and large therapeutic compounds to cross the blood-brain barrier (BBB). Therefore, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. In this review, we will address the different approaches used to increase the transport of therapeutics from blood into the brain parenchyma. We will mainly concentrate on the physiologic approach which takes advantage of specific receptors already expressed on the capillary endothelial cells forming the BBB and necessary for the survival of brain cells. Among all the approaches used for increasing brain delivery of therapeutics, the most accepted method is the use of the physiological approach which takes advantage of the transcytosis capacity of specific receptors expressed at the BBB. The low density lipoprotein receptor related protein (LRP) is the most adapted for such use with the engineered peptide compound (EPiC) platform incorporating the Angiopep peptide in new therapeutics the most advanced with promising data in the clinic.

  9. Reversible Opening of the Blood-Brain Barrier by Anti-Bacterial Antibodies

    Science.gov (United States)

    Tuomanen, Elaine I.; Prasad, Sudha M.; George, Jonathan S.; Hoepelman, Andy I. M.; Ibsen, Per; Heron, Iver; Starzyk, Ruth M.

    1993-08-01

    The leukocyte adhesion molecule CR3 (CD11b/CD18, Mac-1) promotes leukocyte transmigration into tissues by engaging an unknown cognate ligand on the surface of vascular endothelial cells. Filamentous hemagglutinin (FHA), an adhesin of the bacterium Bordetella pertussis, binds to CR3. We hypothesized that FHA mimics the native ligand for the CR3 integrin on endothelial cells and predicted that anti-FHA antibodies should bind to endothelial cells, interfere with leukocyte recruitment, and induce endothelial permeability. Anti-FHA monoclonal antibodies bound to cerebral microvessels in sections from human brain and upon intravenous injection into rabbits. Antibody binding correlated with the ability to recognize two polypeptides in extracts of human cerebral vessels that were also bound by CD18. In vivo, antibody binding not only interfered with transmigration of leukocytes into cerebrospinal fluid but also induced a dose-dependent reversible increase in blood-brain barrier permeability sufficient to improve delivery of intravenously administered therapeutic agents to brain parenchyma.

  10. A Novel Dynamic Neonatal Blood-Brain Barrier on a Chip.

    Directory of Open Access Journals (Sweden)

    Sudhir P Deosarkar

    Full Text Available Studies of neonatal neural pathologies and development of appropriate therapeutics are hampered by a lack of relevant in vitro models of neonatal blood-brain barrier (BBB. To establish such a model, we have developed a novel blood-brain barrier on a chip (B3C that comprises a tissue compartment and vascular channels placed side-by-side mimicking the three-dimensional morphology, size and flow characteristics of microvessels in vivo. Rat brain endothelial cells (RBEC isolated from neonatal rats were seeded in the vascular channels of B3C and maintained under shear flow conditions, while neonatal rat astrocytes were cultured under static conditions in the tissue compartment of the B3C. RBEC formed continuous endothelial lining with a central lumen along the length of the vascular channels of B3C and exhibited tight junction formation, as measured by the expression of zonula occludens-1 (ZO-1. ZO-1 expression significantly increased with shear flow in the vascular channels and with the presence of astrocyte conditioned medium (ACM or astrocytes cultured in the tissue compartment. Consistent with in vivo BBB, B3C allowed endfeet-like astrocyte-endothelial cell interactions through a porous interface that separates the tissue compartment containing cultured astrocytes from the cultured RBEC in the vascular channels. The permeability of fluorescent 40 kDa dextran from vascular channel to the tissue compartment significantly decreased when RBEC were cultured in the presence of astrocytes or ACM (from 41.0 ± 0.9 x 10-6 cm/s to 2.9 ± 1.0 x 10-6 cm/s or 1.1±0.4 x 10-6 cm/s, respectively. Measurement of electrical resistance in B3C further supports that the addition of ACM significantly improves the barrier function in neonatal RBEC. Moreover, B3C exhibits significantly improved barrier characteristics compared to the transwell model and B3C permeability was not significantly different from the in vivo BBB permeability in neonatal rats. In summary, we

  11. Endothelial progenitor cells physiology and metabolic plasticity in brain angiogenesis and blood-brain barrier modeling

    Directory of Open Access Journals (Sweden)

    Natalia Malinovskaya

    2016-12-01

    Full Text Available Currently, there is a considerable interest to the assessment of blood-brain barrier (BBB development as a part of cerebral angiogenesis developmental program. Embryonic and adult angiogenesis in the brain is governed by the coordinated activity of endothelial progenitor cells, brain microvascular endothelial cells, and non-endothelial cells contributing to the establishment of the BBB (pericytes, astrocytes, neurons. Metabolic and functional plasticity of endothelial progenitor cells controls their timely recruitment, precise homing to the brain microvessels, and efficient support of brain angiogenesis. Deciphering endothelial progenitor cells physiology would provide novel engineering approaches to establish adequate microfluidically-supported BBB models and brain microphysiological systems for translational studies.

  12. Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown

    NARCIS (Netherlands)

    Yamazaki, Y.; Baker, D.J.; Tachibana, M.; Liu, C.C.; Deursen, J.M.A. van; Brott, T.G.; Bu, G.; Kanekiyo, T.

    2016-01-01

    BACKGROUND AND PURPOSE: Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to

  13. Anesthesia and Surgery Impair Blood–Brain Barrier and Cognitive Function in Mice

    Directory of Open Access Journals (Sweden)

    Siming Yang

    2017-08-01

    Full Text Available Blood–brain barrier (BBB dysfunction, e.g., increase in BBB permeability, has been reported to contribute to cognitive impairment. However, the effects of anesthesia and surgery on BBB permeability, the underlying mechanisms, and associated cognitive function remain largely to be determined. Here, we assessed the effects of surgery (laparotomy under 1.4% isoflurane anesthesia (anesthesia/surgery for 2 h on BBB permeability, levels of junction proteins and cognitive function in both 9- and 18-month-old wild-type mice and 9-month-old interleukin (IL-6 knockout mice. BBB permeability was determined by dextran tracer (immunohistochemistry imaging and spectrophotometric quantification, and protein levels were measured by Western blot and cognitive function was assessed by using both Morris water maze and Barnes maze. We found that the anesthesia/surgery increased mouse BBB permeability to 10-kDa dextran, but not to 70-kDa dextran, in an IL-6-dependent and age-associated manner. In addition, the anesthesia/surgery induced an age-associated increase in blood IL-6 level. Cognitive impairment was detected in 18-month-old, but not 9-month-old, mice after the anesthesia/surgery. Finally, the anesthesia/surgery decreased the levels of β-catenin and tight junction protein claudin, occludin and ZO-1, but not adherent junction protein VE-cadherin, E-cadherin, and p120-catenin. These data demonstrate that we have established a system to study the effects of perioperative factors, including anesthesia and surgery, on BBB and cognitive function. The results suggest that the anesthesia/surgery might induce an age-associated BBB dysfunction and cognitive impairment in mice. These findings would promote mechanistic studies of postoperative cognitive impairment, including postoperative delirium.

  14. Anesthesia and Surgery Impair Blood–Brain Barrier and Cognitive Function in Mice

    Science.gov (United States)

    Yang, Siming; Gu, Changping; Mandeville, Emiri T.; Dong, Yuanlin; Esposito, Elga; Zhang, Yiying; Yang, Guang; Shen, Yuan; Fu, Xiaobing; Lo, Eng H.; Xie, Zhongcong

    2017-01-01

    Blood–brain barrier (BBB) dysfunction, e.g., increase in BBB permeability, has been reported to contribute to cognitive impairment. However, the effects of anesthesia and surgery on BBB permeability, the underlying mechanisms, and associated cognitive function remain largely to be determined. Here, we assessed the effects of surgery (laparotomy) under 1.4% isoflurane anesthesia (anesthesia/surgery) for 2 h on BBB permeability, levels of junction proteins and cognitive function in both 9- and 18-month-old wild-type mice and 9-month-old interleukin (IL)-6 knockout mice. BBB permeability was determined by dextran tracer (immunohistochemistry imaging and spectrophotometric quantification), and protein levels were measured by Western blot and cognitive function was assessed by using both Morris water maze and Barnes maze. We found that the anesthesia/surgery increased mouse BBB permeability to 10-kDa dextran, but not to 70-kDa dextran, in an IL-6-dependent and age-associated manner. In addition, the anesthesia/surgery induced an age-associated increase in blood IL-6 level. Cognitive impairment was detected in 18-month-old, but not 9-month-old, mice after the anesthesia/surgery. Finally, the anesthesia/surgery decreased the levels of β-catenin and tight junction protein claudin, occludin and ZO-1, but not adherent junction protein VE-cadherin, E-cadherin, and p120-catenin. These data demonstrate that we have established a system to study the effects of perioperative factors, including anesthesia and surgery, on BBB and cognitive function. The results suggest that the anesthesia/surgery might induce an age-associated BBB dysfunction and cognitive impairment in mice. These findings would promote mechanistic studies of postoperative cognitive impairment, including postoperative delirium. PMID:28848542

  15. Zero-Valent Iron Permeable Reactive Barriers: A Review of Performance

    Energy Technology Data Exchange (ETDEWEB)

    Korte, NE

    2001-06-11

    This report briefly reviews issues regarding the implementation of the zero-valent iron permeable reactive barrier (PRB) technology at sites managed by the U.S. Department of Energy (DOE). Initially, the PRB technology, using zero-valent iron for the reactive media, was received with great enthusiasm, and DOE invested millions of dollars testing and implementing PRBs. Recently, a negative perception of the technology has been building. This perception is based on the failure of some deployments to satisfy goals for treatment and operating expenses. The purpose of this report, therefore, is to suggest reasons for the problems that have been encountered and to recommend whether DOE should invest in additional research and deployments. The principal conclusion of this review is that the most significant problems have been the result of insufficient characterization, which resulted in poor engineering implementation. Although there are legitimate concerns regarding the longevity of the reactive media, the ability of zero-valent iron to reduce certain chlorinated hydrocarbons and to immobilize certain metals and radionuclides is well documented. The primary problem encountered at some DOE full-scale deployments has been an inadequate assessment of site hydrology, which resulted in misapplication of the technology. The result is PRBs with higher than expected flow velocities and/or incomplete plume capture. A review of the literature reveals that cautions regarding subsurface heterogeneity were published several years prior to the full-scale implementations. Nevertheless, design and construction have typically been undertaken as if the subsurface was homogeneous. More recently published literature has demonstrated that hydraulic heterogeneity can cause so much uncertainty in performance that use of a passive PRB is precluded. Thus, the primary conclusion of this review is that more attention must be given to site-specific issues. Indeed, the use of a passive PRB requires

  16. The blood brain barrier: Insights from development and ageing.

    Science.gov (United States)

    Delaney, Conor; Campbell, Matthew

    2017-10-02

    The blood brain barrier is a necessity for cerebral homeostasis and response to environmental insult, thus loss in functionality with age creates opportunities for disease to arise in the aged brain. Understanding how the barrier is developed and maintained throughout the earlier years of adult life can identify key processes that may have beneficial applications in the restoration of the aged brain. With an unprecedented increasing global aged population, the prevention and treatment of age-associated disorders has become a rising healthcare priority demanding novel approaches for the development of therapeutic strategies. The aging cardiovascular system has long been recognised to be a major factor in age-associated diseases such as stroke, atherosclerosis and cardiac arrest. Changes in the highly specialised cerebral vasculature may similarly drive neurodegenerative and neuropsychiatric disease.

  17. Bacterial translocation and in vivo assessment of intestinal barrier permeability in Rainbow trout (Oncorhynchus mykiss) with and without soyabean meal-induced inflammation

    NARCIS (Netherlands)

    Mosberian Tanha, Peyman; Overland, M.; Landsverk, Thor; Reveco, Felipe E.; Schrama, J.W.; Roem, A.J.; Agger, Jane W.; Midland, Liv T.

    2016-01-01

    The primary aim of this experiment was to evaluate the intestinal barrier permeability in vivo in rainbow trout (Oncorhynchus mykiss) fed increasing levels of soyabean meal (SBM). The relationship between SBM-induced enteritis (SBMIE) and the permeability markers was also investigated. Our results

  18. Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

    Directory of Open Access Journals (Sweden)

    Jay P. Patel

    2015-01-01

    Full Text Available The blood-brain barrier (BBB regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD, here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.

  19. Histamine Induces Alzheimer's Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures

    Science.gov (United States)

    Sedeyn, Jonathan C.; Wu, Hao; Hobbs, Reilly D.; Levin, Eli C.; Nagele, Robert G.; Venkataraman, Venkat

    2015-01-01

    Among the top ten causes of death in the United States, Alzheimer's disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism as well as establishing platforms for drug screening. In this study, a promising candidate model utilizing primary mouse brain organotypic (MBO) cultures is reported. For the first time, we have demonstrated that the MBO cultures exhibit increased blood brain barrier (BBB) permeability as shown by IgG leakage into the brain parenchyma, astrocyte activation as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and neuronal damage-response as suggested by increased vimentin-positive neurons occur upon histamine treatment. Identical responses—a breakdown of the BBB, astrocyte activation, and neuronal expression of vimentin—were then demonstrated in brains from AD patients compared to age-matched controls, consistent with other reports. Thus, the histamine-treated MBO culture system may provide a valuable tool in combating AD. PMID:26697497

  20. Overview on backfill materials and permeable reactive barriers for nuclear waste disposal facilities.

    Energy Technology Data Exchange (ETDEWEB)

    Moore, Robert Charles; Hasan, Ahmed Ali Mohamed; Holt, Kathleen Caroline; Hasan, Mahmoud A. (Egyptian Atomic Energy Authority, Cairo, Egypt)

    2003-10-01

    A great deal of money and effort has been spent on environmental restoration during the past several decades. Significant progress has been made on improving air quality, cleaning up and preventing leaching from dumps and landfills, and improving surface water quality. However, significant challenges still exist in all of these areas. Among the more difficult and expensive environmental problems, and often the primary factor limiting closure of contaminated sites following surface restoration, is contamination of ground water. The most common technology used for remediating ground water is surface treatment where the water is pumped to the surface, treated and pumped back into the ground or released at a nearby river or lake. Although still useful for certain remediation scenarios, the limitations of pump-and-treat technologies have recently been recognized, along with the need for innovative solutions to ground-water contamination. Even with the current challenges we face there is a strong need to create geological repository systems for dispose of radioactive wastes containing long-lived radionuclides. The potential contamination of groundwater is a major factor in selection of a radioactive waste disposal site, design of the facility, future scenarios such as human intrusion into the repository and possible need for retrieving the radioactive material, and the use of backfills designed to keep the radionuclides immobile. One of the most promising technologies for remediation of contaminated sites and design of radioactive waste repositories is the use of permeable reactive barriers (PRBs). PRBs are constructed of reactive material(s) to intercept and remove the radionuclides from the water and decontaminate the plumes in situ. The concept of PRBs is relatively simple. The reactive material(s) is placed in the subsurface between the waste or contaminated area and the groundwater. Reactive materials used thus far in practice and research include zero valent iron

  1. Gliomas and the vascular fragility of the blood brain barrier

    Directory of Open Access Journals (Sweden)

    Luiz Gustavo eDubois

    2014-12-01

    Full Text Available Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB. By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM, characterized by a highly heterogeneous cell population (including tumor stem cells, extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the blood brain barrier and the concerns that arise when this barrier is affected.

  2. Intestinal barrier function and the brain-gut axis.

    Science.gov (United States)

    Alonso, Carmen; Vicario, María; Pigrau, Marc; Lobo, Beatriz; Santos, Javier

    2014-01-01

    The luminal-mucosal interface of the intestinal tract is the first relevant location where microorganism-derived antigens and all other potentially immunogenic particles face the scrutiny of the powerful mammalian immune system. Upon regular functioning conditions, the intestinal barrier is able to effectively prevent most environmental and external antigens to interact openly with the numerous and versatile elements that compose the mucosal-associated immune system. This evolutionary super system is capable of processing an astonishing amount of antigens and non-immunogenic particles, approximately 100 tons in one individual lifetime, only considering food-derived components. Most important, to develop oral tolerance and proper active immune responses needed to prevent disease and inflammation, this giant immunogenic load has to be managed in a way that physiological inflammatory balance is constantly preserved. Adequate functioning of the intestinal barrier involves local and distant regulatory networks integrating the so-called brain-gut axis. Along this complex axis both brain and gut structures participate in the processing and execution of response signals to external and internal changes coming from the digestive tract, using multidirectional pathways to communicate. Dysfunction of brain-gut axis facilitates malfunctioning of the intestinal barrier, and vice versa, increasing the risk of uncontrolled immunological reactions that may trigger mucosal and brain low-grade inflammation, a putative first step to the initiation of more permanent gut disorders. In this chapter, we describe the structure, function and interactions of intestinal barrier, microbiota and brain-gut axis in both healthy and pathological conditions.

  3. Migration of African trypanosomes across the blood-brain barrier.

    Science.gov (United States)

    Masocha, Willias; Rottenberg, Martin E; Kristensson, Krister

    2007-09-10

    Subspecies of the extracellular parasite, Trypanosoma brucei, which are spread by the tsetse fly in sub-Saharan Africa, cause in humans Sleeping Sickness. In experimental rodent models the parasite can at a certain stage of disease pass through the blood-brain barrier across or between the endothelial cells and the vessel basement membranes. The laminin composition of the basement membranes determines whether they are permissive to parasite penetration. One cytokine, interferon-gamma, plays an important role in regulating the trypanosome trafficking into the brain. Treatment strategies aim at developing drugs that can impede penetration of trypanosomes into the brain and/or that can eliminate trypanosomes once they are inside the brain parenchyma, but have lower toxicity than the ones presently in use.

  4. Blood-Brain Barrier Imaging in Human Neuropathologies

    Science.gov (United States)

    Veksler, Ronel; Shelef, Ilan; Friedman, Alon

    2014-01-01

    The blood–brain barrier (BBB) is essential for normal function of the brain, and its role in many brain pathologies has been the focus of numerous studies during the last decades. Dysfunction of the BBB is not only being shown in numerous brain diseases, but animal studies have indicated that it plays a direct key role in the genesis of neurovascular dysfunction and associated neurodegeneration. As such evidence accumulates, the need for robust and clinically applicable methods for minimally invasive assessment of BBB integrity is becoming urgent. This review provides an introduction to BBB imaging methods in the clinical scenario. First, imaging modalities are reviewed, with a focus on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). We then proceed to review image analysis methods, including quantitative and semi-quantitative methods. The advantages and limitations of each approach are discussed, and future directions and questions are highlighted. PMID:25453223

  5. Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models.

    Directory of Open Access Journals (Sweden)

    Iveta Novakova

    Full Text Available The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line for proper data comparison.

  6. Endomorphin-1 analogues (MELs) penetrate the blood-brain barrier and exhibit good analgesic effects with minimal side effects.

    Science.gov (United States)

    Wang, Yuan; Liu, Xin; Wang, Dan; Yang, Junxian; Zhao, Long; Yu, Jing; Wang, Rui

    2015-10-01

    Endomorphins are endogenous opioid peptides in mammals and display a strong antinociceptive effect after central administration. However, the clinical usage of these peptides is limited because of their diminished analgesic effect following systemic injection and their inability to cross the blood-brain barrier. In this study, we characterized the in vivo effects of four novel endomorphin-1 analogues (termed MELs), which previously showed potential as highly potent analgesics with a good pharmacological profile in vitro. The analogues were administered intravenously to several rodent pain models to examine their antinociception and blood-brain barrier permeability. The tested peptides, especially MEL1214, showed good analgesic activity and blood-brain barrier permeability. Behavioral studies showed dose-dependent analgesic effect after systematic administration of MEL1214 in the tested pain models. Pre-treatment of subcutaneous administration of naloxone methiodide did not affect the antinociception of these peptides. As compared to morphine, MEL1214 was less prone to induce tolerance after consecutive intravenous administration for 5 days. Gastrointestinal transit was evaluated by the isolated colon response and bead expulsion to determine the potential constipation effect. In contrast to morphine, MEL1214 produced no significant constipation effect at an equivalent dose. MEL1214 shows promise as a suitable compound to treat pain with reduced side effects, and exhibits good potential to be further developed as a novel opioid analgesic in pain treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Targeted liposomes for drug delivery across the blood-brain barrier

    OpenAIRE

    van Rooy, I.

    2011-01-01

    Our brain is protected by the blood-brain barrier (BBB). This barrier is formed by specialized endothelial cells of the brain vasculature and prevents toxic substances from entering the brain. The downside of this barrier is that many drugs that have been developed to cure brain diseases cannot cross this barrier and do not reach the brain in therapeutic concentrations. An innovative way to help these drugs to reach the brain is by encapsulating them into nanoparticles (e.g. liposomes). A tar...

  8. The blood-brain barrier in vitro using primary culture

    DEFF Research Database (Denmark)

    Larsen, Annette Burkhart

    and transport of iron across the BBB. Expression of iron-related proteins was investigated at the BBB and it was possible to show expression of the essential iron transport protein; transferrin receptor, ferrireductases, divalent metal transporter 1 (DMT1), ferroportin and ferrooxidases, which was additionally...... obstacle for the treatment of central nervous system (CNS) diseases, as many potentially CNS active drugs are unable to reach their site of action within the brain. In vitro BBB models are, therefore, being developed to investigate the BBB permeability of a drug early in its development. The first part...... to demonstrate protein secretion of recombinant therapeutic polypeptides from BCECs. The third part of the thesis involves iron transport at BCECs, and the study of the transferrin receptor as a carrier for transport into the brain. The transferrin receptor is expressed by the BCECs and is involved in the uptake...

  9. Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors

    DEFF Research Database (Denmark)

    Larsson, H B; Stubgaard, M; Frederiksen, Jette Lautrup Battistini

    1990-01-01

    In this study quantitation of the degree of deficiency of the blood-brain barrier (BBB) in patients with multiple sclerosis or brain tumors, by using MRI, is shown to be possible. As a measure of permeability of the BBB to Gadolinium-DTPA (Gd-DTPA) the flux per unit of distribution volume per unit......, and the results were comparable to results obtained from similar studies using positron emission tomography. The improved possibility of quantitating the defect of the BBB by MRI may give new information about pathogenesis or etiology, and leads to improved methods in monitoring the efficacy of treatments...... of brain mass was used. This quantity was found by introducing the longitudinal relaxation rate (R1) as a measure of concentration of Gd-DTPA in the brain tissue in the mathematical model for the transcapillary transport over the BBB. High accordance between the observed data points and the model was found...

  10. Walker 256 tumour cells increase substance P immunoreactivity locally and modify the properties of the blood-brain barrier during extravasation and brain invasion.

    Science.gov (United States)

    Lewis, Kate M; Harford-Wright, Elizabeth; Vink, Robert; Nimmo, Alan J; Ghabriel, Mounir N

    2013-01-01

    It is not yet known how tumour cells traverse the blood-brain barrier (BBB) to form brain metastases. Substance P (SP) release is a key component of neurogenic inflammation which has been recently shown to increase the permeability of the BBB following CNS insults, making it a possible candidate as a mediator of tumour cell extravasation into the brain. This study investigated the properties of the BBB in the early stages of tumour cell invasion into the brain, and the possible involvement of SP. Male Wistar rats were injected with Walker 256 breast carcinoma cells via the internal carotid artery and euthanised at 1, 3, 6 and 9 days post tumour inoculation. Culture medium-injected animals served as controls at 1 and 9 days. Evidence of tumour cell extravasation across the BBB was first observed at 3 days post-inoculation, which corresponded with significantly increased albumin (p tumoral area (p cerebral metastases may be a SP-mediated process.

  11. Translocating the blood-brain barrier using electrostatics

    Directory of Open Access Journals (Sweden)

    Marta eRibeiro

    2012-10-01

    Full Text Available Mammalian cell membranes regulate homeostasis, protein activity and cell signaling. The charge at the membrane surface has been correlated with these key events.Although mammalian cells are known to be slightly anionic, quantitative information on the membrane charge and the importance of electrostatic interactions in pharmacokinetics and pharmacodynamics remain elusive. Recently, we reported for the first time that brain endothelial cells are more negatively charged than human umbilical cord cells, using zeta-potential dynamic light scattering. Here, we hypothesize that anionicity is a key feature of the blood-brain barrier and contributes to select which compounds cross into the brain. For the sake of comparison, we also studied the membrane surface charge of blood components – red blood cells, platelets and peripheral blood mononuclear cells. To further quantitatively correlate the negative zeta-potential values with membrane charge density, model membranes with different percentages of anionic lipids were also evaluated.From all the cells tested, brain cell membranes are the most anionic and the ones having their lipids mostly exposed, which explains why lipophilic cationic compounds are more prone to cross the blood-brain barrier.

  12. Neuro-inflammation, blood-brain barrier, seizures and autism

    Directory of Open Access Journals (Sweden)

    Theoharides Theoharis C

    2011-11-01

    Full Text Available Abstract Many children with Autism Spectrum Diseases (ASD present with seizure activity, but the pathogenesis is not understood. Recent evidence indicates that neuro-inflammation could contribute to seizures. We hypothesize that brain mast cell activation due to allergic, environmental and/or stress triggers could lead to focal disruption of the blood-brain barrier and neuro-inflammation, thus contributing to the development of seizures. Treating neuro-inflammation may be useful when anti-seizure medications are ineffective.

  13. The vasopressin receptor of the blood-brain barrier in the rat hippocampus is linked to calcium signalling

    DEFF Research Database (Denmark)

    Hess, J.; Jensen, Claus V.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, vasopressin receptor, VI subtype, blood-brain barrier, cerebral endothelium, hippocampus, Fura-2......Neuropathology, vasopressin receptor, VI subtype, blood-brain barrier, cerebral endothelium, hippocampus, Fura-2...

  14. Current progress in the permeability and its enhancement approches for TCM active ingredients across blood-eye barrier

    Directory of Open Access Journals (Sweden)

    Yu-Yang Bai

    2014-10-01

    Full Text Available Blood-eye barrier(BEBis one of the most important structures of organism to maintain homeostasis of the eye. However, it is the major constraint for the medication of intraocular diseases. Traditional Chinese medicines have distinctive advantages for the treatment of intraocular diseases, which can be used to regulate the physiological function of human body with low toxicity. In this article, we have briefly summarized the feature of BEB, with the domestic and foreign literatures combined, and mainly reviewed current progress in the field of study on the permeability of traditional Chinese medicines and effective components in BEB and promoting methods.

  15. The role of the blood-brain barrier in hypertension.

    Science.gov (United States)

    Setiadi, Anthony; Korim, Willian S; Elsaafien, Khalid; Yao, Song T

    2017-10-06

    What is the topic of this review? This review highlights the importance of the blood-brain barrier in the context of diseases involving autonomic dysfunction, such as hypertension and heart failure. What advances does it highlight? It highlights the potential role of pro-inflammatory cytokines, leucocytes and angiotensin II in disrupting the blood-brain barrier in cardiovascular diseases. Advances are highlighted in our understanding of neurovascular unit cells, astrocytes and microglia, with a specific emphasis on their pathogenic roles within the brain. The blood-brain barrier (BBB) is a crucial barrier that provides both metabolic and physical protection to an immune-privileged CNS. The BBB has been shown to be disrupted in hypertension. This review addresses the importance of the BBB in maintaining homeostasis in the context of diseases related to autonomic dysfunction, such as hypertension. We highlight the potentially important roles of the immune system and neurovascular unit in the maintenance of the BBB, whereby dysregulation may lead to autonomic dysfunction in diseases such as heart failure and hypertension. Circulating leucocytes and factors such as angiotensin II and pro-inflammatory cytokines are thought ultimately to downregulate endothelial tight junction proteins that are a crucial component of the BBB. The specific mechanisms underlying BBB disruption and their role in contributing to autonomic dysfunction are not yet fully understood but are a growing area of interest. A greater understanding of these systems and advances in our knowledge of the molecular mechanisms causing BBB disruption will allow for the development of future therapeutic interventions in the treatment of autonomic imbalance associated with diseases such as heart failure and hypertension. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

  16. Blood-brain barrier transcytosis of insulin in developing rabbits.

    Science.gov (United States)

    Duffy, K R; Pardridge, W M

    1987-09-08

    Previous studies with isolated brain microvessels have suggested that blood insulin is selectively transported through the brain capillary, i.e. the blood-brain barrier (BBB), by receptor-mediated transcytosis. The purpose of the present study is to demonstrate in vivo the uptake of circulating 125I-insulin by brain using thaw-mount autoradiography. However, metabolism of systemic 125I-insulin to 125I-tyrosine would allow for brain uptake of 125I-tyrosine and this would preclude interpretation of the autoradiogram. Therefore, the present studies were performed in developing rabbits, since plasma protein degradation of peptides is greatly reduced in developing animals. 125I-insulin was infused via the carotid artery at a rate of 0.25 ml/min for 1, 5, or 10 min, and the mean brain uptake, relative to a [3H]albumin reference, was 99.3 +/- 5.5%, 110.1 +/- 4.3%, and 143.6 +/- 7.9%, respectively. This uptake was saturable by simultaneously infusing unlabeled insulin. Thaw-mount autoradiography of rabbit brain after a 10-min infusion of 125I-insulin revealed silver grains in the pericapillary space and well within the brain parenchyma. HPLC analysis of acid-ethanol extracts of rabbit blood after a 10-min infusion showed virtually all of the 125I-radioactivity co-migrated with a known insulin standard on a reverse-phase column, indicating minimal degradation of infused 125I-insulin. HPLC analysis of brain radioactivity showed the major peak co-migrated with 125I-insulin and this peak was precipitated by an anti-insulin antiserum. The correlation of the transport data, the autoradiography, and the HPLC analysis support the model that brain insulin originates from blood via receptor-mediated transport of the peptide at the BBB.

  17. Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier.

    Directory of Open Access Journals (Sweden)

    Eric C Leuthardt

    Full Text Available Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks.The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.ClinicalTrials.gov NCT01851733.

  18. Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier.

    Science.gov (United States)

    Leuthardt, Eric C; Duan, Chong; Kim, Michael J; Campian, Jian L; Kim, Albert H; Miller-Thomas, Michelle M; Shimony, Joshua S; Tran, David D

    2016-01-01

    Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery. Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption. In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks. The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced. ClinicalTrials.gov NCT01851733.

  19. Candesartan attenuates ischemic brain edema and protects the blood-brain barrier integrity from ischemia/reperfusion injury in rats.

    Science.gov (United States)

    Panahpour, Hamdollah; Nekooeian, Ali Akbar; Dehghani, Gholam Abbas

    2014-01-01

    Angiotensin II (Ang II) has an important role on cerebral microcirculation; however, its direct roles in terms of ischemic brain edema need to be clarified. This study evaluated the role of central Ang II by using candesartan, as an AT1 receptor blocker, in the brain edema formation and blood-brain barrier (BBB) disruption caused by ischemia/reperfusion (I/R) injuries in rat. Rats were exposed to 60-min middle cerebral artery (MCA) occlusion. Vehicle and non-hypotensive doses of candesartan (0.1 mg/kg) were administered one hour before ischemia. Neurological dysfunction scoring was evaluated following 24 h of reperfusion. Animals were then decapitated under deep anesthesia for the assessments of cerebral infarct size, edema formation, and BBB permeability. The outcomes of 24 h reperfusion after 60-min MCA occlusion were severe neurological disability, massive BBB disruption (Evans blue extravasation = 12.5 ± 1.94 µg/g tissue), 4.02% edema, and cerebral infarction (317 ± 21 mm3). Candesartan at a dose of 0.1 mg/kg, without changing arterial blood pressure, improved neurological dysfunction scoring together with significant reductions in BBB disruption (54.9%), edema (59.2%), and cerebral infarction (54.9%). Inactivation of central AT1 receptors, if not accompanied with arterial hypotension, protected cerebral micro-vasculatures from damaging effects of acute stroke.

  20. Candesartan Attenuates Ischemic Brain Edema and Protects the Blood–Brain Barrier Integrity from Ischemia/Reperfusion Injury in Rats

    Science.gov (United States)

    Panahpour, Hamdollah; Nekooeian, Ali Akbar; Dehghani, Gholam Abbas

    2014-01-01

    Background: Angiotensin II (Ang II) has an important role on cerebral microcirculation; however, its direct roles in terms of ischemic brain edema need to be clarified. This study evaluated the role of central Ang II by using candesartan, as an AT1 receptor blocker, in the brain edema formation and blood-brain barrier (BBB) disruption caused by ischemia/reperfusion (I/R) injuries in rat. Methods: Rats were exposed to 60-min middle cerebral artery (MCA) occlusion. Vehicle and non-hypotensive doses of candesartan (0.1 mg/kg) were administered one hour before ischemia. Neurological dysfunction scoring was evaluated following 24 h of reperfusion. Animals were then decapitated under deep anesthesia for the assessments of cerebral infarct size, edema formation, and BBB permeability. Results: The outcomes of 24 h reperfusion after 60-min MCA occlusion were severe neurological disability, massive BBB disruption (Evans blue extravasation = 12.5 ± 1.94 µg/g tissue), 4.02% edema, and cerebral infarction (317 ± 21 mm3). Candesartan at a dose of 0.1 mg/kg, without changing arterial blood pressure, improved neurological dysfunction scoring together with significant reductions in BBB disruption (54.9%), edema (59.2%), and cerebral infarction (54.9%). Conclusions: Inactivation of central AT1 receptors, if not accompanied with arterial hypotension, protected cerebral micro-vasculatures from damaging effects of acute stroke. PMID:25326022

  1. Zika Virus Infects, Activates, and Crosses Brain Microvascular Endothelial Cells, without Barrier Disruption

    Directory of Open Access Journals (Sweden)

    Michelle P. Papa

    2017-12-01

    Full Text Available Zika virus (ZIKV has been associated to central nervous system (CNS harm, and virus was detected in the brain and cerebrospinal fluids of microcephaly and meningoencephalitis cases. However, the mechanism by which the virus reaches the CNS is unclear. Here, we addressed the effects of ZIKV replication in human brain microvascular endothelial cells (HBMECs, as an in vitro model of blood brain barrier (BBB, and evaluated virus extravasation and BBB integrity in an in vivo mouse experimental model. HBMECs were productively infected by African and Brazilian ZIKV strains (ZIKVMR766 and ZIKVPE243, which induce increased production of type I and type III IFN, inflammatory cytokines and chemokines. Infection with ZIKVMR766 promoted earlier cellular death, in comparison to ZIKVPE243, but infection with either strain did not result in enhanced endothelial permeability. Despite the maintenance of endothelial integrity, infectious virus particles crossed the monolayer by endocytosis/exocytosis-dependent replication pathway or by transcytosis. Remarkably, both viruses' strains infected IFNAR deficient mice, with high viral load being detected in the brains, without BBB disruption, which was only detected at later time points after infection. These data suggest that ZIKV infects and activates endothelial cells, and might reach the CNS through basolateral release, transcytosis or transinfection processes. These findings further improve the current knowledge regarding ZIKV dissemination pathways.

  2. Maternal Obesity in the Mouse Compromises the Blood-Brain Barrier in the Arcuate Nucleus of Offspring.

    Science.gov (United States)

    Kim, Dong Won; Glendining, Kelly A; Grattan, David R; Jasoni, Christine L

    2016-06-01

    The arcuate nucleus (ARC) regulates body weight in response to blood-borne signals of energy balance. Blood-brain barrier (BBB) permeability in the ARC is determined by capillary endothelial cells (ECs) and tanycytes. Tight junctions between ECs limit paracellular entry of blood-borne molecules into the brain, whereas EC transporters and fenestrations regulate transcellular entry. Tanycytes appear to form a barrier that prevents free diffusion of blood-borne molecules. Here we tested the hypothesis that gestation in an obese mother alters BBB permeability in the ARC of offspring. A maternal high-fat diet model was used to generate offspring from normal-weight (control) and obese dams (OffOb). Evans Blue diffusion into the ARC was higher in OffOb compared with controls, indicating that ARC BBB permeability was altered. Vessels investing the ARC in OffOb had more fenestrations than controls, although the total number of vessels was not changed. A reduced number of tanycytic processes in the ARC of OffOb was also observed. The putative transporters, Lrp1 and dysferlin, were up-regulated and tight junction components were differentially expressed in OffOb compared with controls. These data suggest that maternal obesity during pregnancy can compromise BBB formation in the fetus, leading to altered BBB function in the ARC after birth.

  3. Polyunsaturated fatty acids support epithelial barrier integrity and reduce IL-4 mediated permeability in vitro.

    NARCIS (Netherlands)

    Willemsen, L.E.M.; Koetsier, Marjolein; Balvers, M.; Beermann, C.; Stahl, B.; Tol, EA van

    2008-01-01

    BACKGROUND: The intestinal mucosa functions as a barrier against harmful dietary and microbial antigens. An intact gut barrier forms a prerequisite for protection against infection and allergy. Both allergic and inflammatory mediators (e.g. IL-4, IFN-gamma) are known to compromise the epithelial

  4. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.

    Science.gov (United States)

    Maggioli, E; McArthur, S; Mauro, C; Kieswich, J; Kusters, D H M; Reutelingsperger, C P M; Yaqoob, M; Solito, E

    2016-01-01

    Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

  5. Japanese encephalitis virus disrupts blood-brain barrier and modulates apoptosis proteins in THBMEC cells.

    Science.gov (United States)

    Al-Obaidi, Mazen M Jamil; Bahadoran, Azadeh; Har, Lee Sau; Mui, Wang Seok; Rajarajeswaran, Jayakumar; Zandi, Keivan; Manikam, Rishya; Sekaran, Shamala Devi

    2017-04-02

    Japanese encephalitis (JE) is a neurotropic flavivirus that causes inflammation in central nervous system (CNS), neuronal death and also compromises the structural and functional integrity of the blood-brain barrier (BBB). The aim of this study was to evaluate the BBB disruption and apoptotic process in Japanese encephalitis virus (JEV)-infected transfected human brain microvascular endothelial cells (THBMECs). THBMECs were overlaid by JEV with different MOIs (0.5, 1.0, 5.0 and 10.0) and monitored by electrical cell-substrate impedance sensing (ECIS) in a real-time manner in order to observe the barrier function of THBMECs. Additionally, the level of 43 apoptotic proteins was quantified in the virally infected cells with different MOIs at 24h post infection. Infection of THBMEC with JEV induced an acute reduction in transendothelial electrical resistance (TEER) after viral infection. Also, significant up-regulation of Bax, BID, Fas and Fasl and down-regulation of IGFBP-2, BID, p27 and p53 were observed in JEV infected THBMECs with 0.5 and 10 MOIs compared to uninfected cells. Hence, the permeability of THBMECs is compromised during the JEV infection. In addition high viral load of the virus has the potential to subvert the host cell apoptosis to optimize the course of viral infection through deactivation of pro-apoptotic proteins. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model

    Science.gov (United States)

    Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

    2015-03-01

    Effective drug delivery to brain tumors is often challenging because of the heterogeneous permeability of the ‘blood tumor barrier’ (BTB) along with other factors such as increased interstitial pressure and drug efflux pumps. Focused ultrasound (FUS) combined with microbubbles can enhance the permeability of the BTB in brain tumors, as well as the blood-brain barrier in the surrounding tissue. In this study, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to characterize the FUS-induced permeability changes of the BTB in a rat glioma model at different times after implantation. 9L gliosarcoma cells were implanted in both hemispheres in male rats. At day 9, 14, or 17 days after implantation, FUS-induced BTB disruption using 690 kHz ultrasound and definity microbubbles was performed in one tumor in each animal. Before FUS, liposomal doxorubicin was administered at a dose of 5.67 mg kg-1. This chemotherapy agent was previously shown to improve survival in animal glioma models. The transfer coefficient Ktrans describing extravasation of the MRI contrast agent Gd-DTPA was measured via DCE-MRI before and after sonication. We found that tumor doxorubicin concentrations increased monotonically (823  ±  600, 1817  ±  732 and 2432  ±  448 ng g-1) in the control tumors at 9, 14 and 17 d. With FUS-induced BTB disruption, the doxorubicin concentrations were enhanced significantly (P drug delivery are relatively consistent over time, at least in this tumor model. These results are encouraging for the use of large drug carriers, as they suggest that even large/late-stage tumors can benefit from FUS-induced drug enhancement. Corresponding enhancements in Ktrans were found to be variable in large/late-stage tumors and not significantly different than controls, perhaps reflecting the size mismatch between the liposomal drug (~100 nm) and Gd-DTPA (molecular weight: 938 Da; hydrodynamic diameter: ≃2 nm). It may be necessary

  7. How Glutamate Is Managed by the Blood–Brain Barrier

    Directory of Open Access Journals (Sweden)

    Richard A. Hawkins

    2016-10-01

    Full Text Available A facilitative transport system exists on the blood–brain barrier (BBB that has been tacitly assumed to be a path for glutamate entry to the brain. However, glutamate is a non-essential amino acid whose brain content is much greater than plasma, and studies in vivo show that glutamate does not enter the brain in appreciable quantities except in those small regions with fenestrated capillaries (circumventricular organs. The situation became understandable when luminal (blood facing and abluminal (brain facing membranes were isolated and studied separately. Facilitative transport of glutamate and glutamine exists only on the luminal membranes, whereas Na+-dependent transport systems for glutamate, glutamine, and some other amino acids are present only on the abluminal membrane. The Na+-dependent cotransporters of the abluminal membrane are in a position to actively transport amino acids from the extracellular fluid (ECF into the endothelial cells of the BBB. These powerful secondary active transporters couple with the energy of the Na+-gradient to move glutamate and glutamine into endothelial cells, whereupon glutamate can exit to the blood on the luminal facilitative glutamate transporter. Glutamine may also exit the brain via separate facilitative transport system that exists on the luminal membranes, or glutamine can be hydrolyzed to glutamate within the BBB, thereby releasing ammonia that is freely diffusible. The γ-glutamyl cycle participates indirectly by producing oxoproline (pyroglutamate, which stimulates almost all secondary active transporters yet discovered in the abluminal membranes of the BBB.

  8. Evaluation of a horizontal permeable reactive barrier for preventing upward diffusion of volatile organic compounds through the unsaturated zone.

    Science.gov (United States)

    Mahmoodlu, Mojtaba G; Hassanizadeh, S Majid; Hartog, Niels; Raoof, Amir; van Genuchten, Martinus Th

    2015-11-01

    Permeable reactive barriers are commonly used to treat contaminant plumes in the saturated zone. However, no known applications of horizontal permeable reactive barriers (HPRBs) exist for oxidizing volatile organic compounds (VOCs) in the unsaturated zone. In this study, laboratory column experiments were carried out to investigate the ability of a HPRB containing solid potassium permanganate, to oxidize the vapors of trichloroethylene (TCE), toluene, and ethanol migrating upward from a contaminated saturated zone. Results revealed that an increase in initial water saturation and HPRB thickness strongly affected the removal efficiency of the HPRB. Installing the HPRB relatively close to the water table was more effective due to the high background water content and enhanced diffusion of protons and/or hydroxides away from the HPRB. Inserting the HPRB far above the water table caused rapid changes in pH within the HPRB, leading to lower oxidation rates. The pH effects were included in a reactive transport model, which successfully simulated the TCE and toluene experimental observations. Simulations for ethanol were not affected by pH due to condensation of water during ethanol oxidation, which caused some dilution in the HRPB. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Enhancement of tight junctional barrier function by micronutrients: compound-specific effects on permeability and claudin composition.

    Directory of Open Access Journals (Sweden)

    Joanna Mercado

    Full Text Available Amid an increasing number of reports in the literature concerning epithelial barrier enhancement by various nutrient compounds, there has never been a study performing side-by-side comparisons of these agents in a single epithelial model. We compare five nutrient compounds (previously reported in various epithelial models to enhance barrier function regarding their ability to increase transepithelial electrical resistance (R(t and decrease transepithelial mannitol permeability (J(m across LLC-PK₁ renal epithelial cell layers. The effects of these nutrients on the abundance of various tight junctional proteins are also compared. In the overall group of nutrients tested--zinc, indole, quercetin, butyrate and nicotine--only nicotine failed to improve barrier function by either parameter. Nicotine also was without effect on tight junctional proteins. Quercetin simultaneously increased R(t and decreased J(m. Zinc, butyrate and indole only exhibited statistically significant enhancement of R(t. Each of these four effective nutrient compounds had unique patterns of effects on the panel of tight junctional proteins studied. No two compounds produced the same pattern of effects. This unique pattern of effects on tight junctional complex composition by each compound establishes the chance for additive or even synergistic improvement of barrier function by combinations of compounds. A synergistic effect of the combination of quercetin and zinc on R(t is shown.

  10. Neuroprotection of brain-permeable iron chelator VK-28 against intracerebral hemorrhage in mice.

    Science.gov (United States)

    Li, Qian; Wan, Jieru; Lan, Xi; Han, Xiaoning; Wang, Zhongyu; Wang, Jian

    2017-09-01

    Iron overload plays a key role in the secondary brain damage that develops after intracerebral hemorrhage (ICH). The significant increase in iron deposition is associated with the generation of reactive oxygen species (ROS), which leads to oxidative brain damage. In this study, we examined the protective effects of VK-28, a brain-permeable iron chelator, against hemoglobin toxicity in an ex vivo organotypic hippocampal slice culture (OHSC) model and in middle-aged mice subjected to an in vivo, collagenase-induced ICH model. We found that the effects of VK-28 were similar to those of deferoxamine (DFX), a well-studied iron chelator. Both decreased cell death and ROS production in OHSCs and in vivo, decreased iron-deposition and microglial activation around hematoma in vivo, and improved neurologic function. Moreover, compared with DFX, VK-28 polarized microglia to an M2-like phenotype, reduced brain water content, deceased white matter injury, improved neurobehavioral performance, and reduced overall death rate after ICH. The protection of VK-28 was confirmed in a blood-injection ICH model and in aged-male and young female mice. Our findings indicate that VK-28 is protective against iron toxicity after ICH and that, at the dosage tested, it has better efficacy and less toxicity than DFX does.

  11. A theory for the impact of a wave breaking onto a permeable barrier with jet generation

    OpenAIRE

    Cooker, MJ

    2013-01-01

    We model a water wave impact onto a porous breakwater. The breakwater surface is modelled as a thin barrier composed of solid matter pierced by channels through which water can flow freely. The water in the wave is modelled as a finite-length volume of inviscid, incompressible fluid in quasi-one-dimensional flow during its impact and flow through a typical hole in the barrier. The fluid volume moves at normal incidence to the barrier. After the initial impact the wave water starts to slow dow...

  12. Treatment with the NK1 antagonist emend reduces blood brain barrier dysfunction and edema formation in an experimental model of brain tumors.

    Directory of Open Access Journals (Sweden)

    Elizabeth Harford-Wright

    Full Text Available The neuropeptide substance P (SP has been implicated in the disruption of the blood-brain barrier (BBB and development of cerebral edema in acute brain injury. Cerebral edema accumulates rapidly around brain tumors and has been linked to several tumor-associated deficits. Currently, the standard treatment for peritumoral edema is the corticosteroid dexamethasone, prolonged use of which is associated with a number of deleterious side effects. As SP is reported to increase in many cancer types, this study examined whether SP plays a role in the genesis of brain peritumoral edema. A-375 human melanoma cells were injected into the right striatum of male Balb/c nude mice to induce brain tumor growth, with culture medium injected in animals serving as controls. At 2, 3 or 4 weeks following tumor cell inoculation, non-treated animals were perfusion fixed for immunohistochemical detection of Albumin, SP and NK1 receptor. A further subgroup of animals was treated with a daily injection of the NK1 antagonist Emend (3 mg/kg, dexamethasone (8 mg/kg or saline vehicle at 3 weeks post-inoculation. Animals were sacrificed a week later to determine BBB permeability using Evan's Blue and brain water content. Non-treated animals demonstrated a significant increase in albumin, SP and NK1 receptor immunoreactivity in the peritumoral area as well as increased perivascular staining in the surrounding brain tissue. Brain water content and BBB permeability was significantly increased in tumor-inoculated animals when compared to controls (p<0.05. Treatment with Emend and dexamethasone reduced BBB permeability and brain water content when compared to vehicle-treated tumor-inoculated mice. The increase in peritumoral staining for both SP and the NK1 receptor, coupled with the reduction in brain water content and BBB permeability seen following treatment with the NK1 antagonist Emend, suggests that SP plays a role in the genesis of peritumoral edema, and thus warrants

  13. Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action.

    Science.gov (United States)

    Nicolas, Jean-Marie; Hannestad, Jonas; Holden, Daniel; Kervyn, Sophie; Nabulsi, Nabeel; Tytgat, Dominique; Huang, Yiyun; Chanteux, Hugues; Staelens, Ludovicus; Matagne, Alain; Mathy, François-Xavier; Mercier, Joël; Stockis, Armel; Carson, Richard E; Klitgaard, Henrik

    2016-02-01

    Rapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high-affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivara-cetam (BRV) for its rate of brain penetration and its onset of action. BRV was compared with levetiracetam (LEV). In vitro permeation studies were performed using Caco-2 cells. Plasma and brain levels were measured over time after single oral dosing to audiogenic mice and were correlated with anticonvulsant activity. Tissue distribution was investigated after single dosing to rat (BRV and LEV) and dog (LEV only). Positron emission tomography (PET) displacement studies were performed in rhesus monkeys using the SV2A PET tracer [11C]UCB-J. The time course of PET tracer displacement was measured following single intravenous (IV) dosing with LEV or BRV. Rodent distribution data and physiologically based pharmacokinetic (PBPK) modeling were used to compute blood-brain barrier permeability (permeability surface area product, PS) values and then predict brain kinetics in man. In rodents, BRV consistently showed a faster entry into the brain than LEV; this correlated with a faster onset of action against seizures in audiogenic susceptible mice. The higher permeability of BRV was also demonstrated in human cells in vitro. PBPK modeling predicted that, following IV dosing to human subjects, BRV might distribute to the brain within a few minutes compared with approximately 1 h for LEV (PS of 0.315 and 0.015 ml/min/g for BRV and LEV, respectively). These data were supported by a nonhuman primate PET study showing faster SV2A occupancy by BRV compared with LEV. These preclinical data demonstrate that BRV has rapid brain entry and fast brain SV2A occupancy, consistent with the fast onset of action in the audiogenic seizure mice assay. The potential benefit of BRV for treatment of acute seizures remains to be confirmed in clinical

  14. Impacts of Blood-Brain Barrier in Drug Delivery and Targeting of Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yadollah Omidi

    2012-02-01

    Full Text Available Introduction: Entry of blood circulating agents into the brain is highly selectively controlled by specific transport machineries at the blood brain barrier (BBB, whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Methods: Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Results: Brain capillary endothelial cells (BCECs form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics. Conclusion: The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent.

  15. Involvement of the Blood-Brain Barrier in Metabolic Regulation.

    Science.gov (United States)

    Kastin, Abba J; Pan, Weihong

    2016-01-01

    Pertinent to pandemic obesity, the discovery of endogenous peptides that affect the ingestion of food has led to the question of how these ingestive peptides exert their actions in the brain. Whereas peripheral sources provide a ready reserve, the availability of ingestive peptides to their central nervous system targets can be regulated by the blood-brain barrier (BBB). Some of the peptides/polypeptides are transported by saturable mechanisms from blood to brain. Examples include leptin, insulin, mahogany, and pancreatic polypeptide. Some enter the brain by passive diffusion, such as neuropeptide Y, orexin A, cocaine- and amphetamine-regulated transcript, cyclo His-Pro, and amylin. Some others may have essentially no penetration of the BBB; this class includes agouti-related protein, melanin-concentrating hormone, and urocortin. The regulatory function of the BBB can be seen in various physiological states. Hyperglycemia may upregulate transport systems for leptin, urocortin, and galanin-like peptide, whereas fasting can down-regulate those for leptin and galanin-like peptide. Thus, the BBB plays a dynamic role in modulating the passage of ingestive peptides from blood to brain.

  16. Potential of biopartitioning micellar chromatography as an in vitro technique for predicting drug penetration across the blood-brain barrier.

    Science.gov (United States)

    Escuder-Gilabert, L; Molero-Monfort, M; Villanueva-Camañas, R M; Sagrado, S; Medina-Hernández, M J

    2004-08-05

    The blood-brain barrier (BBB) is considered to be the main barrier to drug transport into the central nervous system (CNS). The BBB restricts the passive diffusion of many drugs from blood to brain. The ease with which any particular drug diffuses across the BBB is determined largely by the molecular features of drugs, and it is therefore possible to predict the BBB permeability of a drug from its molecular structure. Biopartitioning micellar chromatography (BMC), a mode of micellar liquid chromatography that uses micellar mobile phases of Brij35 in adequate experimental conditions, can be useful in mimicking the drug partitioning process into biological systems. Retention in BMC depends on the hydrophobicity, electronic and steric properties of drugs. In this paper, the usefulness of BMC for predicting the BBB penetration ability of drugs expressed as the brain/blood distribution coefficient (BB) is demonstrated. A multiple linear regression (MLR) model that relates the BB distribution coefficients data with BMC retention data and total molar charge is proposed. The model is obtained using 44 heterogeneous drugs including, neutral, anionic, and cationic compounds. A comparison with other reported methodologies to predict the BBB permeability is also presented.

  17. Excitotoxicity triggered by neonatal monosodium glutamate treatment and blood-brain barrier function.

    Science.gov (United States)

    Gudiño-Cabrera, Graciela; Ureña-Guerrero, Monica E; Rivera-Cervantes, Martha C; Feria-Velasco, Alfredo I; Beas-Zárate, Carlos

    2014-11-01

    It is likely that monosodium glutamate (MSG) is the excitotoxin that has been most commonly employed to characterize the process of excitotoxicity and to improve understanding of the ways that this process is related to several pathological conditions of the central nervous system. Excitotoxicity triggered by neonatal MSG treatment produces a significant pathophysiological impact on adulthood, which could be due to modifications in the blood-brain barrier (BBB) permeability and vice versa. This mini-review analyzes this topic through brief descriptions about excitotoxicity, BBB structure and function, role of the BBB in the regulation of Glu extracellular levels, conditions that promote breakdown of the BBB, and modifications induced by neonatal MSG treatment that could alter the behavior of the BBB. In conclusion, additional studies to better characterize the effects of neonatal MSG treatment on excitatory amino acids transporters, ionic exchangers, and efflux transporters, as well as the role of the signaling pathways mediated by erythropoietin and vascular endothelial growth factor in the cellular elements of the BBB, should be performed to identify the mechanisms underlying the increase in neurovascular permeability associated with excitotoxicity observed in several diseases and studied using neonatal MSG treatment. Copyright © 2015 IMSS. Published by Elsevier Inc. All rights reserved.

  18. Transport of Poly(n-butylcyano-acrylate) nanoparticles across the blood-brain barrier in vitro and their influence on barrier integrity.

    Science.gov (United States)

    Rempe, Ralf; Cramer, Sandra; Hüwel, Sabine; Galla, Hans-Joachim

    2011-03-04

    In previous studies it was shown that polysorbate 80(PS80)-coated poly(n-butylcyano-acrylate) nanoparticles (PBCA-NP) are able to cross the blood-brain barrier (BBB) in vitro and in vivo. In order to explore and extend the potential applications of PBCA-NP as drug carriers, it is important to ascertain their effect on the BBB. The objective of the present study was to determine the effect of PS80-coated PBCA-NP on the BBB integrity of a porcine in vitro model. This has been investigated by monitoring the development of the transendothelial electrical resistance (TEER) after the addition of PBCA-NP employing impedance spectroscopy. Additionally, the integrity of the BBB in vitro was verified by measuring the passage of the reference substances (14)C-sucrose and FITC-BSA after addition of PBCA-NP. In this study we will show that the application of PS80-coated PBCA-NP leads to a reversible disruption of the barrier after 4h. The observed disruption of the barrier could also be confirmed by (14)C-sucrose and FITC-BSA permeability studies. Comparing the TEER and permeability studies the lowest resistances and maximal values for permeabilities were both observed after 4h. These results indicate that PS80-coated PBCA-NP might be suitable for the use as drug carriers. The reversible disruption also offers the possibility to use these particles as specific opener of the BBB. Instead of incorporating the therapeutic agents into the NP, the drugs may cross the BBB after being applied simultaneously with the PBCA-NP. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Nanoparticle- and liposome-carried drugs: new strategies for active targeting and drug delivery across blood-brain barrier.

    Science.gov (United States)

    Pinzón-Daza, Martha Leonor; Campia, Ivana; Kopecka, Joanna; Garzón, Ruth; Ghigo, Dario; Riganti, Chiara

    2013-07-01

    The blood-brain barrier (BBB), the unusual microvascular endothelial interface between the central nervous system (CNS) and the circulatory system, is a major hindrance to drug delivery in the brain parenchyma. Besides the absence of fenestrations and the abundance of tight junctions, ATP-binding cassette (ABC) transporters critically reduce drug entry within the CNS, as they carry many drugs back into the bloodstream. Nanoparticle- and liposome-carried drugs, because of their increased cellular uptake and reduced efflux through ABC transporters, have been developed in recent times to circumvent the low drug permeability of the BBB. This review discusses the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle- and liposome-based strategies to increase drug delivery across the BBB and new therapeutic strategies for using nanoparticle- and liposome-carried drugs in different conditions, ranging from CNS tumors and neurodegenerative diseases to viral infections and epilepsy.

  20. Vascular Pathology and Blood-Brain Barrier Disruption in Cognitive and Psychiatric Complications of Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Yonatan Serlin

    2011-01-01

    Full Text Available Vascular pathology is recognized as a principle insult in type 2 diabetes mellitus (T2DM. Co-morbidities such as structural brain abnormalities, cognitive, learning and memory deficits are also prevailing in T2DM patients. We previously suggested that microvascular pathologies involving blood-brain barrier (BBB breakdown results in leakage of serum-derived components into the brain parenchyma, leading to neuronal dysfunction manifested as psychiatric illnesses. The current postulate focuses on the molecular mechanisms controlling BBB permeability in T2DM, as key contributors to the pathogenesis of mental disorders in patients. Revealing the mechanisms underlying BBB dysfunction and inflammatory response in T2DM and their role in metabolic disturbances, abnormal neurovascular coupling and neuronal plasticity, would contribute to the understanding of the mechanisms underlying psychopathologies in diabetic patients. Establishing this link would offer new targets for future therapeutic interventions.

  1. Study of the interactions bacteria - phenanthrene - activated carbon for the preparation of a permeable reactive barrier; Etude des interactions bacteries - phenanthrene - charbon en vue de l'elaboration d'une barriere permeable reactive

    Energy Technology Data Exchange (ETDEWEB)

    Leglize, P.

    2004-12-01

    Permeable Reactive Barrier (PRB) is a new way for the remediation of contaminated groundwater, but up to now Polycyclic Aromatic Hydrocarbons (PAHs) were rarely considered. We investigated PAH - bacteria - materials interactions in order to validate the feasibility of PRB for PAH contamination. PHE Adsorption/desorption kinetics onto different materials, activated carbons (CA), pozzolana (Pz) and pozzolana coated with heavy fuel (PzF), were investigated. PHE biodegradation were performed on batch using PAH degrading bacteria and the PRB materials. CA was a good media for PRB process: Phenanthrene sorption capacity is 100 to 10000 fold higher than PzF and Pz. Phenanthrene mineralization with CA was higher than without material. Bacterial properties affected PHE biodegradation. Bio-film production improved PHE biodegradation by PAH degrading bacteria. Column studies showed that inoculation of the column improved its efficiency: adsorbed PHE degradation and increased retardation of PHE. (author)

  2. Protection of the Blood-Brain Barrier as a Therapeutic Strategy for Brain Damage.

    Science.gov (United States)

    Michinaga, Shotaro; Koyama, Yutaka

    2017-01-01

    Severe brain damage by trauma, ischemia, and hemorrhage lead to fatal conditions including sudden death, subsequent complications of the extremities and cognitive dysfunctions. Despite the urgent need for treatments for these complications, currently available therapeutic drugs are limited. Blood-brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage. The characteristic pathophysiological conditions caused by BBB disruption are brain edema resulting from an excessive increase of brain water content, inflammatory damage caused by infiltrating immune cells, and hemorrhage caused by the breakdown of microvessel structures. Because these pathogenic features induced by BBB disruption cause fatal conditions, their improvement is a desirable strategy. Many studies using experimental animal models have focused on molecules involved in BBB disruption, including vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs) and endothelins (ETs). The inhibition of these factors in several experimental animals was protective against BBB disruption caused by several types of brain damage, and ameliorated brain edema, inflammatory damage, and hemorrhagic transformation. In patients with brain damage, the up-regulation of these factors was observed and was related to brain damage severity. Thus, BBB protection by targeting VEGFs, MMPs, and ETs might be a novel strategy for the treatment of brain damage.

  3. Determination of hexavalent chromium reduction using Cr stable isotopes: isotopic fractionation factors for permeable reactive barrier materials.

    Science.gov (United States)

    Basu, Anirban; Johnson, Thomas M

    2012-05-15

    Cr stable isotope measurements can provide improved estimates of the extent of Cr(VI) reduction to less toxic Cr(III). The relationship between observed (53)Cr/(52)Cr ratio shifts and the extent of reduction can be calibrated by determining the isotopic fractionation factor for relevant reactions. Permeable reactive barriers (PRB) made of Fe(0) and in situ redox manipulation (ISRM) zones effectively remediate Cr-contaminated aquifers. Here, we determine the isotopic fractionations for dominant reductants in reactive barriers and reduced sediments obtained from an ISRM zone at the US DOE's Hanford site. In all cases, significant isotopic fractionation was observed; fractionation (expressed as ε) was -3.91‰ for Fe(II)-doped goethite, -2.11‰ for FeS, -2.65‰ for green rust, -2.67‰ for FeCO(3), and -3.18‰ for ISRM zone sediments. These results provide a better calibration of the relationship between Cr isotope ratios and the extent of Cr(VI) reduction and aid in interpretation of Cr isotope data from systems with reactive barriers.

  4. High permeability cores to optimize the stimulation of deeply located brain regions using transcranial magnetic stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Salvador, R; Miranda, P C [Institute of Biophysics and Biomedical Engineering, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon (Portugal); Roth, Y [Advanced Technology Center, Sheba Medical Center, Tel-Hashomer (Israel); Zangen, A [Neurobiology Department, Weizmann Institute of Science, Rehovot 76100 (Israel)], E-mail: rnsalvador@fc.ul.pt

    2009-05-21

    Efficient stimulation of deeply located brain regions with transcranial magnetic stimulation (TMS) poses many challenges, arising from the fact that the induced field decays rapidly and becomes less focal with depth. We propose a new method to improve the efficiency of TMS of deep brain regions that combines high permeability cores, to increase focality and field intensity, with a coil specifically designed to induce a field that decays slowly with increasing depth. The performance of the proposed design was investigated using the finite element method to determine the total electric field induced by this coil/core arrangement on a realistically shaped homogeneous head model. The calculations show that the inclusion of the cores increases the field's magnitude by as much as 25% while also decreasing the field's decay with depth along specific directions. The focality, as measured by the area where the field's norm is greater than 1/{radical}2 of its maximum value, is also improved by as much as 15% with some core arrangements. The coil's inductance is not significantly increased by the cores. These results show that the presence of the cores might make this specially designed coil even more suited for the effective stimulation of deep brain regions.

  5. Topical antihistamines display potent anti-inflammatory activity linked in part to enhanced permeability barrier function

    DEFF Research Database (Denmark)

    Lin, Tzu-Kai; Man, Mao-Qiang; Santiago, Juan-Luis

    2013-01-01

    antagonists likely oppose mast cell-derived histamines. In four immunologically diverse, murine disease models, characterized by either inflammation alone (acute irritant contact dermatitis, acute allergic contact dermatitis) or by prominent barrier abnormalities (subacute allergic contact dermatitis, atopic...... of epidermal differentiation, leading to thickened cornified envelopes; and (ii) enhanced epidermal lipid synthesis and secretion. As barrier homeostasis was enhanced to a comparable extent in mast cell-deficient mice, with no further improvement following application of topical H1/2r antagonists, H1/2r...... dermatitis), topical H1/2r agonists aggravated, whereas H1/2r antagonists improved, inflammation and/or barrier function. The apparent ability of topical H1r/2r antagonists to target epidermal H1/2r could translate into increased efficacy in the treatment of inflammatory dermatoses, likely due to decreased...

  6. Physical insights into the blood-brain barrier translocation mechanisms

    Science.gov (United States)

    Theodorakis, Panagiotis E.; Müller, Erich A.; Craster, Richard V.; Matar, Omar K.

    2017-08-01

    The number of individuals suffering from diseases of the central nervous system (CNS) is growing with an aging population. While candidate drugs for many of these diseases are available, most of these pharmaceutical agents cannot reach the brain rendering most of the drug therapies that target the CNS inefficient. The reason is the blood-brain barrier (BBB), a complex and dynamic interface that controls the influx and efflux of substances through a number of different translocation mechanisms. Here, we present these mechanisms providing, also, the necessary background related to the morphology and various characteristics of the BBB. Moreover, we discuss various numerical and simulation approaches used to study the BBB, and possible future directions based on multi-scale methods. We anticipate that this review will motivate multi-disciplinary research on the BBB aiming at the design of effective drug therapies.

  7. The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier

    NARCIS (Netherlands)

    Reijerkerk, A.; Kooij, G.; van der Pol, S.M.A.; Leyen, T.A.; Lakeman, K.; Van Het Hof, B; Vivien, D.; de Vries, H.E.

    2010-01-01

    Normal neuronal functioning is dependent on the blood-brain barrier. This barrier is confined to specialized brain endothelial cells lining the inner vessel wall, and tightly controlling transport of nutrients, efflux of potentially harmful molecules and entry of immune cells into the brain. Loss of

  8. Viral Infection of the Central Nervous System and Neuroinflammation Precede Blood-Brain Barrier Disruption during Japanese Encephalitis Virus Infection.

    Science.gov (United States)

    Li, Fang; Wang, Yueyun; Yu, Lan; Cao, Shengbo; Wang, Ke; Yuan, Jiaolong; Wang, Chong; Wang, Kunlun; Cui, Min; Fu, Zhen F

    2015-05-01

    Japanese encephalitis is an acute zoonotic, mosquito-borne disease caused by Japanese encephalitis virus (JEV). Japanese encephalitis is characterized by extensive inflammation in the central nervous system (CNS) and disruption of the blood-brain barrier (BBB). However, the pathogenic mechanisms contributing to the BBB disruption are not known. Here, using a mouse model of intravenous JEV infection, we show that virus titers increased exponentially in the brain from 2 to 5 days postinfection. This was accompanied by an early, dramatic increase in the level of inflammatory cytokines and chemokines in the brain. Enhancement of BBB permeability, however, was not observed until day 4, suggesting that viral entry and the onset of inflammation in the CNS occurred prior to BBB damage. In vitro studies revealed that direct infection with JEV could not induce changes in the permeability of brain microvascular endothelial cell monolayers. However, brain extracts derived from symptomatic JEV-infected mice, but not from mock-infected mice, induced significant permeability of the endothelial monolayer. Consistent with a role for inflammatory mediators in BBB disruption, the administration of gamma interferon-neutralizing antibody ameliorated the enhancement of BBB permeability in JEV-infected mice. Taken together, our data suggest that JEV enters the CNS, propagates in neurons, and induces the production of inflammatory cytokines and chemokines, which result in the disruption of the BBB. Japanese encephalitis (JE) is the leading cause of viral encephalitis in Asia, resulting in 70,000 cases each year, in which approximately 20 to 30% of cases are fatal, and a high proportion of patients survive with serious neurological and psychiatric sequelae. Pathologically, JEV infection causes an acute encephalopathy accompanied by BBB dysfunction; however, the mechanism is not clear. Thus, understanding the mechanisms of BBB disruption in JEV infection is important. Our data demonstrate

  9. Creation of a subsurface permeable treatment barrier using in situ redox manipulation

    Energy Technology Data Exchange (ETDEWEB)

    Fruchter, J.S.; Cole, C.R.; Williams, M.D. [Pacific Northwest National Lab., Richland, WA (United States)] [and others

    1997-12-31

    The goal of in situ redox manipulation is to create a permeable treatment zone in the subsurface for remediating redox-sensitive contaminants in groundwater. The permeable treatment zone is created just downstream of the contaminant plume or contaminant source through the injection of reagents and/or microbial nutrients to alter the redox potential of the aquifer fluids and sediments. Contaminant plumes migrating through this manipulated zone can then be destroyed or immobilized. In a field test at the Hanford Site, {approximately}77,000 L of buffered sodium dithionite solution were successfully injected into the unconfined aquifer at the 100-H Area in September 1995. The target contaminant was chromate. No significant plugging of the well screen or the formation was detected during any phase of the test. Dithionite was detected in monitoring wells at least 7.5 m from the injection point. Data were obtained from all three phases of the test (i.e., injection, reaction, withdrawal). Preliminary core data show that from 60% to 100% of the available reactive iron in the targeted aquifer sediments was reduced by the injected dithionite. One year after the injection, groundwater in the treatment zone remains anoxic. Total and hexavalent chromium levels in groundwater have been reduced from a preexperiment concentration of {approximately}60 {mu}g/L to below the detection limit of the analytical methods.

  10. Diel coral reef acidification driven by porewater advection in permeable sands, Heron Island, Great Barrier Reef

    DEFF Research Database (Denmark)

    Santos, Isaac R.; Glud, Ronnie N.; Maher, Damien

    2011-01-01

    Little is known about how biogeochemical processes in permeable sediments affect the pH of coastal waters. We demonstrate that seawater recirculation in permeable sands can play a major role in proton (H+) cycling in a coral reef lagoon. The diel pH range (up to 0.75 units) in the Heron Island...... lagoon was the broadest ever reported for reef waters, and the night‐time pH (7.69) was comparable to worst‐case scenario predictions for seawater pH in 2100. The net contribution of coarse carbonate sands to the whole system H+ fluxes was only 9% during the day, but approached 100% at night when small...... scale (i.e., flow and topography‐induced pressure gradients) and large scale (i.e., tidal pumping as traced by radon) seawater recirculation processes were synergistic. Reef lagoon sands were a net sink for H+, and the sink strength was a function of porewater flushing rate. Our observations suggest...

  11. Effects of ambient air particulate exposure on blood-gas barrier permeability and lung function

    DEFF Research Database (Denmark)

    Bräuner, Elvira Vaclavik; Mortensen, Jann; Møller, Peter

    2009-01-01

    Particulate air pollution is associated with increased risk of pulmonary diseases and detrimental outcomes related to the cardiovascular system, including altered vessel functions. This study's objective was too evaluate the effects of ambient particle exposure on the blood-gas permeability, lung...... function and Clara cell 16 (CC16) protein release in healthy young subjects. Twenty-nine nonsmokers participated in a randomized, two-factor crossover study with or without biking exercise for 180 min and with 24-h exposure to particle-rich (6169-15,362 particles/cm(3); 7.0-11.6 microg/m(3) PM(2.5); 7.......5-15.8 microg/m(3) PM(10-2.5)) or filtered (91-542 particles/cm(3)) air collected above a busy street. The clearance rate of aerosolized (99m)Tc-labeled diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) was measured as an index for the alveolar epithelial membrane integrity and permeability of the lung blood-gas...

  12. Perlecan and the Blood-Brain Barrier: Beneficial Proteolysis?

    Directory of Open Access Journals (Sweden)

    Jill eRoberts

    2012-08-01

    Full Text Available The cerebral microvasculature is important for maintaining brain homeostasis. This is achieved via the blood-brain barrier (BBB, composed of endothelial cells with specialized tight junctions, astrocytes and a basement membrane. Prominent components of the basement membrane extracellular matrix (ECM include fibronectin, laminin, collagen IV and perlecan, all of which regulate cellular processes via signal transduction through various cell membrane bound ECM receptors. Expression and proteolysis of these ECM components can be rapidly altered during pathological states of the central nervous system. In particular, proteolysis of perlecan, a heparan sulfate proteoglycan, occurs within hours following ischemia induced by experimental stroke. Proteolysis of ECM components following stroke results in the degradation of the basement membrane and further disruption of the BBB. While it is clear that such proteolysis has negative consequences for the BBB, we propose that it also may lead to generation of ECM protein fragments, including the C-terminal domain V (DV of perlecan, that potentially have a positive influence on other aspects of CNS health. Indeed, perlecan DV has been shown to be persistently generated after stroke and beneficial as a neuroprotective molecule and promoter of post-stroke brain repair. This mini-review will discuss beneficial roles of perlecan protein fragment generation within the brain during stroke.

  13. Sorting Tubules Regulate Blood-Brain Barrier Transcytosis

    Directory of Open Access Journals (Sweden)

    Roberto Villaseñor

    2017-12-01

    Full Text Available Transcytosis across the blood-brain barrier (BBB regulates key processes of the brain, but the intracellular sorting mechanisms that determine successful receptor-mediated transcytosis in brain endothelial cells (BECs remain unidentified. Here, we used Transferrin receptor-based Brain Shuttle constructs to investigate intracellular transport in BECs, and we uncovered a pathway for the regulation of receptor-mediated transcytosis. By combining live-cell imaging and mathematical modeling in vitro with super-resolution microscopy of the BBB, we show that intracellular tubules promote transcytosis across the BBB. A monovalent construct (sFab sorted for transcytosis was localized to intracellular tubules, whereas a bivalent construct (dFab sorted for degradation formed clusters with impaired transport along tubules. Manipulating tubule biogenesis by overexpressing the small GTPase Rab17 increased dFab transport into tubules and induced its transcytosis in BECs. We propose that sorting tubules regulate transcytosis in BECs and may be a general mechanism for receptor-mediated transport across the BBB.

  14. PERMEABLE REACTIVE BARRIER PERFORMANCE MONITORING: LONG-TERM TRENDS IN GEOCHEMICAL PARAMETERS AT TWO SITES

    Science.gov (United States)

    A major goal of research on the long-term performance of subsurface reactive barriers is to identify standard ground-water monitoring parameters that may be useful indicators of declining performance or impending system failure. Results are presented from studies conducted over ...

  15. Integrated evaluation of the performance of a more than seven year old permeable reactive barrier at a site contaminated with chlorinated aliphatic hydrocarbons (CAHs)

    DEFF Research Database (Denmark)

    Muchitsch, Nanna; Nooten, Thomas Van; Bastiaens, Leen

    2011-01-01

    An important issue of concern for permeable reactive iron barriers is the long-term efficiency of the barriers due to the long operational periods required. Mineral precipitation resulting from the anaerobic corrosion of the iron filings and bacteria present in the barrier may play an important...... indicated the presence of a microbial consortium in the barrier. A wide range of species were identified including sulfate and iron reducing bacteria, together with Dehalococcoides and Desulfuromonas species indicating microbial reductive dehalogenation potential. The microbes had a profound effect...

  16. Observations of Anomalous Subcrustal Reflections Along the East Pacific Rise: Possible Detection of a Melt Permeability Barrier

    Science.gov (United States)

    Arnoux, G. M.; Toomey, D. R.

    2013-12-01

    Crustal accretion at mid-ocean ridges primarily occurs within the narrow neovolcanic zone at the spreading axis, with supplementary lower crustal accumulation thought to originate from the crystallization of magma bodies at the base of the crust. The narrowness of the neovolcanic zone requires melt focusing - a process that has been proposed to arise from the presence of melt impermeable boundaries, or permeability barriers, within the thermal boundary layer near the base of the lithosphere that inhibit the upward migration of melt, effectively focusing it laterally to the ridge axis. Numerical simulations, as well as structural and petrological characteristics of the Oman ophiolite, suggest the existence of such melt impermeable boundaries. A recent analysis of seismic data from the East Pacific Rise (EPR) between the Siqueiros and Clipperton transform faults (8°15'N-10°20'N) reveals anomalous subcrustal reflections ~20 km east of the rise axis and ~20-50 km south of the Clipperton transform. The reflections are characterized by large amplitudes, high frequency content on the order of 20-30 Hz, and a travel time curve that is parabolic with arrival times increasing rapidly at ranges <20 km from the receiver. The approximate depth, slope, and geographical extent of the reflector are estimated by back projecting the onset times of the anomalous reflections into a predefined velocity model. This method reveals that the reflector dips both away from the ridge axis and northward toward the Clipperton transform with a minimum depth below seafloor of ~7.2 km (0.7 km below the Moho) nearest to the ridge. Further off-axis and roughly 20 km to the north, closest to the Clipperton transform, the depth of the reflector increases to ~10.6 km (4 km below the Moho). The slope of the observed reflector thus conforms to the base of the thermal boundary layer (i.e. the 1200-1300° C isotherms) in thermal models adjacent to oceanic transform faults (Roland et al., 2010). The 1240

  17. In situ construction of low permeable barrier in soil to prevent pollutant migration by applying weak electric field.

    Science.gov (United States)

    Chen, Si; Liu, Xiang; Wang, Li; Wan, Chunli

    2017-05-15

    In order to prevent vertical migration of pollutant in soil matrix, this study firstly proposed to construct an in situ low permeable barrier (LPB) through synchronously transporting calcium and carbonate. After LPB construction, the soil permeability was declined tenfold. Exchangeable calcium (37.3%) and calcium bonding to carbonate (41.7%) respectively alleviated flocculation of microaggregates and cementation of marcoaggregates. Accordingly, smaller particles (2 mm) after electrokinetic remediation. The other soil characters like pH, moisture, and bacterial communities were well preserved after remediation. In addition, the pollutant prevention was divided into two phases as unsaturated phase and saturated phase. In unsaturated phase, phenol, F(-), Cd(2+), and Ni(2+) in filtrate were all lower than 0.1 mg, and Cr2O4(2-)-Cr discharged from LPB was 1/5.1 than that from initial soil. In saturated phase, LPB prevented 4.3-12.1 fold pollutant than initial soil. Taken together, proposed method could effectively prevent vertical migration of pollutants, indicating significant values for saving soil remediation cost or avoiding contamination of underground water. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. The role of the blood–brain barrier in the development and treatment of migraine and other pain disorders

    Science.gov (United States)

    DosSantos, Marcos F.; Holanda-Afonso, Rosenilde C.; Lima, Rodrigo L.; DaSilva, Alexandre F.; Moura-Neto, Vivaldo

    2014-01-01

    The function of the blood–brain barrier (BBB) related to chronic pain has been explored for its classical role in regulating the transcellular and paracellular transport, thus controlling the flow of drugs that act at the central nervous system, such as opioid analgesics (e.g., morphine) and non-steroidal anti-inflammatory drugs. Nonetheless, recent studies have raised the possibility that changes in the BBB permeability might be associated with chronic pain. For instance, changes in the relative amounts of occludin isoforms, resulting in significant increases in the BBB permeability, have been demonstrated after inflammatory hyperalgesia. Furthermore, inflammatory pain produces structural changes in the P-glycoprotein, the major efflux transporter at the BBB. One possible explanation for these findings is the action of substances typically released at the site of peripheral injuries that could lead to changes in the brain endothelial permeability, including substance P, calcitonin gene-related peptide, and interleukin-1 beta. Interestingly, inflammatory pain also results in microglial activation, which potentiates the BBB damage. In fact, astrocytes and microglia play a critical role in maintaining the BBB integrity and the activation of those cells is considered a key mechanism underlying chronic pain. Despite the recent advances in the understanding of BBB function in pain development as well as its interference in the efficacy of analgesic drugs, there remain unknowns regarding the molecular mechanisms involved in this process. In this review, we explore the connection between the BBB as well as the blood–spinal cord barrier and blood–nerve barrier, and pain, focusing on cellular and molecular mechanisms of BBB permeabilization induced by inflammatory or neuropathic pain and migraine. PMID:25339863

  19. Melatonin modulates permeability transition pore and 5-hydroxydecanoate induced KATPchannel inhibition in isolated brain mitochondria.

    Science.gov (United States)

    Waseem, Mohammad; Tabassum, Heena; Parvez, Suhel

    2016-11-01

    There is increasing recognition of the magnitude of mitochondria in neurodegenerative disorders. Mitochondria play a key role in apoptotic and necrotic cell death. Melatonin (Mel), an indoleamine produced in several organs including the pineal gland has been known for its neuroprotective actions. In our study, we have investigated whether the mitochondrial ATP sensitive potassium (mtK ATP ) channel blocker 5-hydroxydecanoate (5-HD) and calcium (Ca 2+ ) affects permeability transition pore (PTP) alterations in isolated brain mitochondria treated with melatonin (Mel) and cyclosporin A (CsA). Mitochondrial swelling, mitochondrial membrane potential (Δψ m ), ROS measurement and mitochondrial respiration were evaluated in isolated brain mitochondria. In our results, mitochondrial swelling stimulated by exposing Ca 2+ ions and 5-HD associated by mPTP opening as depicted by modulation of CsA and Mel. In addition, Ca 2+ and 5-HD decreased Δψ m , depleted intracellular ROS, and inhibition of mitochondrial respiration (state 3 and state 4) in isolated brain mitochondria. Addition of Mel and CsA has shown significant restoration in mitochondrial swelling, Δψ m , intracellular ROS measurement and mitochondrial respiration in isolated brain mitochondria. Therefore, we speculate the modulatory effect of Mel and CsA in mitochondria treated with 5-HD and Ca 2+ hinders the mPTP-mediated mitochondrial dysfunction and cellular oxidative stress. We conclude that inhibition of mPT is one likely mechanism of CsA's and its neuroprotective actions. Development of neuroprotective agents including Mel targeting the mPTP therefore bears hope for future treatment of severe neurodegenerative diseases. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  20. Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status.

    Science.gov (United States)

    Liu, Hao-Li; Yang, Hung-Wei; Hua, Mu-Yi; Wei, Kuo-Chen

    2012-01-01

    Malignant glioma is a severe primary CNS cancer with a high recurrence and mortality rate. The current strategy of surgical debulking combined with radiation therapy or chemotherapy does not provide good prognosis, tumor progression control, or improved patient survival. The blood-brain barrier (BBB) acts as a major obstacle to chemotherapeutic treatment of brain tumors by severely restricting drug delivery into the brain. Because of their high toxicity, chemotherapeutic drugs cannot be administered at sufficient concentrations by conventional delivery methods to significantly improve long-term survival of patients with brain tumors. Temporal disruption of the BBB by microbubble-enhanced focused ultrasound (FUS) exposure can increase CNS-blood permeability, providing a promising new direction to increase the concentration of therapeutic agents in the brain tumor and improve disease control. Under the guidance and monitoring of MR imaging, a brain drug-delivery platform can be developed to control and monitor therapeutic agent distribution and kinetics. The success of FUS BBB disruption in delivering a variety of therapeutic molecules into brain tumors has recently been demonstrated in an animal model. In this paper the authors review a number of critical studies that have demonstrated successful outcomes, including enhancement of the delivery of traditional clinically used chemotherapeutic agents or application of novel nanocarrier designs for actively transporting drugs or extending drug half-lives to significantly improve treatment efficacy in preclinical animal models.

  1. The blood-brain barrier as a cause of obesity.

    Science.gov (United States)

    Banks, William A

    2008-01-01

    The dramatic increase in the number of obese and overweight persons has spurred interest in control of appetite, body weight, and adiposity. Leptin is the humoral component of a negative feedback loop between adipose tissue and brain. Leptin is secreted from fat in proportion to the degree of adiposity, is transported across the blood-brain barrier (BBB), and acts in the brain to decrease appetite and increase thermogenesis, actions that ultimately decrease adiposity. However, leptin fails as an adipostat because leptin resistance arises in obesity. The BBB transporter is the first part of the feedback loop to fail, producing the so called "peripheral resistance" to leptin. In this sense, obesity is a disease of the BBB. Failure of leptin as an adipostat raises the question of what its primary role is as does its effects on reproduction, bone, immunity, breathing, cognition, and neurogenesis. Kinetics analysis shows that the BBB transporter performs most efficiently at low serum levels of leptin, suggesting that the feedback loop evolved to operate at lower leptin levels than those seen in ideal body weight. We suggest that low levels of serum leptin inform the brain that adipose reserves are adequate to expend calories on functions other than feeding, such as reproduction and the immune system. This feedback loop is short-circuited when an animal enters starvation. Hallmarks of starvation include decreased secretion of leptin by adipose tissue and hypertriglyceridemia. Triglycerides inhibit the transport of leptin across the BBB, thus attenuating the leptin signal across the BBB and providing a mechanism for peripheral leptin resistance. Triglycerides are elevated in both starvation and obesity. We postulate that hypertriglyceridemia evolved as a starvation signal to the brain that acts in part to inhibit the transport of the leptin across the BBB. The hypertriglyceridemia of obesity invokes this aspect of the starvation response, inducing leptin resistance at the

  2. Transport across the blood-brain barrier of pluronic leptin.

    Science.gov (United States)

    Price, Tulin O; Farr, Susan A; Yi, Xiang; Vinogradov, Serguei; Batrakova, Elena; Banks, William A; Kabanov, Alexander V

    2010-04-01

    Leptin is a peptide hormone produced primarily by adipose tissue that acts as a major regulator of food intake and energy homeostasis. Impaired transport of leptin across the blood-brain barrier (BBB) contributes to leptin resistance, which is a cause of obesity. Leptin as a candidate for the treatment of this obesity is limited because of the short half-life in circulation and the decreased BBB transport that arises in obesity. Chemical modification of polypeptides with amphiphilic poly(ethylene oxide)-poly(propylene oxide) block copolymers (Pluronic) is a promising technology to improve efficiency of delivery of polypeptides to the brain. In the present study, we determined the effects of Pluronic P85 (P85) with intermediate hydrophilic-lipophilic balance conjugated with leptin via a degradable SS bond [leptin(ss)-P85] on food intake, clearance, stability, and BBB uptake. The leptin(ss)-P85 exhibited biological activity when injected intracerebroventricularly after overnight food deprivation and 125I-leptin(ss)-P85 was stable in blood, with a half-time clearance of 32.3 min (versus 5.46 min for leptin). 125I-Leptin(ss)-P85 crossed the BBB [blood-to-brain unidirectional influx rate (K(i)) = 0.272 +/- 0.037 microl/g x min] by a nonsaturable mechanism unrelated to the leptin transporter. Capillary depletion showed that most of the 125I-leptin(ss)-P85 taken up by the brain reached the brain parenchyma. Food intake was reduced when 3 mg of leptin(ss)-P85 was administered via tail vein in normal body weight mice [0-30 min, p penetration by a mechanism-independent BBB leptin transporter.

  3. Pulsed focused ultrasound combined with micro-bubble contrast agent can open the blood-brain barrier of gliblastoma patients and improve the efficacy of Temozolomide treatment

    Directory of Open Access Journals (Sweden)

    Qian DONG

    2017-06-01

    Full Text Available Objective This research examined the effect of microbubble contrast agent plus ultrasound on the permeability of blood-brain barrier, and explored whether it affects the efficacy of chemotherapeutic drugs on cerebral glioblastoma. Methods Wistar rats were divided into three groups to find the optimal concentration of ultrasonic contrast agent. To identify the best ultrasound mode that affected the permeability of blood brain barrier, we employed transmission electron microscopy for study of brain ultrastructure. Western blotting was used to detect the tight junction protein claudin-5. Evans blue staining of brain tissues was utilized to identify the best ultrasonic contrast agent concentration and mode. Rat glioma cells (line 9L were injected into Wistar rats. After temozolomide chemotherapy, the tumor size was measured and the tumor marker GFAP in serum was detected by ELISA. Results The best contrast agent concentration which increases permeability of BBB in rats was found to be 1ml/kg and the best ultrasound mode was intermittently- triggered pulses lasting for 10min (with interval was set at 400ms. More Evans blue passed the blood-brain barrier in ultrasonic cavitation effect group than in control group (P<0.05. After temozolomide chemotherapy, more tumor marker GFAP was detected in ultrasonic cavitation effect group than in control group (P<0.05. Conclusion The permeability of BBB was increased and more temozolomide went through BBB when the rats were subjected to intermittently triggered ultrasonic pulses and were injected at contrast agent at 1ml/kg, which could help to achieve better therapeutic efficacy for glioblastoma. DOI: 10.11855/j.issn.0577-7402.2017.05.06

  4. Blood-brain barrier: a definition of normal and altered function.

    Science.gov (United States)

    Pollay, M; Roberts, P A

    1980-06-01

    The anatomical component of the blood-brain barrier (BBB) has been shown to be the cerebral capillary. These capillary endothelial cells are connected by continuous tight intercellular junctions and under normal conditions do not demonstrate transendothelial channels or pinocytotic vesicles. The rate that substances penetrate the BBB is related to molecular size, lipid solubility, and the presence of a specific carrier-mediated transport system. This latter mechanism for transendothelial passage is utilized for the movement of a wide variety of biologically important compounds such as sugars, amino acids, and organic acids. In certain pathological conditions, the permeability of the BBB is altered so that normally excluded plasma proteins and fluid enter the brain extracellular space, with the subsequent development of cerebral edema. In other abnormal conditions, alterations in the specialized transport systems operating across the cerebral capillary result in adverse changes in cerebral and neurotransmitter metabolism. An understanding of the unique properties of the BBB and of the changes that occur in pathological conditions has allowed the development of rational therapeutic strategies for a wide variety of diseases of the central nervous system.

  5. The phenotype of the human materno-fetal endothelial barrier: molecular occupancy of paracellular junctions dictate permeability and angiogenic plasticity.

    Science.gov (United States)

    Leach, Lopa

    2002-06-01

    In vitro models predict that molecular occupancy of endothelial junctions may regulate both barrier function and angiogenesis. Whether this is true in human vascular beds undergoing physiological angiogenesis has not been shown. This review presents data which demonstrate there are two distinct junctional phenotypes, 'activated' and 'stable', present in the vascular tree of the human placenta taken from two distinct highly angiogenic gestational periods (first and last trimester). Stability is conferred by the presence of occludin in tight junctions and plakoglobin in adherens junctions. Their localization may be influenced by vascular endothelial growth factor and angiopoietins 1 and 2 that have a similar temporal and site-specific differential expression. The junctional phenotypes are reversible, as shown in studies with endothelial cells isolated from placental microvessels and grown in the presence/absence of cAMP-enhancing agents. Reductions in protein levels and loss of junctional localization of adhesion molecules result in increased permeability to macromolecules, whilst up-regulation and re-targeting of these molecules inhibit cell proliferation and increase transendothelial resistance. These studies suggest junctional adhesion molecules can regulate physiological angiogenesis and vascular re-modelling. Moreover, the activated junctional phenotype of placental microvessels allows them to participate in increased growth and proliferation. This junctional immaturity appears to be at the expense of barrier function resulting in sites of maximal materno-fetal solute exchange.

  6. Remediation of chromium-contaminated soil by electrokinetics and electrokinetics coupled with CaAl-LDH permeable reaction barrier.

    Science.gov (United States)

    Xu, Yunfeng; Xia, Wei; Hou, Hetian; Zhang, Jia; Qian, Guangren

    2017-09-01

    The remediation of Cr(VI)-contaminated soil was investigated by electrokinetic (EK) and permeable-reactive-barrier assisted electrokinetic (EK-PRB). The medium of PRB was hydrocalumite (CaAl-LDH). The results showed that removal efficiency of hexavalent chromium (Cr(VI)) in EK-PRB and EK system was 96.49 and 85.50%, respectively. Simultaneously, the removal efficiency of total chromium (TCr) was 69.34 and 40.97% after 120-h treatment. The XRD, FTIR, and XPS analyses indicated that the reactive barrier media of CaAl-LDH successfully captured the chromium. Besides, the migration rate of chromium in EK-PRB was relatively faster than EK, since the media of PRB captured chromium in-time and reduced the influence of chromium accumulation on the migration of chromium. Moreover, the trivalent chromium (Cr(III)) was generated in EK/EK-PRB, and the chromium was stabilized in soil with the chemical speciations of oxidizable and residual fractions. Therefore, the treatment of EK-PRB and EK both increased the removal of chromium and decreased its environmental risks.

  7. REMOVAL OF ADDED NITRATE IN THE SINGLE, BINARY, AND TERNARY SYSTEMS OF COTTON BURR COMPOST, ZEROVALENT IRON, AND SEDIMENT: IMPLICATIONS FOR GROUNDWATER NITRATE REMEDIATION USING PERMEABLE REACTIVE BARRIERS

    Science.gov (United States)

    Recent research has shown that carbonaceous solid materials and zerovalent iron (Fe0) may potentially be used as media in permeable reactive barriers (PRBs) to degrade groundwater nitrate via heterotrophic denitrification in the solid carbon system, and via abiotic reduction and ...

  8. ENVIRONMENTAL RESEARCH BRIEF: LONG-TERM PERFORMANCE OF PERMEABLE REACTIVE BARRIERS USING ZERO-VALENT IRON: AN EVALUATION AT TWO SITES

    Science.gov (United States)

    Geochemical and microbiological factors that control long-term performance of subsurface permeable reactive barriers were evaluated at the Elizabeth City, NC and the Denver Federal Center, CO sites. These groundwater treatment systems use zero-valent iron filings to intercept an...

  9. Blood-retinal barrier glycerol permeability in diabetic macular edema and healthy eyes: estimations from macular volume changes after peroral glycerol

    DEFF Research Database (Denmark)

    Thornit, Dorte Nellemann; Vinten, Carl Martin; Sander, Birgit

    2010-01-01

    PURPOSE: To compare the changes in macular volume (MV) between healthy subjects and patients with diabetic macular edema (DME) after an osmotic load and to determine the glycerol permeability (P(gly)) of the blood-retinal barrier (BRB). METHODS: In this unmasked study, 13 patients with DME and 5 ...

  10. Metformin induces up-regulation of blood-brain barrier functions by activating AMP-activated protein kinase in rat brain microvascular endothelial cells.

    Science.gov (United States)

    Takata, Fuyuko; Dohgu, Shinya; Matsumoto, Junichi; Machida, Takashi; Kaneshima, Shuji; Matsuo, Mai; Sakaguchi, Shinya; Takeshige, Yuki; Yamauchi, Atsushi; Kataoka, Yasufumi

    2013-04-19

    Blood-brain barrier (BBB) disruption occurs frequently in CNS diseases and injuries. Few drugs have been developed as therapeutic candidates for facilitating BBB functions. Here, we examined whether metformin up-regulates BBB functions using rat brain microvascular endothelial cells (RBECs). Metformin, concentration- and time-dependently increased transendothelial electrical resistance of RBEC monolayers, and decreased RBEC permeability to sodium fluorescein and Evans blue albumin. These effects of metformin were blocked by compound C, an inhibitor of AMP-activated protein kinase (AMPK). AMPK stimulation with an AMPK activator, AICAR, enhanced BBB functions. These findings indicate that metformin induces up-regulation of BBB functions via AMPK activation. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Caveolin-1 expression regulates blood-retinal barrier permeability and retinal neovascularization in oxygen-induced retinopathy.

    Science.gov (United States)

    Tian, Xiao-Feng; Xia, Xiao-Bo; Xu, Hui-Zhuo; Xiong, Si-Qi; Jiang, Jian

    2012-01-01

    Caveolin-1 expression correlates with the permeability of endothelial barriers and angiogenesis. However, the role of caveolin-1 in retinal neovascularization remains unknown. We evaluated the effect of caveolin-1 on the blood-retina barrier and retinal neovascularization in a murine model of oxygen-induced retinopathy. Starting at postnatal day 7, mice were exposed to 75 ± 5% oxygen for 5 days and then returned to room air conditions to induce retinal neovascularization. Effects on blood-retina barrier were evaluated by Western blot analysis of extravasated albumin in the retina. Retinal neovascularization morphology was studied by fluorescence angiography and was quantified by counts of the endothelial nuclei that protruded into the vitreous cavity. Reverse transcription-polymerase chain reaction and Western blot analysis was used to examine retinal expression levels of caveolin-1. siRNA against caveolin-1 was injected intravitreally in the oxygen-induced retinopathy models. Effects on caveolin-1 mRNA and protein, and retinal neovascularization were assessed as described above. Caveolin-1 expression was found to increase during hypoxia and overexpression of caveolin-1 correlated with the appearance of extravascular albumin. Caveolin-1 siRNA reduced caveolin-1 mRNA and protein levels by 47.94% and 54.76%, respectively. Furthermore, caveolin-1 siRNA inhibition reduced retinal neovascularization by 51.3% and reduced albumin leakage by 56.32%. Caveolin-1 may play an important role in induction of retinal neovascularization. SiRNA against caveolin-1 can inhibit experimental retinal hyperpermeability and neovascularization. Therefore, the inhibition of caveolin-1 may be a powerful and novel therapeutic tool for the treatment of ischaemia-induced retinal diseases. © 2011 The Authors. Clinical and Experimental Ophthalmology © 2011 Royal Australian and New Zealand College of Ophthalmologists.

  12. Blood-brain barrier damage in vascular dementia.

    Science.gov (United States)

    Ueno, Masaki; Chiba, Yoichi; Matsumoto, Koichi; Murakami, Ryuta; Fujihara, Ryuji; Kawauchi, Machi; Miyanaka, Hiroshi; Nakagawa, Toshitaka

    2016-04-01

    New findings on flow or drainage pathways of brain interstitial fluid and cerebrospinal fluid have been made. The interstitial fluid flow has an effect on the passage of blood-borne substances in the brain parenchyma, especially in areas near blood-brain barrier (BBB)-free regions. Actually, blood-borne substances can be transferred in areas with intact BBB function, such as the hippocampus, the corpus callosum, periventricular areas, and medial portions of the amygdala, presumably through leaky vessels in the subfornical organs or the choroid plexus. Increasing evidence indicates that dysfunction of the BBB function may play a significant role in the pathogenesis of vascular dementia. Accordingly, we have examined which insults seen in patients suffering from vascular dementia have an effect on the BBB using experimental animal models exhibiting some phenotypes of vascular dementia. The BBB in the hippocampus was clearly deteriorated in Mongolian gerbils exposed to acute ischemia followed by reperfusion and also in stroke-prone spontaneously hypertensive rats (SHRSP) showing hypertension. The BBB in the corpus callosum was clearly deteriorated in Wistar rats with permanent ligation of the bilateral common carotid arteries showing chronic hypoperfusion. The BBB in the hippocampus and the olfactory bulb was mildly deteriorated in aged senescence accelerated prone mice (SAMP8) showing cognitive dysfunction. The BBB in the hippocampus was mildly deteriorated in aged animals with hydrocephalus. Mild endothelial damage was seen in hyperglycemic db/db mice. In addition, mRNA expression of osteopontin, matrix metalloproteinase-13 (MMP-13), and CD36 was increased in vessels showing BBB damage in hypertensive SHRSP. As osteopontin, MMP-13 and CD36 are known to be related to brain injury and amyloid β accumulation or clearance, BBB damage followed by increased gene expression of these molecules not only contributes to the pathogenesis of vascular dementia, but also bridges

  13. Permeable reactive barriers for the remediation of groundwater in a mining area: results for a pilot-scale project

    Science.gov (United States)

    Martinez-Sanchez, Maria Jose; Perez-Sirvent, Carmen; Garcia-Lorenzo, Maria Luz; Martinez-Lopez, Salvadora; Perez-Espinosa, Victor; Gonzalez-Ciudad, Eva; Belen Martinez-Martinez, Lucia; Hernandez, Carmen; Molina-Ruiz, Jose

    2017-04-01

    The Sierra Minera of Cartagena-La Union is located in the Region of Murcia, Southeast of Spain. This zone presents high levels of heavy metals due to natural, geogenic reasons. In addition, the prolonged mining activity, and subsequent abandonment of farms, has had consequences on the environment, including severe affectation of the groundwater in the area. To remediate this situation, the Permeable Reactive Barrier (PRB) technology was assayed, which required in addition to the hydro-geological study of the zone, a careful optimization study for the design and construction of PRBs. For such a purpose a pilot-scale project was developed, and this communication reports some of the most relevant findings obtained after a four-years monitorization period. The selected reactive material for the PRBs was limestone filler. The filler is a waste material produced in many factories in the zone. These residues have good adsorption properties, high alkalinity, low cost and high availability, which make them suitable for use in remediation. The PRB was constituted by a 50% limestone filler and 50% sand, a proportion optimized by means of independent batch experiments. A layer of gravel was placed at the top, and on it a layer of natural soil. The barrier was designed in the form of a continuous trench, because the level of the contaminated groundwater was not very deep. In this way, the barrier could be prepared with standard excavation equipment. Parallel to the barrier, 6 wells where arranged downstream for sample collection. The pH and conductivity of the samples was measured directly in situ, and the content of Zn, Cd, Cu, Fe, and Pb were analyzed in the laboratory. All the samples collected after the PRB was constructed had basic pH values between 7.5 and 8. The conductivity was between 5 and 11 mS / cm except for the well 4, which had a value of 3.70 mS / cm. The concentration values of trace elements were below the detection limit (atomic absorption measurement) in

  14. Computing the blood brain barrier (BBB) diffusion coefficient: A molecular dynamics approach

    Energy Technology Data Exchange (ETDEWEB)

    Shamloo, Amir, E-mail: shamloo@sharif.edu; Pedram, Maysam Z.; Heidari, Hossein; Alasty, Aria, E-mail: aalasti@sharif.edu

    2016-07-15

    Various physical and biological aspects of the Blood Brain Barrier (BBB) structure still remain unfolded. Therefore, among the several mechanisms of drug delivery, only a few have succeeded in breaching this barrier, one of which is the use of Magnetic Nanoparticles (MNPs). However, a quantitative characterization of the BBB permeability is desirable to find an optimal magnetic force-field. In the present study, a molecular model of the BBB is introduced that precisely represents the interactions between MNPs and the membranes of Endothelial Cells (ECs) that form the BBB. Steered Molecular Dynamics (SMD) simulations of the BBB crossing phenomenon have been carried out. Mathematical modeling of the BBB as an input-output system has been considered from a system dynamics modeling viewpoint, enabling us to analyze the BBB behavior based on a robust model. From this model, the force profile required to overcome the barrier has been extracted for a single NP from the SMD simulations at a range of velocities. Using this data a transfer function model has been obtained and the diffusion coefficient is evaluated. This study is a novel approach to bridge the gap between nanoscale models and microscale models of the BBB. The characteristic diffusion coefficient has the nano-scale molecular effects inherent, furthermore reducing the computational costs of a nano-scale simulation model and enabling much more complex studies to be conducted. - Highlights: • Molecular dynamics simulation of crossing nano-particles through the BBB membrane at different velocities. • Recording the position of nano-particle and the membrane-NP interaction force profile. • Identification of a frequency domain model for the membrane. • Calculating the diffusion coefficient based on MD simulation and identified model. • Obtaining a relation between continuum medium and discrete medium.

  15. Delivery of a peptide-drug conjugate targeting the blood brain barrier improved the efficacy of paclitaxel against glioma.

    Science.gov (United States)

    Li, Ying; Zheng, Xuemin; Gong, Min; Zhang, Jianning

    2016-11-29

    The challenge of effectively delivering therapeutic agents to the brain has created an entire field of active research devoted to overcoming the blood brain barrier (BBB) and efficiently delivering drugs to the brain. Angiopep-2 can trigger transcytosis and traverse the BBB by recognizing low-density lipoprotein related protein-1 (LRP-1) expressed on the brain capillary endothelial cells. Here, we designed a novel strategy for the delivery of drugs to the brain. The novel drug delivery system was a combination of a receptor-targeting ligand, such as low-density lipoprotein related protein 1, and a cell-penetrating peptide (CPP). It was hypothesized that this conjugate will enhance the delivery of associated therapeutic cargo across the BBB and increase the permeability of a solid tumor. Our findings indicate that the combination of these two agents in a delivery vehicle significantly improved translocation of small molecules (paclitaxel) into the brain compared to the vehicle treatment, which contained only receptor-targeting ligand. The application of this strategy could potentially expand the horizons for the treatment of central nervous system disorders.

  16. Rapidly profiling blood-brain barrier penetration with liposome EKC.

    Science.gov (United States)

    Wang, Yongjun; Sun, Jin; Liu, Hongzhuo; He, Zhonggui

    2007-07-01

    This report intended to study the potential of liposome EKC (LEKC) as a convenient and high-throughput screening tool to assess drug penetration across the blood-brain barrier (BBB). The retention factors (k) of 24 structurally diverse compounds were determined with LEKC and vesicle EKC (VEKC), respectively. Principal component analysis of the steady-state concentrations ratio of compounds in the brain and in the blood expressed as log BB, log k(LEKC), log k(VEKC), and other lipophilic descriptors including octanol/water partition coefficient (Clog P), octanol/water distribution coefficients (log D(7.4)), and polar surface area (PSA), showed the maximum similarity of partitioning processes in LEKC to drug penetration across the BBB. Furthermore, the log BB were correlated with the above five lipophilic descriptors, and the results showed that log k(LEKC) gave the better correlation coefficient (r(2) = 0.811, p <0.0001) than those of log D(7.4), Clog P, PSA, and log k(VEKC) (r(2) = 0.730, 0.672, 0.627, and 0.620, p <0.0001). This is the first report of the use of LEKC as a promising rapid tool to profile drug penetration across the BBB.

  17. The effect of regadenoson on the integrity of the human blood-brain barrier, a pilot study.

    Science.gov (United States)

    Jackson, Sadhana; George, Richard T; Lodge, Martin A; Piotrowski, Anna; Wahl, Richard L; Gujar, Sachin K; Grossman, Stuart A

    2017-05-01

    Regadenoson is an FDA approved adenosine receptor agonist which increases blood-brain barrier (BBB) permeability in rodents. Regadenoson is used clinically for pharmacologic cardiac stress testing using SPECT or CT imaging agents that do not cross an intact BBB. This study was conducted to determine if standard doses of regadenoson transiently disrupt the human BBB allowing higher concentrations of systemically administered imaging agents to enter the brain. Patients without known intracranial disease undergoing clinically indicated pharmacologic cardiac stress tests were eligible for this study. They received regadenoson (0.4 mg) followed by brain imaging with either 99m Tc-sestamibi for SPECT or visipaque for CT imaging. Pre- and post-regadenoson penetration of imaging agents into brain were quantified [SPECT: radioactive counts, CT: Hounsfield units (HU)] and compared using a matched-pairs t-test. Twelve patients (33% male, median 60 yo) were accrued: 7 SPECT and 5 CT. No significant differences were noted in pre- and post-regadenoson values using mean radionuclide counts (726 vs. 757) or HU (29 vs. 30). While animal studies have demonstrated that regadenoson transiently increases the permeability of the BBB to dextran and temozolomide, we were unable to document changes in the penetration of contrast agents in humans with intact BBB using the FDA approved doses of regadenoson for cardiac evaluation. Further studies are needed exploring alternate regadenoson dosing, schedules, and studies in patients with brain tumors; as transiently disrupting the BBB to improve drug entry into the brain is critical to improving the care of patients with CNS malignancies.

  18. Blood-brain barrier and cerebral blood flow: Age differences in hemorrhagic stroke

    Directory of Open Access Journals (Sweden)

    Semyachkina-Glushkovskaya Oxana

    2015-11-01

    Full Text Available Neonatal stroke is similar to the stroke that occurs in adults and produces a significant morbidity and long-term neurologic and cognitive deficits. There are important differences in the factors, clinical events and outcomes associated with the stroke in infants and adults. However, mechanisms underlying age differences in the stroke development remain largely unknown. Therefore, treatment guidelines for neonatal stroke must extrapolate from the adult data that is often not suitable for children. The new information about differences between neonatal and adult stroke is essential for identification of significant areas for future treatment and effective prevention of neonatal stroke. Here, we studied the development of stress-induced hemorrhagic stroke and possible mechanisms underlying these processes in newborn and adult rats. Using histological methods and magnetic resonance imaging, we found age differences in the type of intracranial hemorrhages. Newborn rats demonstrated small superficial bleedings in the cortex while adult rats had more severe deep bleedings in the cerebellum. Using Doppler optical coherent tomography, we found higher stress-reactivity of the sagittal sinus to deleterious effects of stress in newborn vs. adult rats suggesting that the cerebral veins are more vulnerable to negative stress factors in neonatal vs. adult brain in rats. However, adult but not newborn rats demonstrated the stroke-induced breakdown of blood brain barrier (BBB permeability. The one of possible mechanisms underlying the higher resistance to stress-related stroke injures of cerebral vessels in newborn rats compared with adult animals is the greater expression of two main tight junction proteins of BBB (occludin and claudin-5 in neonatal vs. mature brain in rats.

  19. Effect of chemical permeation enhancers on stratum corneum barrier lipid organizational structure and interferon alpha permeability.

    Science.gov (United States)

    Moghadam, Shadi H; Saliaj, Evi; Wettig, Shawn D; Dong, Chilbert; Ivanova, Marina V; Huzil, J Torin; Foldvari, Marianna

    2013-06-03

    The outermost layer of the skin, known as the stratum corneum (SC), is composed of dead corneocytes embedded in an intercellular lipid matrix consisting of ceramides, free fatty acids, and cholesterol. The high level of organization within this matrix protects the body by limiting the permeation of most compounds through the skin. While essential for its protective functions, the SC poses a significant barrier for the delivery of topically applied pharmaceutical agents. Chemical permeation enhancers (CPEs) can increase delivery of small drug compounds into the skin by interacting with the intercellular lipids through physical processes including extraction, fluidization, increased disorder, and phase separation. However, it is not clear whether these same mechanisms are involved in delivery of biotherapeutic macromolecules, such as proteins. Here we describe the effect of three categories of CPEs {solvents [ethanol, propylene glycol, diethylene glycol monoethyl ether (transcutol), oleic acid], terpenes [menthol, nerol, camphor, methyl salicylate], and surfactants [Tween 80, SDS, benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (Cremophor RH40), didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide (DTAB)]} on the lipid organizational structure of human SC as determined by X-ray scattering studies. Small- and wide-angle X-ray scattering studies were conducted to correlate the degree of structural changes and hydrocarbon chain packing in SC lipids caused by these various classes of CPEs to the extent of permeation of interferon alpha-2b (IFNα), a 19 kDa protein drug, into human skin. With the exception of solvents, propylene glycol and ethanol, all classes of CPEs caused increased disordering of lamellar and lateral packing of lipids. We observed that the highest degree of SC lipid disordering was caused by surfactants (especially SDS, DDAB, and DTAB) followed by terpenes, such as nerol. Interestingly, in vitro skin permeation studies

  20. Neurosurgical Techniques for Disruption of the Blood–Brain Barrier for Glioblastoma Treatment

    Directory of Open Access Journals (Sweden)

    Analiz Rodriguez

    2015-08-01

    Full Text Available The blood–brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood–brain barrier (BBB. We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE. These technologies can lead to transient BBB and blood–brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal.

  1. Intestinal permeability to glucose after experimental traumatic brain injury: effect of gadopentetate dimeglumine administration.

    Science.gov (United States)

    Santos, Alejandro; Gonçalves, Pedro; Araújo, João R; Martel, Fátima

    2008-09-01

    Traumatic injuries are the leading cause of mortality in individuals aged 1-44 years, and brain injury significantly contributes to the outcome in nearly one half of all deaths from trauma. At the intestinal level, traumatic brain injury (TBI) induces profound effects, including gastrointestinal mucosa ischaemia and motility dysfunction. However, nothing is known concerning the effect of TBI on the intestinal absorption of glucose. Hence, the aim of this study was to investigate the effect of TBI on the intestinal absorption of glucose by investigating the effect of TBI on the jejunal mucosal-to-serosal apparent permeability (AP-to-BL P(app)) to two glucose model substrates, (3)H-2-deoxy-D-glucose ((3)H-DG) and (3)H-3-O-methyl-D-glucose ((3)H-OMG), and to (14)C-sorbitol. Additionally, we tested if gadopentetate dimeglumine administration could prevent any of the changes observed after TBI. Traumatic brain injury induced an increase in the AP-to-BL P(app) to (3)H-DG. After a 100-min. perfusion of the jejunum, the AP-to-BL P(app) to (3)H-DG in TBI rats was almost 70% higher than in the control rats. There was no change, however, in the AP-to-BL P(app) to neither (3)H-OMG nor (14)C-sorbitol. Interestingly enough, gadopentetate dimeglumine was able to prevent the increase in the AP-to-BL P(app) to (3)H-DG observed after TBI. Given the differences in transport characteristics between (3)H-DG and (3)H-OMG, our results point to the possibility of the Na(+)-independent glucose transporter 2 (GLUT2) being activated by TBI (as the P(app) to (3)H-DG, a GLUT2 substrate, was increased) and the Na(+)-dependent glucose co-transporter (SGLT1) being inhibited by TBI (as the P(app) to (3)H-OMG, a GLUT2 and SGLT1 substrate, remained unchanged). Moreover, gadopentetate dimeglumine prevented these changes associated with TBI.

  2. Influence of dissolved inorganic carbon and calcium on gas formation and accumulation in iron permeable reactive barriers.

    Science.gov (United States)

    Ruhl, Aki S; Weber, Anne; Jekel, Martin

    2012-11-01

    Uncertainties in long-term reactivity and gas accumulation in Fe(0) permeable reactive barriers still hinder a broad application of this groundwater remediation technology. In this study long-term column experiments were conducted under varying geochemical conditions. Generation of hydrogen by anaerobic corrosion in Fe(0) reactive filters was mainly influenced by the mass flux of dissolved inorganic carbon. Both increased concentrations and volume flows led to a substantial rise in gas generation but only to slight differences of gas accumulation within the pores of the reactive filter. Comparisons of columns with different lengths showed higher averaged corrosion rates in the shorter and lower corrosion rates in the longer columns. Calcium in conjunction with dissolved inorganic carbon formed compact and localized aragonite minerals, while in the absence of calcium chukanovite dominated, which covered and passivated the reactive surface to a higher extent. Magnetite was the major crystalline corrosion product in the absence of carbonate and no decline in long term corrosion rates was observed within up to 700 days of operation. Total gas yields of columns were restricted by passivation and approached a volume of approximately 13.5 mL/g granulated cast iron. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. Formation of ferrihydrite and associated iron corrosion products in permeable reactive barriers of zero-valent iron

    Science.gov (United States)

    Furukawa, Yoko; Kim, Jin-Wook; Watkins, Janet; Wilkin, Richard T.

    2002-01-01

    Ferrihydrite, which is known to form in the presence of oxygen and to be stabilized by the adsorption of Si, PO4 and SO4, is ubiquitous in the fine-grained fractions of permeable reactive barrier (PRB) samples from the U.S. Coast Guard Support Center (Elizabeth City, NC) and the Denver Federal Center (Lakewood, CO) studied by high-resolution transmission electron microscopy and selected area electron diffraction. The concurrent energy-dispersive X-ray data indicate a strong association between ferrihydrite and metals such as Si, Ca, and Cr. Magnetite, green rust 1, aragonite, calcite, mackinawite, greigite and lepidocrocite were also present, indicative of a geochemical environment that is temporally and spatially heterogeneous. Whereas magnetite, which is known to form due to anaerobic Fe0 corrosion, passivates the Fe0 surface, ferrihydrite precipitation occurs away from the immediate Fe0 surface, forming small (<0.1 microm) discrete clusters. Consequently, Fe0-PRBs may remain effective for a longer period of time in slightly oxidized groundwater systems where ferrihydrite formation occurs compared to oxygen-depleted systems where magnetite passivation occurs. The ubiquitous presence of ferrihydrite suggests that the use of Fe0-PRBs may be extended to applications that require contaminant adsorption rather than, or in addition to, redox-promoted contaminant degradation.

  4. Enhanced remediation of Cr(VI)-contaminated soil by incorporating a calcined-hydrotalcite-based permeable reactive barrier with electrokinetics.

    Science.gov (United States)

    Zhang, Jia; Xu, Yunfeng; Li, Wentao; Zhou, Jizhi; Zhao, Jun; Qian, Guangren; Xu, Zhi Ping

    2012-11-15

    This paper describes the enhanced Cr(VI)-contaminated soil remediation via a combination of electrokinetics (EK) with a calcined-hydrotalcite-based permeable reactive barrier (PRB). First, this combination proved to be feasible, and remarkably facilitated Cr(VI) remediation in a column test. Then, lightly-to-severely (0.16-1.65 mg/g) Cr(VI)-contaminated soil was remediated in a simulated test with the calcined hydrotalcite as the PRB under an voltage of 10-30 V (i.e. an electric field intensity of 0.7-2.0 V/cm). The observations demonstrated that both PRB and EK are critical to efficient remediation and the high de-contamination efficiency is supposedly attributed to the synergistic effect, for which EK concentrates anionic chromate to the anode region and PRB media (calcined hydrotalcite) absorbs and immobilizes it. Thus we have shown that the combined PRB-EK system is highly adaptive and effective in remediation of a larger area contaminated with chromate and various anionic pollutants. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Column test-based optimization of the permeable reactive barrier (PRB) technique for remediating groundwater contaminated by landfill leachates

    Science.gov (United States)

    Zhou, Dan; Li, Yan; Zhang, Yinbo; Zhang, Chang; Li, Xiongfei; Chen, Zhiliang; Huang, Junyi; Li, Xia; Flores, Giancarlo; Kamon, Masashi

    2014-11-01

    We investigated the optimum composition of permeable reactive barrier (PRB) materials for remediating groundwater heavily contaminated by landfill leachate, in column tests using various mixtures of zero-valent iron (ZVI), zeolite (Zeo) and activated carbon (AC) with 0.01-0.25, 3.0-5.0 and 0.7-1.0 mm grain sizes, respectively. The main contributors to the removal of organic/inorganic contaminants were ZVI and AC, and the optimum weight ratio of the three PRB materials for removing the contaminants and maintaining adequate hydraulic conductivity was found to be 5:1:4. Average reductions in chemical oxygen demand (COD) and contents of total nitrogen (TN), ammonium, Ni, Pb and 16 polycyclic aromatic hydrocarbons (PAHs) from test samples using this mixture were 55.8%, 70.8%, 89.2%, 70.7%, 92.7% and 94.2%, respectively. We also developed a systematic method for estimating the minimum required thickness and longevity of the PRB materials. A ≥ 309.6 cm layer with the optimum composition is needed for satisfactory longevity, defined here as meeting the Grade III criteria (the Chinese National Bureau of Standards: GB/T14848/93) for in situ treatment of the sampled groundwater for ≥ 10 years.

  6. Biological permeable reactive barriers coupled with electrokinetic soil flushing for the treatment of diesel-polluted clay soil.

    Science.gov (United States)

    Mena, Esperanza; Ruiz, Clara; Villaseñor, José; Rodrigo, Manuel A; Cañizares, Pablo

    2015-01-01

    Removal of diesel from spiked kaolin has been studied in the laboratory using coupled electrokinetic soil flushing (EKSF) and bioremediation through an innovative biological permeable reactive barriers (Bio-PRBs) positioned between electrode wells. The results show that this technology is efficient in the removal of pollutants and allows the soil to maintain the appropriate conditions for microorganism growth in terms of pH, temperature, and nutrients. At the same time, EKSF was demonstrated to be a very interesting technology for transporting pollutants, microorganisms and nutrients, although results indicate that careful management is necessary to avoid the depletion of nutrients, which are effectively transported by electro-migration. After two weeks of operation, 30% of pollutants are removed and energy consumption is under 70 kWh m(-3). Main fluxes (electroosmosis and evaporation) and changes in the most relevant parameters (nutrients, diesel, microorganisms, surfactants, moisture conductivity and pH) during treatment and in a complete post-study analysis are studied to give a comprehensive description of the most relevant processes occurring in the soil (pollutant transport and biodegradation). Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Microbial and mineral evolution in zero valent iron-based permeable reactive barriers during long-term operations.

    Science.gov (United States)

    Kumar, Naresh; Millot, Romain; Battaglia-Brunet, Fabienne; Omoregie, Enoma; Chaurand, Perrine; Borschneck, Daniel; Bastiaens, Leen; Rose, Jérôme

    2016-03-01

    Impacts of subsurface biogeochemical processes over time have always been a concern for the long-term performance of zero valent iron (Fe(0))-based permeable reactive barriers (PRBs). To evaluate the biogeochemical impacts, laboratory experiments were performed using flow-through glass columns for 210 days at controlled temperature (20 °C). Two different particle sizes of Fe(0) were used in the columns, and to simulate indigenous microbial activity, extra carbon source was provided in the two columns (biotic columns) and the remaining two columns were kept abiotic using gamma radiations. Heavy metals (Zn, As) were removed efficiently in all the columns, and no exhaustion of treatment capability or clogging was observed during our experimental duration. Newly formed Fe mineral phases and precipitates were characterized using X-ray diffraction (XRD), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), and micro-XRF techniques in solid phase at the end of the experiment. In addition, 16S rRNA gene extraction was used for microbial community identification in biotic columns. During the incubation, microbial population shifted in favor of Desulfosporosinus species (sulfate-reducing bacteria) from initial dominance of Acidithiobacillus ferrooxidans in sediments. Dominant mineral phases detected in biotic columns were mackinawite (FeS) and sulfate green rust, while in abiotic columns, magnetite/maghemite phases were more prevalent.

  8. Assessing degradation rates of chlorinated ethylenes in column experiments with commercial iron materials used in permeable reactive barriers.

    Science.gov (United States)

    Ebert, Markus; Köber, Ralf; Parbs, Anika; Plagentz, Volkmar; Schäfer, Dirk; Dahmke, Andreas

    2006-03-15

    Multiple column experiments were performed using two commercial iron materials to evaluate the necessity and usefulness of preliminary investigations in permeable reactive barrier (PRB) design for chlorinated organics. Experiments were performed with contaminated groundwater and involved fresh iron granules or altered iron material excavated from PRBs. The determination of first-order rate coefficients by global nonlinear least-squares fittings indicated a variability in rate coefficients on 1 or 2 orders of magnitude. Geometric mean values of surface area normalized rate coefficients (in 10(-5) L m(-2) h(-1)) for fresh gray cast iron and iron sponge, respectively, are: tetrachloroethene (4.5, 2.6), trichloroethene (8.1, 3.3), cis-1,2-dichloroethene (3.1, 2.9), trans-1,2-dichloroethene (9.5, 5.3), 1,1-dichloroethene (4.0, 4.4), and vinyl chloride (1.6, 6.1). The increasing rate coefficients with decreasing grade of chlorination, which characterize degradation at iron sponge are linearly related to diffusion coefficients in water, suggesting diffusion limitation in the degradation process for this particular material, possibly due to a high inner surface. The variability in rate coefficients seems to be too high to use mean rate coefficients from published studies in the design procedure of PRBs, and variabilities cannot be related to groundwater characteristics, waterflow through the reactive cells, or secondary corrosion reactions.

  9. Environmental life cycle assessment of permeable reactive barriers: effects of construction methods, reactive materials and groundwater constituents.

    Science.gov (United States)

    Mak, Mark S H; Lo, Irene M C

    2011-12-01

    The effects of the construction methods, materials of reactive media and groundwater constituents on the environmental impacts of a permeable reactive barrier (PRB) were evaluated using life cycle assessment (LCA). The PRB is assumed to be installed at a simulated site contaminated by either Cr(VI) alone or Cr(VI) and As(V). Results show that the trench-based construction method can reduce the environmental impacts of the remediation remarkably compared to the caisson-based method due to less construction material consumption by the funnel. Compared to using the zerovalent iron (Fe(0)) and quartz sand mixture, the use of the Fe(0) and iron oxide-coated sand (IOCS) mixture can reduce the environmental impacts. In the presence of natural organic matter (NOM) in groundwater, the environmental impacts generated by the reactive media were significantly increased because of the higher usage of Fe(0). The environmental impacts are lower by using the Fe(0) and IOCS mixture in the groundwater with NOM, compared with using the Fe(0) and quartz sand mixture. Since IOCS can enhance the removal efficiency of Cr(VI) and As(V), the usage of the Fe(0) can be reduced, which in turn reduces the impacts induced by the reactive media.

  10. Reactive Transport Modeling for Mobilization of Arsenic in a Sediment Downgradient from an Iron Permeable Reactive Barrier

    Directory of Open Access Journals (Sweden)

    Sung-Wook Jeen

    2017-11-01

    Full Text Available Arsenic (As can be naturally present in the native aquifer materials and can be released to groundwater through reduction dissolution of iron oxides containing As. While granular iron permeable reactive barriers (PRBs can be effective for the treatment of arsenic in groundwater, the mobilization of arsenic in the sediment downgradient of the PRB might be an issue due to the reduced geochemical conditions generated by reactions in the PRB. The release of arsenic in the sediment downgradient from a proposed iron PRB was studied through laboratory column experiments and reactive transport modeling. The laboratory column experiments showed a significant removal of arsenic from the groundwater by granular iron (from the influent concentration of about 0.7 mg L−1 to less than 0.006 mg L−1 at the effluent; however, arsenic can be flushed out from the aquifer sediments (up to 0.09 mg L−1. The reactive transport modeling based on the geochemical reactions as suggested from the experiments, i.e., reductive dissolution of As-bearing goethite, was successful to reproduce the observed geochemical trends in the column experiments. This study can provide implications regarding the installation of iron PRBs to treat arsenic in groundwater and also be useful to understand geochemical behavior of arsenic under reduced conditions.

  11. Performance of iron filings and activated sludge as media for permeable reactive barriers to treat zinc contaminated groundwater

    Directory of Open Access Journals (Sweden)

    Chayapat Hassapak

    2015-02-01

    Full Text Available Zinc is one of the important contaminants in groundwater. Removal of zinc by iron filings, activated sludge and lateritic soil was studied with batch test. The lowest optimum pH for removal of zinc by iron filings, activated sludge and lateritic soil was 6. From isotherm studies iron filings and activated sludge were chosen as media for permeable reactive barrier (PRB. The PRB of 0.5-m thick was simulated in the unconfined aquifer with the distance of 21.5 m downgradient of the zinc contaminated site having constant concentration of 100 mg/l. The groundwater flow in the site was induced by the hydraulic gradient of 0.02. Simulation results indicated that the concentration of zinc of treated groundwater was less than 5 mg/l, which met Thai Groundwater Quality Standard for Drinking Purposes. The continuous PRBs using iron filings and activated sludge could treat zinc for 2,170 and 2,248 days, respectively

  12. Formation of ferrihydrite and associated iron corrosion products in permeable reactive barriers of zero-valent iron.

    Science.gov (United States)

    Furukawa, Yoko; Kim, Jin-Wook; Watkins, Janet; Wilkin, Richard T

    2002-12-15

    Ferrihydrite, which is known to form in the presence of oxygen and to be stabilized by the adsorption of Si, PO4 and SO4, is ubiquitous in the fine-grained fractions of permeable reactive barrier (PRB) samples from the U.S. Coast Guard Support Center (Elizabeth City, NC) and the Denver Federal Center (Lakewood, CO) studied by high-resolution transmission electron microscopy and selected area electron diffraction. The concurrent energy-dispersive X-ray data indicate a strong association between ferrihydrite and metals such as Si, Ca, and Cr. Magnetite, green rust 1, aragonite, calcite, mackinawite, greigite and lepidocrocite were also present, indicative of a geochemical environment that is temporally and spatially heterogeneous. Whereas magnetite, which is known to form due to anaerobic Fe0 corrosion, passivates the Fe0 surface, ferrihydrite precipitation occurs away from the immediate Fe0 surface, forming small (<0.1 microm) discrete clusters. Consequently, Fe0-PRBs may remain effective for a longer period of time in slightly oxidized groundwater systems where ferrihydrite formation occurs compared to oxygen-depleted systems where magnetite passivation occurs. The ubiquitous presence of ferrihydrite suggests that the use of Fe0-PRBs may be extended to applications that require contaminant adsorption rather than, or in addition to, redox-promoted contaminant degradation.

  13. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses.

    Science.gov (United States)

    Deeken, John F; Löscher, Wolfgang

    2007-03-15

    Despite scientific advances in understanding the causes and treatment of human malignancy, a persistent challenge facing basic and clinical investigators is how to adequately treat primary and metastatic brain tumors. The blood-brain barrier is a physiologic obstruction to the delivery of systemic chemotherapy to the brain parenchyma and central nervous system (CNS). A number of physiologic properties make the endothelium in the CNS distinct from the vasculature found in the periphery. Recent evidence has shown that a critical aspect of this barrier is composed of xenobiotic transporters which extrude substrates from the brain into the cerebrospinal fluid and systemic circulation. These transporters also extrude drugs and toxins if they gain entry into the cytoplasm of brain endothelial cells before they enter the brain. This review highlights the properties of the blood-brain barrier, including the location, function, and relative importance of the drug transporters that maintain this barrier. Primary and metastatic brain malignancy can compromise this barrier, allowing some access of chemotherapy treatment to reach the tumor. The responsiveness of brain tumors to systemic treatment found in past clinical research is discussed, as are possible explanations as to why CNS tumors are nonetheless able to evade therapy. Finally, strategies to overcome this barrier and better deliver chemotherapy into CNS tumors are presented.

  14. An isogenic blood-brain barrier model comprising brain endothelial cells, astrocytes, and neurons derived from human induced pluripotent stem cells.

    Science.gov (United States)

    Canfield, Scott G; Stebbins, Matthew J; Morales, Bethsymarie Soto; Asai, Shusaku W; Vatine, Gad D; Svendsen, Clive N; Palecek, Sean P; Shusta, Eric V

    2017-03-01

    The blood-brain barrier (BBB) is critical in maintaining a physical and metabolic barrier between the blood and the brain. The BBB consists of brain microvascular endothelial cells (BMECs) that line the brain vasculature and combine with astrocytes, neurons and pericytes to form the neurovascular unit. We hypothesized that astrocytes and neurons generated from human-induced pluripotent stem cells (iPSCs) could induce BBB phenotypes in iPSC-derived BMECs, creating a robust multicellular human BBB model. To this end, iPSCs were used to form neural progenitor-like EZ-spheres, which were in turn differentiated to neurons and astrocytes, enabling facile neural cell generation. The iPSC-derived astrocytes and neurons induced barrier tightening in primary rat BMECs indicating their BBB inductive capacity. When co-cultured with human iPSC-derived BMECs, the iPSC-derived neurons and astrocytes significantly elevated trans-endothelial electrical resistance, reduced passive permeability, and improved tight junction continuity in the BMEC cell population, while p-glycoprotein efflux transporter activity was unchanged. A physiologically relevant neural cell mixture of one neuron: three astrocytes yielded optimal BMEC induction properties. Finally, an isogenic multicellular BBB model was successfully demonstrated employing BMECs, astrocytes, and neurons from the same donor iPSC source. It is anticipated that such an isogenic facsimile of the human BBB could have applications in furthering understanding the cellular interplay of the neurovascular unit in both healthy and diseased humans. Read the Editorial Highlight for this article on page 843. © 2016 International Society for Neurochemistry.

  15. Uptake and metabolism of sulphated steroids by the blood-brain barrier in the adult male rat.

    Science.gov (United States)

    Qaiser, M Zeeshan; Dolman, Diana E M; Begley, David J; Abbott, N Joan; Cazacu-Davidescu, Mihaela; Corol, Delia I; Fry, Jonathan P

    2017-09-01

    Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism. Using rat brain perfusion in situ, we have found (3) H-PregS to enter more rapidly than (3) H-DHEAS and both to undergo extensive (> 50%) desulphation within 0.5 min of uptake. Enzyme activity for the steroid sulphatase catalysing this deconjugation was enriched in the capillary fraction of the blood-brain barrier and its mRNA expressed in cultures of rat brain endothelial cells and astrocytes. Although permeability measurements suggested a net efflux, addition of the efflux inhibitors GF120918 and/or MK571 to the perfusate reduced rather than enhanced the uptake of (3) H-DHEAS and (3) H-PregS; a further reduction was seen upon the addition of unlabelled steroid sulphate, suggesting a saturable uptake transporter. Analysis of brain fractions after 0.5 min perfusion with the (3) H-steroid sulphates showed no further metabolism of PregS beyond the liberation of free steroid pregnenolone. By contrast, DHEAS underwent 17-hydroxylation to form androstenediol in both the steroid sulphate and the free steroid fractions, with some additional formation of androstenedione in the latter. Our results indicate a gain of free steroid from circulating steroid sulphates as hormone precursors at the blood-brain barrier, with implications for ageing, neurogenesis, neuronal survival, learning and memory. © 2017 International Society for Neurochemistry.

  16. Interleukin-1β induces blood-brain barrier disruption by downregulating Sonic hedgehog in astrocytes.

    Directory of Open Access Journals (Sweden)

    Yue Wang

    Full Text Available The blood-brain barrier (BBB is composed of capillary endothelial cells, pericytes, and perivascular astrocytes, which regulate central nervous system homeostasis. Sonic hedgehog (SHH released from astrocytes plays an important role in the maintenance of BBB integrity. BBB disruption and microglial activation are common pathological features of various neurologic diseases such as multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Interleukin-1β (IL-1β, a major pro-inflammatory cytokine released from activated microglia, increases BBB permeability. Here we show that IL-1β abolishes the protective effect of astrocytes on BBB integrity by suppressing astrocytic SHH production. Astrocyte conditioned media, SHH, or SHH signal agonist strengthened BBB integrity by upregulating tight junction proteins, whereas SHH signal inhibitor abrogated these effects. Moreover, IL-1β increased astrocytic production of pro-inflammatory chemokines such as CCL2, CCL20, and CXCL2, which induce immune cell migration and exacerbate BBB disruption and neuroinflammation. Our findings suggest that astrocytic SHH is a potential therapeutic target that could be used to restore disrupted BBB in patients with neurologic diseases.

  17. Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model.

    Science.gov (United States)

    Machida, Takashi; Takata, Fuyuko; Matsumoto, Junichi; Miyamura, Tomoyuki; Hirata, Ryosuke; Kimura, Ikuya; Kataoka, Yasufumi; Dohgu, Shinya; Yamauchi, Atsushi

    2017-01-01

    Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood-brain barrier (BBB) exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS). We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD) for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and 125I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin-treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. 125I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1) and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte-thrombin interaction may play a key role in causing BBB dysfunction in obesity

  18. In vitro models of the blood-brain barrier

    DEFF Research Database (Denmark)

    Helms, Hans Christian Cederberg; Abbott, N Joan; Burek, Malgorzata

    2016-01-01

    components of plasma and xenobiotics. This "blood-brain barrier" function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug...

  19. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier

    NARCIS (Netherlands)

    Zuhorn, Inge; Georgieva, Julia V.; Hoekstra, Dick

    2015-01-01

    The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics

  20. Quantitative atlas of blood-brain barrier transporters, receptors, and tight junction proteins in rats and common marmoset.

    Science.gov (United States)

    Hoshi, Yutaro; Uchida, Yasuo; Tachikawa, Masanori; Inoue, Takashi; Ohtsuki, Sumio; Terasaki, Tetsuya

    2013-09-01

    The purpose of this study was to determine the protein amounts of blood-brain barrier (BBB) permeability-related transporters, receptors, and tight junction proteins in Sprague Dawley and Wistar rats and common marmoset, and also to investigate inter-species and inter-strain differences across rodents and primates. Quantification of target proteins in isolated brain capillaries was conducted by liquid chromatography-tandem mass spectrometry-based quantitative targeted absolute proteomics, with in silico peptide selection. Most target proteins showed inter-rodent, inter-primate species, and inter-rat strain differences of less than 2-fold. Comparison of rat and human BBB showed that P-glycoprotein, multidrug resistance-associated protein 4, monocarboxylate transporter 1, l-type amino acid transporter, and organic anion transporter 3 exhibited differences of more than two-fold in protein abundance, whereas the amounts of breast cancer resistance protein, glucose transporter 1, and insulin receptor were similar in rat and human. In contrast, the differences between marmoset and human BBB were less than 2-fold for almost all measured proteins. Thus, the molecular basis of BBB functions may be similar in marmoset and human, whereas that of rats shows significant differences. The marmoset may be a good model to access in vivo human BBB permeability characteristics, as an alternative to rat and macaque monkey. Copyright © 2013 Wiley Periodicals, Inc.

  1. Human Brain Microvascular Endothelial Cells Derived from the BC1 iPS Cell Line Exhibit a Blood-Brain Barrier Phenotype.

    Science.gov (United States)

    Katt, Moriah E; Xu, Zinnia S; Gerecht, Sharon; Searson, Peter C

    2016-01-01

    The endothelial cells that form capillaries in the brain are highly specialized, with tight junctions that minimize paracellular transport and an array of broad-spectrum efflux pumps that make drug delivery to the brain extremely challenging. One of the major limitations in blood-brain barrier research and the development of drugs to treat central nervous system diseases is the lack of appropriate cell lines. Recent reports indicate that the derivation of human brain microvascular endothelial cells (hBMECs) from human induced pluripotent stem cells (iPSCs) may provide a solution to this problem. Here we demonstrate the derivation of hBMECs extended to two new human iPSC lines: BC1 and GFP-labeled BC1. These hBMECs highly express adherens and tight junction proteins VE-cadherin, ZO-1, occludin, and claudin-5. The addition of retinoic acid upregulates VE-cadherin expression, and results in a significant increase in transendothelial electrical resistance to physiological values. The permeabilities of tacrine, rhodamine 123, and Lucifer yellow are similar to values obtained for MDCK cells. The efflux ratio for rhodamine 123 across hBMECs is in the range 2-4 indicating polarization of efflux transporters. Using the rod assay to assess cell organization in small vessels and capillaries, we show that hBMECs resist elongation with decreasing diameter but show progressive axial alignment. The derivation of hBMECs with a blood-brain barrier phenotype from the BC1 cell line highlights that the protocol is robust. The expression of GFP in hBMECs derived from the BC1-GFP cell line provides an important new resource for BBB research.

  2. YiQiFuMai powder injection ameliorates blood–brain barrier dysfunction and brain edema after focal cerebral ischemia–reperfusion injury in mice

    Directory of Open Access Journals (Sweden)

    Cao GS

    2016-01-01

    Full Text Available Guosheng Cao, Xinyi Ye, Yingqiong Xu, Mingzhu Yin, Honglin Chen, Junping Kou, Boyang Yu Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Complex Prescription of TCM, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: YiQiFuMai powder injection (YQFM is a modern preparation derived from the traditional Chinese medicine Sheng-Mai-San. YQFM is widely used in clinical practice in the People’s Republic of China, mainly for the treatment of microcirculatory disturbance-related diseases. However, little is known about its role in animals with ischemic stroke. The aim of this study was to examine the effect of YQFM on brain edema and blood–brain barrier (BBB dysfunction induced by cerebral ischemia–reperfusion (I/R injury. Male C57BL/6J mice underwent right middle cerebral artery occlusion for 1 hour with a subsequent 24-hour reperfusion to produce I/R injury. YQFM (three doses: 0.336, 0.671, and 1.342 g/kg was then given intraperitoneally (IP. The results demonstrated that YQFM significantly decreased infarct size, improved neurological deficits, reduced brain water content, and increased cerebral blood flow after I/R injury. 18F-fluorodeoxyglucose micro-positron emission tomography imaging and hematoxylin and eosin staining results indicated that YQFM is able to ameliorate brain metabolism and histopathological damage after I/R. Moreover, YQFM administration reduced BBB leakage and upregulated the expression of zona occludens-1 (ZO-1 and occludin, which was confirmed by Evans Blue extravasation, Western blotting, and immunofluorescence assay. Our findings suggest that YQFM provides protection against focal cerebral I/R injury in mice, possibly by improving BBB dysfunction via upregulation of the expression of tight junction proteins. Keywords: YiQiFuMai powder injection, YQFM, ischemic stroke, blood–brain barrier, microvascular permeability, tight junctions

  3. Fluid and ion transfer across the blood-brain and blood-cerebrospinal fluid barriers; a comparative account of mechanisms and roles.

    Science.gov (United States)

    Hladky, Stephen B; Barrand, Margery A

    2016-10-31

    The two major interfaces separating brain and blood have different primary roles. The choroid plexuses secrete cerebrospinal fluid into the ventricles, accounting for most net fluid entry to the brain. Aquaporin, AQP1, allows water transfer across the apical surface of the choroid epithelium; another protein, perhaps GLUT1, is important on the basolateral surface. Fluid secretion is driven by apical Na(+)-pumps. K(+) secretion occurs via net paracellular influx through relatively leaky tight junctions partially offset by transcellular efflux. The blood-brain barrier lining brain microvasculature, allows passage of O2, CO2, and glucose as required for brain cell metabolism. Because of high resistance tight junctions between microvascular endothelial cells transport of most polar solutes is greatly restricted. Because solute permeability is low, hydrostatic pressure differences cannot account for net fluid movement; however, water permeability is sufficient for fluid secretion with water following net solute transport. The endothelial cells have ion transporters that, if appropriately arranged, could support fluid secretion. Evidence favours a rate smaller than, but not much smaller than, that of the choroid plexuses. At the blood-brain barrier Na(+) tracer influx into the brain substantially exceeds any possible net flux. The tracer flux may occur primarily by a paracellular route. The blood-brain barrier is the most important interface for maintaining interstitial fluid (ISF) K(+) concentration within tight limits. This is most likely because Na(+)-pumps vary the rate at which K(+) is transported out of ISF in response to small changes in K(+) concentration. There is also evidence for functional regulation of K(+) transporters with chronic changes in plasma concentration. The blood-brain barrier is also important in regulating HCO3(-) and pH in ISF: the principles of this regulation are reviewed. Whether the rate of blood-brain barrier HCO3(-) transport is slow or

  4. Wnt activation of immortalized brain endothelial cells as a tool for generating a standardized model of the blood brain barrier in vitro.

    Directory of Open Access Journals (Sweden)

    Roberta Paolinelli

    Full Text Available Reproducing the characteristics and the functional responses of the blood-brain barrier (BBB in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.

  5. Tailoring Particle Size of Mesoporous Silica Nanosystem To Antagonize Glioblastoma and Overcome Blood-Brain Barrier.

    Science.gov (United States)

    Mo, Jianbin; He, Lizhen; Ma, Bin; Chen, Tianfeng

    2016-03-23

    The blood-brain barrier (BBB) is the main bottleneck to prevent some macromolecular substance entering the cerebral circulation, resulting the failure of chemotherapy in the treatment of glioma. Cancer nanotechnology displays potent applications in glioma therapy owing to their penetration across BBB and accumulation into the tumor core. In this study, we have tailored the particle size of mesoporous silica nanoparticles (MSNs) through controlling the hydrolysis rate and polycondensation degree of reactants, and optimized the nanosystem that could effectively penetrate BBB and target the tumor tissue to achieve enhanced antiglioma efficacy. The nanoparticle was conjugated with cRGD peptide to enhance its cancer targeting effect, and then used to load antineoplastic doxorubicin. Therefore, the functionalized nanosystem (DOX@MSNs) selectively recognizes and binds to the U87 cells with higher expression level of ανβ3 integrin, sequentially enhancing the cellular uptake and inhibition to glioma cells, especially the particle size at 40 nm. This particle could rapidly enter cancer cells and was difficult to excrete outside the cells, thus leading to high drug accumulation. Furthermore, DOX@MSNs exhibited much higher selectivity and anticancer activity than free DOX and induced the glioma cells apoptosis through triggering ROS overproduction. Interestingly, DOX@MSNs at about 40 nm exhibited stronger permeability across the BBB, and could disrupt the VM-capability of glioma cells by regulating the expression of E-cadherin, FAK, and MMP-2, thus achieving satisfactory antiglioblastoma efficacy and avoiding the unwanted toxic side effects to normal brain tissue. Taken together, these results suggest that tailoring the particle size of MSNs nanosystem could be an effective strategy to antagonize glioblastoma and overcome BBB.

  6. Hydraulic and geochemical performance of a permeable reactive barrier containing zero-valent iron, Denver Federal Center

    Science.gov (United States)

    McMahon, P.B.; Dennehy, K.F.; Sandstrom, M.W.

    1999-01-01

    The hydraulic and geochemical performance of a 366 m long permeable reactive barrier (PRB) at the Denver Federal Center; Denver, Colorado, was evaluated. The funnel and gate system, which was installed in 1996 to intercept and remediate ground water contaminated with chlorinated aliphatic hydrocarbons (CAHs), contained four 12.2 m wide gates filled with zero-valent iron. Ground water mounding on the upgradient side of the PRB resulted in a tenfold increase in the hydraulic gradient and ground water velocity through the gates compared to areas of the aquifer unaffected by the PRB. Water balance calculations for April 1997 indicate that about 75% of the ground water moving toward the PRB from upgradient areas moved through the gates. The rest of the water either accumulated on the upgradient side of the PRB or bypassed the PRB. Chemical data from monitoring wells screened down-gradient, beneath, and at the ends of the PRB indicate that contaminants had not bypassed the PRB, except in a few isolated areas. Greater than 99% of the CAH mass entering the gates was retained by the iron. Fifty-one percent of the CAH carbon entering one gate was accounted for in dissolved C1 and C2 hydrocarbons, primarily ethane and ethene, which indicates that CAHs may adsorb to the iron prior to being dehalogenated. Treated water exiting the gates displaced contaminated ground water at a distance of at least 3 m downgradient from the PRB by the end of 1997. Measurements of dissolved inorganic ions in one gate indicate that calcite and siderite precipitation in the gate could reduce gate porosity by about 0.35% per year. Results from this study indicate that funnel and gate systems containing zero-valent iron can effectively treat ground water contaminated with CAHs. However, the hydrologic impacts of the PRB on the flow system need to be fully understood to prevent contaminants from bypassing the PRB.

  7. Risk mitigation by waste-based permeable reactive barriers for groundwater pollution control at e-waste recycling sites.

    Science.gov (United States)

    Beiyuan, Jingzi; Tsang, Daniel C W; Yip, Alex C K; Zhang, Weihua; Ok, Yong Sik; Li, Xiang-Dong

    2017-02-01

    Permeable reactive barriers (PRBs) have proved to be a promising passive treatment to control groundwater contamination and associated human health risks. This study explored the potential use of low-cost adsorbents as PRBs media and assessed their longevity and risk mitigation against leaching of acidic rainfall through an e-waste recycling site, of which Cu, Zn, and Pb were the major contaminants. Batch adsorption experiments suggested a higher adsorption capacity of inorganic industrial by-products [acid mine drainage sludge (AMDS) and coal fly ash (CFA)] and carbonaceous recycled products [food waste compost (FWC) and wood-derived biochar] compared to natural inorganic minerals (limestone and apatite). Continuous leaching tests of sand columns with 10 wt% low-cost adsorbents were then conducted to mimic the field situation of acidic rainfall infiltration through e-waste-contaminated soils (collected from Qingyuan, China) by using synthetic precipitation leaching procedure (SPLP) solution. In general, Zn leached out first, followed by Cu, and finally delayed breakthrough of Pb. In the worst-case scenario (e.g., at initial concentrations equal to 50-fold of average SPLP result), the columns with limestone, apatite, AMDS, or biochar were effective for a relatively short period of about 20-40 pore volumes of leaching, after which Cu breakthrough caused non-cancer risk concern and later-stage Pb leaching considerably increased both non-cancer and lifetime cancer risk associated with portable use of contaminated water. In contrast, the columns with CFA or FWC successfully mitigated overall risks to an acceptable level for a prolonged period of 100-200 pore volumes. Therefore, with proper selection of low-cost adsorbents (or their mixture), waste-based PRBs is a technically feasible and economically viable solution to mitigate human health risk due to contaminated groundwater at e-waste recycling sites.

  8. FeS-coated sand for removal of arsenic(III) under anaerobic conditions in permeable reactive barriers

    Science.gov (United States)

    Han, Y.-S.; Gallegos, T.J.; Demond, A.H.; Hayes, K.F.

    2011-01-01

    Iron sulfide (as mackinawite, FeS) has shown considerable promise as a material for the removal of As(III) under anoxic conditions. However, as a nanoparticulate material, synthetic FeS is not suitable for use in conventional permeable reactive barriers (PRBs). This study developed a methodology for coating a natural silica sand to produce a material of an appropriate diameter for a PRB. Aging time, pH, rinse time, and volume ratios were varied, with a maximum coating of 4.0 mg FeS/g sand achieved using a pH 5.5 solution at a 1:4 volume ratio (sand: 2 g/L FeS suspension), three days of aging and no rinsing. Comparing the mass deposited on the sand, which had a natural iron-oxide coating, with and without chemical washing showed that the iron-oxide coating was essential to the formation of a stable FeS coating. Scanning electron microscopy images of the FeS-coated sand showed a patchwise FeS surface coating. X-ray photoelectron spectroscopy showed a partial oxidation of the Fe(II) to Fe(III) during the coating process, and some oxidation of S to polysulfides. Removal of As(III) by FeS-coated sand was 30% of that by nanoparticulate FeS at pH 5 and 7. At pH 9, the relative removal was 400%, perhaps due to the natural oxide coating of the sand or a secondary mineral phase from mackinawite oxidation. Although many studies have investigated the coating of sands with iron oxides, little prior work reports coating with iron sulfides. The results suggest that a suitable PRB material for the removal of As(III) under anoxic conditions can be produced through the deposition of a coating of FeS onto natural silica sand with an iron-oxide coating. ?? 2010 Elsevier Ltd.

  9. Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption

    NARCIS (Netherlands)

    Kobus, T.; Zervantonakis, I.K.; Zhang, Y; McDannold, N.J.

    2016-01-01

    HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the

  10. PDCD10 (CCM3) regulates brain endothelial barrier integrity in cerebral cavernous malformation type 3: role of CCM3-ERK1/2-cortactin cross-talk.

    Science.gov (United States)

    Stamatovic, Svetlana M; Sladojevic, Nikola; Keep, Richard F; Andjelkovic, Anuska V

    2015-11-01

    Impairment of brain endothelial barrier integrity is critical for cerebral cavernous malformation (CCM) lesion development. The current study investigates changes in tight junction (TJ) complex organization when PDCD10 (CCM3) is mutated/depleted in human brain endothelial cells. Analysis of lesions with CCM3 mutation and brain endothelial cells transfected with CCM3 siRNA (CCM3-knockdown) showed little or no increase in TJ transmembrane and scaffolding proteins mRNA expression, but proteins levels were generally decreased. CCM3-knockdown cells had a redistribution of claudin-5 and occludin from the membrane to the cytosol with no alterations in protein turnover but with diminished protein-protein interactions with ZO-1 and ZO-1 interaction with the actin cytoskeleton. The most profound effect of CCM3 mutation/depletion was on an actin-binding protein, cortactin. CCM3 depletion caused cortactin Ser-phosphorylation, dissociation from ZO-1 and actin, redistribution to the cytosol and degradation. This affected cortical actin ring organization, TJ complex stability and consequently barrier integrity, with constant hyperpermeability to inulin. A potential link between CCM3 depletion and altered cortactin was tonic activation of MAP kinase ERK1/2. ERK1/2 inhibition increased cortactin expression and incorporation into the TJ complex and improved barrier integrity. This study highlights the potential role of CCM3 in regulating TJ complex organization and brain endothelial barrier permeability.

  11. Immortalized endothelial cell lines for in vitro blood-brain barrier models: A systematic review.

    Science.gov (United States)

    Rahman, Nurul Adhwa; Rasil, Alifah Nur'ain Haji Mat; Meyding-Lamade, Uta; Craemer, Eva Maria; Diah, Suwarni; Tuah, Ani Afiqah; Muharram, Siti Hanna

    2016-07-01

    Endothelial cells play the most important role in construction of the blood-brain barrier. Many studies have opted to use commercially available, easily transfected or immortalized endothelial cell lines as in vitro blood-brain barrier models. Numerous endothelial cell lines are available, but we do not currently have strong evidence for which cell lines are optimal for establishment of such models. This review aimed to investigate the application of immortalized endothelial cell lines as in vitro blood-brain barrier models. The databases used for this review were PubMed, OVID MEDLINE, ProQuest, ScienceDirect, and SpringerLink. A narrative systematic review was conducted and identified 155 studies. As a result, 36 immortalized endothelial cell lines of human, mouse, rat, porcine and bovine origins were found for the establishment of in vitro blood-brain barrier and brain endothelium models. This review provides a summary of immortalized endothelial cell lines as a guideline for future studies and improvements in the establishment of in vitro blood-brain barrier models. It is important to establish a good and reproducible model that has the potential for multiple applications, in particular a model of such a complex compartment such as the blood-brain barrier. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Alterations of the Blood-Brain Barrier and Regional Perfusion in Tumor Development: MRI Insights from a Rat C6 Glioma Model.

    Directory of Open Access Journals (Sweden)

    Monika Huhndorf

    Full Text Available Angiogenesis and anti-angiogenetic medications play an important role in progression and therapy of glioblastoma. In this context, in vivo characterization of the blood-brain-barrier and tumor vascularization may be important for individual prognosis and therapy optimization.We analyzed perfusion and capillary permeability of C6-gliomas in rats at different stages of tumor-growth by contrast enhanced MRI and dynamic susceptibility contrast (DSC MRI at 7 Tesla. The analyses included maps of relative cerebral blood volume (CBV and signal recovery derived from DSC data over a time period of up to 35 days after tumor cell injections.In all rats tumor progression was accompanied by temporal and spatial changes in CBV and capillary permeability. A leakage of the blood-brain barrier (slow contrast enhancement was observed as soon as the tumor became detectable on T2-weighted images. Interestingly, areas of strong capillary permeability (fast signal enhancement were predominantly localized in the center of the tumor. In contrast, the tumor rim was dominated by an increased CBV and showed the highest vessel density compared to the tumor center and the contralateral hemisphere as confirmed by histology.Substantial regional differences in the tumor highlight the importance of parameter maps in contrast or in addition to region-of-interest analyses. The data vividly illustrate how MRI including contrast-enhanced and DSC-MRI may contribute to a better understanding of tumor development.

  13. Alterations of the Blood-Brain Barrier and Regional Perfusion in Tumor Development: MRI Insights from a Rat C6 Glioma Model.

    Science.gov (United States)

    Huhndorf, Monika; Moussavi, Amir; Kramann, Nadine; Will, Olga; Hattermann, Kirsten; Stadelmann, Christine; Jansen, Olav; Boretius, Susann

    2016-01-01

    Angiogenesis and anti-angiogenetic medications play an important role in progression and therapy of glioblastoma. In this context, in vivo characterization of the blood-brain-barrier and tumor vascularization may be important for individual prognosis and therapy optimization. We analyzed perfusion and capillary permeability of C6-gliomas in rats at different stages of tumor-growth by contrast enhanced MRI and dynamic susceptibility contrast (DSC) MRI at 7 Tesla. The analyses included maps of relative cerebral blood volume (CBV) and signal recovery derived from DSC data over a time period of up to 35 days after tumor cell injections. In all rats tumor progression was accompanied by temporal and spatial changes in CBV and capillary permeability. A leakage of the blood-brain barrier (slow contrast enhancement) was observed as soon as the tumor became detectable on T2-weighted images. Interestingly, areas of strong capillary permeability (fast signal enhancement) were predominantly localized in the center of the tumor. In contrast, the tumor rim was dominated by an increased CBV and showed the highest vessel density compared to the tumor center and the contralateral hemisphere as confirmed by histology. Substantial regional differences in the tumor highlight the importance of parameter maps in contrast or in addition to region-of-interest analyses. The data vividly illustrate how MRI including contrast-enhanced and DSC-MRI may contribute to a better understanding of tumor development.

  14. Stress plays provoking role in hypertension-related stroke: injuries of blood-brain barrier function

    Science.gov (United States)

    Semyachkina-Glushkovskaya, O.; Shirokov, A.; Gekalyuk, A.; Abakumov, M.; Navolokin, N.; Abdurashitov, A.; Pavlov, A.; Ulanova, M.; Fedorova, V.; Razubaeva, V.; Saranceva, E.; Li, P.; Huang, Q.; Zhu, D.; Luo, Q.; Tuchin, V.; Kurths, J.

    2017-02-01

    Chronic hypertension itself does not cause stroke but significantly decreases the resistant to stroke induced by stress due to exhausting of adaptive capacity of cerebral endothelium and decrease resistance of blood-brain barrier to stress.

  15. Dehydroepiandrosterone sulfate augments blood-brain barrier and tight junction protein expression in brain endothelial cells.

    Science.gov (United States)

    Papadopoulos, Dimitrios; Scheiner-Bobis, Georgios

    2017-08-01

    Tight junctions (TJ) between brain endothelial cells are essential for formation and maintenance of the blood-brain barrier (BBB). Although loss of BBB integrity is associated with several neuropathological disorders, treatments that augment or stabilise the BBB are scarce. Here we show that physiological concentrations of dehydroepiandrosterone sulfate (DHEAS) stimulate the expression of the TJ proteins zonula occludens-1 (ZO-1) and claudin-3 in the brain-derived endothelial cell line bEnd.3 and promote TJ formation between neighbouring cells, demonstrated by augmented transendothelial resistance across cell monolayers. Silencing androgen receptor expression by siRNA does not prevent DHEAS-induced stimulation of ZO-1 expression, indicating that conversion of DHEAS into testosterone is not required for its actions. Suppression of Gnα11 expression by siRNA prevents DHEAS actions, pointing towards a G-protein-coupled receptor as being a mediator of the DHEAS effects. These results are consistent with the idea that DHEAS, acting as a hormone in its own right, supports the integrity of the BBB. The current findings might help in developing new strategies for the prevention or treatment of neurological disorders associated with BBB defects. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. High and Low Molecular Weight Fluorescein Isothiocyanate (FITC)-Dextrans to Assess Blood-Brain Barrier Disruption: Technical Considerations.

    Science.gov (United States)

    Hoffmann, Angelika; Bredno, Jörg; Wendland, Michael; Derugin, Nikita; Ohara, Peter; Wintermark, Max

    2011-03-01

    This note is to report how histological preparation techniques influence the extravasation pattern of the different molecular sizes of fluorescein isothiocyanate (FITC)-dextrans, typically used as markers for blood-brain barrier leakage. By using appropriate preparation methods, false negative results can be minimized. Wistar rats underwent a 2-h middle cerebral artery occlusion and magnetic resonance imaging. After the last imaging scan, Evans blue and FITC-dextrans of 4, 40, and 70 kDa molecular weight were injected. Different histological preparation methods were used. Sites of blood-brain barrier leakage were analyzed by fluorescence microscopy. Extravasation of Evans blue and high molecular FITC-dextrans (40 and 70 kDa) in the infarcted region could be detected with all preparation methods used. If exposed directly to saline, the signal intensity of these FITC-dextrans decreased. Extravasation of the 4-kDa low molecular weight FITC-dextran could only be detected using freshly frozen tissue sections. Preparations involving paraformaldehyde and sucrose resulted in the 4-kDa FITC-dextran dissolving in these reactants and being washed out, giving the false negative result of no extravasation. FITC-dextrans represent a valuable tool to characterize altered blood-brain barrier permeability in animal models. Diffusion and washout of low molecular weight FITC-dextran can be avoided by direct immobilization through immediate freezing of the tissue. This pitfall needs to be known to avoid the false impression that there was no extravasation of low molecular weight FITC-dextrans.

  17. Disruption of the blood–brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels

    Science.gov (United States)

    2013-01-01

    Background Increasing evidence suggests seizures cause blood–brain barrier (BBB) dysfunction including decreased seizure threshold and higher onset potential of future seizures. However, the mechanisms underlying BBB damage in seizures remains poorly understood. Evidence in human and animal models shows BBB disruption is associated with activation of matrix metalloproteinase-9 (MMP-9) after cerebral ischemia and inflammation. The objective of this study was to determine whether MMP-9 concentrations in cerebral spinal fluid (CSF) are associated with BBB disruption in patients after epileptic seizures. Methods Thirty-one patients with generalized tonic-clonic (GTC) seizures were included in the study: 20 had recurrent GTC seizures (RS), and 11 had a single GTC seizure (SS) episode. Twenty-five adult non-seizure patients were used as controls. CSF samples were collected by lumbar puncture within 24 h after seizure cessation (range: 3–15 h, mean 6.2 h). CSF MMP-9 levels were determined by an enzyme-linked immunosorbent assay (ELISA). MMP enzyme activity was measured by gelatin zymography. The CSF/serum albumin ratio (albumin quotient, QAlb) was used as a measure of blood–brain barrier permeability. Results We found significantly higher CSF MMP-9 concentrations in seizure patients compared with controls (P seizures. Gelatin zymography showed MMP-9 proteolytic activity only in GTC seizure patients. Conclusions Our results suggest MMP-9 plays a role in BBB dysfunction, characterized by invasion of leukocytes into the CSF during seizures. PMID:23829879

  18. Disruption of the blood-brain barrier after generalized tonic-clonic seizures correlates with cerebrospinal fluid MMP-9 levels.

    Science.gov (United States)

    Li, Ya-Jun; Wang, Zheng-Hai; Zhang, Bei; Zhe, Xiao; Wang, Ming-Jue; Shi, Shao-Ting; Bai, Jing; Lin, Tao; Guo, Chang-Jiang; Zhang, Shi-Jun; Kong, Xiang-Li; Zuo, Xing; Zhao, Hang

    2013-07-05

    Increasing evidence suggests seizures cause blood-brain barrier (BBB) dysfunction including decreased seizure threshold and higher onset potential of future seizures. However, the mechanisms underlying BBB damage in seizures remains poorly understood. Evidence in human and animal models shows BBB disruption is associated with activation of matrix metalloproteinase-9 (MMP-9) after cerebral ischemia and inflammation. The objective of this study was to determine whether MMP-9 concentrations in cerebral spinal fluid (CSF) are associated with BBB disruption in patients after epileptic seizures. Thirty-one patients with generalized tonic-clonic (GTC) seizures were included in the study: 20 had recurrent GTC seizures (RS), and 11 had a single GTC seizure (SS) episode. Twenty-five adult non-seizure patients were used as controls. CSF samples were collected by lumbar puncture within 24 h after seizure cessation (range: 3-15 h, mean 6.2 h). CSF MMP-9 levels were determined by an enzyme-linked immunosorbent assay (ELISA). MMP enzyme activity was measured by gelatin zymography. The CSF/serum albumin ratio (albumin quotient, QAlb) was used as a measure of blood-brain barrier permeability. We found significantly higher CSF MMP-9 concentrations in seizure patients compared with controls (P seizures. Gelatin zymography showed MMP-9 proteolytic activity only in GTC seizure patients. Our results suggest MMP-9 plays a role in BBB dysfunction, characterized by invasion of leukocytes into the CSF during seizures.

  19. Organization of Endothelial Cells, Pericytes, and Astrocytes into a 3D Microfluidic in Vitro Model of the Blood-Brain Barrier.

    Science.gov (United States)

    Wang, Jack D; Khafagy, El-Sayed; Khanafer, Khalil; Takayama, Shuichi; ElSayed, Mohamed E H

    2016-03-07

    The endothelial cells lining the capillaries supplying the brain with oxygen and nutrients form a formidable barrier known as the blood-brain barrier (BBB), which exhibits selective permeability to small drug molecules and virtually impermeable to macromolecular therapeutics. Current in vitro BBB models fail to replicate this restrictive behavior due to poor integration of the endothelial cells with supporting cells (pericytes and astrocytes) following the correct anatomical organization observed in vivo. We report the coculture of mouse brain microvascular endothelial cells (b.End3), pericytes, with/without C8-D1A astrocytes in layered microfluidic channels forming three-dimensional (3D) bi- and triculture models of the BBB. The live/dead assay indicated high viability of all cultured cells up to 21 days. Trans-endothelial electrical resistance (TEER) values confirmed the formation of intact monolayers after 3 days in culture and showed statistically higher values for the triculture model compared to the single and biculture models. Screening the permeability of [(14)C]-mannitol and [(14)C]-urea showed the ability of bi- and triculture models to discriminate between different markers based on their size. Further, permeability of [(14)C]-mannitol across the triculture model after 18 days in culture matched its reported permeability across the BBB in vivo. Mathematical calculations also showed that the radius of the tight junctions pores (R) in the triculture model is similar to the reported diameter of the BBB in vivo. Finally, both the bi- and triculture models exhibited functional expression of the P-glycoprotein efflux pump, which increased with the increase in the number of days in culture. These results collectively indicate that the triculture model is a robust in vitro model of the BBB.

  20. Protozoa traversal of the blood-brain barrier to invade the central nervous system.

    Science.gov (United States)

    Elsheikha, Hany M; Khan, Naveed Ahmed

    2010-07-01

    Neuropathogenic protozoa have evolved strategies to breach the blood-brain barrier and invade the central nervous system. These include transcellular, paracellular and the Trojan horse routes but the associated molecular mechanisms remain incompletely understood. Here, we summarize the current understanding of protozoa penetration across the blood-brain barrier, focusing on Plasmodium, Babesia, Trypanosoma, Toxoplasma, Acanthamoeba and Balamuthia. Advances in understanding the molecular pathways will offer opportunities for the rational development of novel therapeutic interventions.

  1. Stroke and Drug Delivery--In Vitro Models of the Ischemic Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Tornabene, Erica; Brodin, Birger

    2016-01-01

    and Drug Administration-approved tissue plasminogen activator for treatment of acute ischemic stroke being the most prominent example. A large number of potential drug candidates for treatment of ischemic brain tissue have been developed and subsequently failed in clinical trials. A deeper understanding......Stroke is a major cause of death and disability worldwide. Both cerebral hypoperfusion and focal cerebral infarcts are caused by a reduction of blood flow to the brain, leading to stroke and subsequent brain damage. At present, only few medical treatments of stroke are available, with the Food...... of permeation pathways across the barrier in ischemic and postischemic brain endothelium is important for development of new medical treatments. The blood-brain barrier, that is, the endothelial monolayer lining the brain capillaries, changes properties during an ischemic event. In vitro models of the blood-brain...

  2. Confocal imaging of xenobiotic transport across the blood-brain barrier.

    Science.gov (United States)

    Miller, David S

    2003-11-01

    The brain capillary endothelium is a formidable barrier to entry of foreign chemicals into the central nervous system (CNS). For the most part it poorly distinguishes between therapeutics and neurotoxins and thus the blood-brain barrier both protects the brain from toxic chemicals and limits our ability to treat a variety of CNS disorders. Two elements underlie the barrier function of the brain capillary endothelium: 1). a physical barrier comprised of tight junctions, which form an effective seal to intercellular diffusion, and the cells themselves, which exhibit a low rate of endocytosis, and 2). a metabolic/active barrier, comprised of specific membrane transporters expressed by the endothelial cells. We have recently developed an experimental system based on confocal microscopy to study mechanisms of transport in freshly isolated brain capillaries. Here I review studies demonstrating a major role for the ATP-driven, xenobiotic export pump, p-glycoprotein, in barrier function and recent experiments showing that transient inhibition of pump function can have substantial benefit for chemotherapy in an animal model of brain cancer. Copyright 2003 Wiley-Liss, Inc.

  3. Transport of Glial Cell Line-Derived Neurotrophic Factor into Liposomes across the Blood-Brain Barrier: In Vitro and in Vivo Studies

    Directory of Open Access Journals (Sweden)

    Shaoling Wu

    2014-02-01

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF was encapsulated into liposomes in order to protect it from enzyme degradation in vivo and promote its permeability across the blood-brain barrier (BBB. In this study, GDNF conventional liposomes (GDNF-L and GDNF target sterically stabilized liposomes (GDNF-SSL-T were prepared. The average size of liposomes was below 90 nm. A primary model of BBB was established and evaluated by transendothelial electrical resistance (TEER and permeability. This BBB model was employed to study the permeability of GDNF liposomes in vitro. The results indicated that the liposomes could enhance transport of GDNF across the BBB and GDNF-SSL-T had achieved the best transport efficacy. The distribution of GDNF liposomes was studied in vivo. Free GDNF and GDNF-L were eliminated rapidly in the circulation. GDNF-SSL-T has a prolonged circulation time in the blood and favorable brain delivery. The values of the area under the curve (AUC(0–1 h in the brain of GDNF-SSL-T was 8.1 times and 6.8 times more than that of free GDNF and GDNF-L, respectively. These results showed that GDNF-SSL-T realized the aim of targeted delivery of therapeutic proteins to central nervous system.

  4. Enhancing the Attenuation of Acid-Mine Drainage at Davis Mine, Rowe, Massachusetts via Installation of a Permeable Reactive Barrier.

    Science.gov (United States)

    Gillmor, A. M.; Yuretich, R. F.

    2008-12-01

    Acid Mine Drainage affects thousands of streams in the United States, sustaining the need for low-cost passive treatment options. Davis Mine, a 100 years-abandoned FeS2 mine in Western Massachusetts, is representative of the types of mines best suited for passive treatments; fairly remote, abandoned, and discharging moderately affected water (pH 100mg/L, SO42- >500mg/L) and is a good candidate for a 'starting point' of low-cost, low environmental impact remediation. We here report the shifts in pH, SO42-, and Fe following placement of reactive fill (50% CaMg(CO3)2, 25% cow manure, 25% seaweed compost) in a permeable reactive barrier placed below ground mid-way along the acidic effluent's path. Yearlong monitoring of water from 1 multi-level well (with ports in the shallow groundwater, middle groundwater, and bedrock) placed within the tailings pile over a previous year (2003-2004) showed for the three levels, respectively; pH 3.16, 4.24, and 4.04, Fe average concentrations of 4.5 mg/L, 6.5 mg/L, and 3.2 mg/L, and SO42- average concentrations of 235mg/L, 330mg/L, and 292 mg/L. One year (2007-2008) after placement of remediation mix, the three levels now average respectively; pH 4.16, 4.60, and 4.53, Fe concentrations of 0.7 mg/L, 4.8 mg/L, and 1.4 mg/L, and SO42- concentrations of 217 mg/L, 294 mg/L, and 266 mg/L. The most noticeable improvement in pH is seen in the shallow groundwater, consistent with its proximity to the reactive fill depth. Although complex microbial communities have been characterized at the site, uncertainty remains as to whether they are active in this case, and it is possible that these results may be explained solely by neutralization reactions. Results of this study indicate a good likelihood that this low environmental impact remediation could be effective.

  5. Regulation of brain copper homeostasis by the brain barrier systems: Effects of Fe-overload and Fe-deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Monnot, Andrew D.; Behl, Mamta; Ho, Sanna; Zheng, Wei, E-mail: wzheng@purdue.edu

    2011-11-15

    Maintaining brain Cu homeostasis is vital for normal brain function. The role of systemic Fe deficiency (FeD) or overload (FeO) due to metabolic diseases or environmental insults in Cu homeostasis in the cerebrospinal fluid (CSF) and brain tissues remains unknown. This study was designed to investigate how blood-brain barrier (BBB) and blood-SCF barrier (BCB) regulated Cu transport and how FeO or FeD altered brain Cu homeostasis. Rats received an Fe-enriched or Fe-depleted diet for 4 weeks. FeD and FeO treatment resulted in a significant increase (+ 55%) and decrease (- 56%) in CSF Cu levels (p < 0.05), respectively; however, neither treatment had any effect on CSF Fe levels. The FeD, but not FeO, led to significant increases in Cu levels in brain parenchyma and the choroid plexus. In situ brain perfusion studies demonstrated that the rate of Cu transport into the brain parenchyma was significantly faster in FeD rats (+ 92%) and significantly slower (- 53%) in FeO rats than in controls. In vitro two chamber Transwell transepithelial transport studies using primary choroidal epithelial cells revealed a predominant efflux of Cu from the CSF to blood compartment by the BCB. Further ventriculo-cisternal perfusion studies showed that Cu clearance by the choroid plexus in FeD animals was significantly greater than control (p < 0.05). Taken together, our results demonstrate that both the BBB and BCB contribute to maintain a stable Cu homeostasis in the brain and CSF. Cu appears to enter the brain primarily via the BBB and is subsequently removed from the CSF by the BCB. FeD has a more profound effect on brain Cu levels than FeO. FeD increases Cu transport at the brain barriers and prompts Cu overload in the CNS. The BCB plays a key role in removing the excess Cu from the CSF.

  6. Sustained pharmacological inhibition of δPKC protects against hypertensive encephalopathy through prevention of blood-brain barrier breakdown in rats

    OpenAIRE

    Qi, Xin; Inagaki, Koichi; Sobel, Raymond A.; Mochly-Rosen, Daria

    2007-01-01

    Hypertensive encephalopathy is a potentially fatal condition associated with cerebral edema and the breakdown of the blood-brain barrier (BBB). The molecular pathways leading to this condition, however, are unknown. We determined the role of δPKC, which is thought to regulate microvascular permeability, in the development of hypertensive encephalopathy using δV1-1 — a selective peptide inhibitor of δPKC. As a model of hypertensive encephalopathy, Dahl salt-sensitive rats were fed an 8% high-s...

  7. Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound

    NARCIS (Netherlands)

    Kobus, T.; Vykhodtseva, N.; Pilatou, M.; Zhang, Y.; McDannold, N.

    2016-01-01

    The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between

  8. The immune system mediates blood-brain barrier damage; Possible implications for pathophysiology of neuropsychiatric illnesses

    NARCIS (Netherlands)

    VanderWerf, YD; DeJongste, MJL; terHorst, GJ

    1995-01-01

    The immune system mediates blood-brain barrier damage; possible implications for pathophysiology of neuropsychiatric illnesses. In this investigation the effects of immune activation on the brain are characterized In order to study this, we used a model for chronic immune activation, the myocardial

  9. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio.

    Science.gov (United States)

    Yang, Tianzhi; Martin, Paige; Fogarty, Brittany; Brown, Alison; Schurman, Kayla; Phipps, Roger; Yin, Viravuth P; Lockman, Paul; Bai, Shuhua

    2015-06-01

    The blood-brain barrier (BBB) essentially restricts therapeutic drugs from entering into the brain. This study tests the hypothesis that brain endothelial cell derived exosomes can deliver anticancer drug across the BBB for the treatment of brain cancer in a zebrafish (Danio rerio) model. Four types of exosomes were isolated from brain cell culture media and characterized by particle size, morphology, total protein, and transmembrane protein markers. Transport mechanism, cell uptake, and cytotoxicity of optimized exosome delivery system were tested. Brain distribution of exosome delivered anticancer drugs was evaluated using transgenic zebrafish TG (fli1: GFP) embryos and efficacies of optimized formations were examined in a xenotransplanted zebrafish model of brain cancer model. Four exosomes in 30-100 diameters showed different morphologies and exosomes derived from brain endothelial cells expressed more CD63 tetraspanins transmembrane proteins. Optimized exosomes increased the uptake of fluorescent marker via receptor mediated endocytosis and cytotoxicity of anticancer drugs in cancer cells. Images of the zebrafish showed exosome delivered anticancer drugs crossed the BBB and entered into the brain. In the brain cancer model, exosome delivered anticancer drugs significantly decreased fluorescent intensity of xenotransplanted cancer cells and tumor growth marker. Brain endothelial cell derived exosomes could be potentially used as a carrier for brain delivery of anticancer drug for the treatment of brain cancer.

  10. Brain barriers and functional interfaces with sequential appearance of ABC efflux transporters during human development

    DEFF Research Database (Denmark)

    Møllgård, Kjeld; Dziegielewska, Katarzyna M.; Holst, Camilla B.

    2017-01-01

    Adult brain is protected from entry of drugs and toxins by specific mechanisms such as ABC (ATP-binding Cassette) efflux transporters. Little is known when these appear in human brain during development. Cellular distribution of three main ABC transporters (ABCC1, ABCG2, ABCB1) was determined...... at blood-brain barriers and interfaces in human embryos and fetuses in first half of gestation. Antibodies against claudin-5 and-11 and antibodies to α-fetoprotein were used to describe morphological and functional aspects of brain barriers. First exchange interfaces to be established, probably at 4...... three transporters. Results provide evidence for sequential establishment of brain exchange interfaces and spatial and temporal timetable for three main ABC transporters in early human brain....

  11. Chronic depletion of gonadal testosterone leads to blood-brain barrier dysfunction and inflammation in male mice.

    Science.gov (United States)

    Atallah, Afnan; Mhaouty-Kodja, Sakina; Grange-Messent, Valérie

    2017-09-01

    A dysfunction in the blood-brain barrier (BBB) is associated with many neurological and metabolic disorders. Although sex steroid hormones have been shown to impact vascular tone, endothelial function, oxidative stress, and inflammatory responses, there are still no data on the role of testosterone in the regulation of BBB structure and function. In this context, we investigated the effects of gonadal testosterone depletion on the integrity of capillary BBB and the surrounding parenchyma in male mice. Our results show increased BBB permeability for different tracers and endogenous immunoglobulins in chronically testosterone-depleted male mice. These results were associated with disorganization of tight junction structures shown by electron tomography and a lower amount of tight junction proteins such as claudin-5 and ZO-1. BBB leakage was also accompanied by activation of astrocytes and microglia, and up-regulation of inflammatory molecules such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin 1 beta (IL-1β), and tumor necrosis factor (TNF). Supplementation of castrated male mice with testosterone restored BBB selective permeability, tight junction integrity, and almost completely abrogated the inflammatory features. The present demonstration that testosterone transiently impacts cerebrovascular physiology in adult male mice should help gain new insights into neurological and metabolic diseases linked to hypogonadism in men of all ages.

  12. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier.

    Science.gov (United States)

    Georgieva, Julia V; Hoekstra, Dick; Zuhorn, Inge S

    2014-11-17

    The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood-brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier-drug system ("Trojan horse complex") is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain.

  13. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood–Brain Barrier

    Directory of Open Access Journals (Sweden)

    Julia V. Georgieva

    2014-11-01

    Full Text Available The blood–brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood–brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier–drug system (“Trojan horse complex” is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain.

  14. A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

    Science.gov (United States)

    Xu, Hui; Li, Zhongyu; Yu, Yue; Sizdahkhani, Saman; Ho, Winson S.; Yin, Fangchao; Wang, Li; Zhu, Guoli; Zhang, Min; Jiang, Lei; Zhuang, Zhengping; Qin, Jianhua

    2016-11-01

    The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes-permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research.

  15. Paving the way towards complex blood-brain barrier models using pluripotent stem cells

    DEFF Research Database (Denmark)

    Lauschke, Karin; Frederiksen, Lise; Hall, Vanessa Jane

    2017-01-01

    A tissue with great need to be modelled in vitro is the blood-brain barrier (BBB). The BBB is a tight barrier that covers all blood vessels in the brain and separates the brain microenvironment from the blood system. It consists of three cell types (neurovascular unit (NVU)) that contribute......, it is now possible to produce many cell types from the BBB and even partially recapitulate this complex tissue in vitro. In this review, we summarize the most recent developments in PSC differentiation and modelling of the BBB. We also suggest how patient-specific human induced PSCs could be used to model...

  16. Electroconvulsive therapy, hypertensive surge, blood-brain barrier breach, and amnesia

    DEFF Research Database (Denmark)

    Andrade, Chittaranjan; Bolwig, Tom G

    2014-01-01

    Preclinical and clinical evidence show that electroconvulsive therapy (ECT)-induced intraictal surge in blood pressure may result in a small, transient breach in the blood-brain barrier, leading to mild cerebral edema and a possible leach of noxious substances from blood into brain tissues...... convincing evidence of benefits. It is concluded that there is insufficient support, at present, for the hypothesis that the hypertensive surge during ECT and the resultant blood-brain barrier breach contribute meaningfully to ECT-induced cognitive deficits. Future research should address the subset...

  17. Imaging blood-brain barrier dysfunction as a biomarker for epileptogenesis.

    Science.gov (United States)

    Bar-Klein, Guy; Lublinsky, Svetlana; Kamintsky, Lyn; Noyman, Iris; Veksler, Ronel; Dalipaj, Hotjensa; Senatorov, Vladimir V; Swissa, Evyatar; Rosenbach, Dror; Elazary, Netta; Milikovsky, Dan Z; Milk, Nadav; Kassirer, Michael; Rosman, Yossi; Serlin, Yonatan; Eisenkraft, Arik; Chassidim, Yoash; Parmet, Yisrael; Kaufer, Daniela; Friedman, Alon

    2017-06-01

    A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood-brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood-brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood-brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood-brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Effects of deferoxamine on blood-brain barrier disruption after subarachnoid hemorrhage

    OpenAIRE

    Yanjiang Li; Heng Yang; Wei Ni; Yuxiang Gu

    2017-01-01

    Blood brain barrier (BBB) disruption is a key mechanism of subarachnoid hemorrhage (SAH)-induced brain injury. This study examined the mechanism of iron-induced BBB disruption after SAH and investigated the potential therapeutic effect of iron chelation on SAH. Male adult Sprague-Dawley rats had an endovascular perforation of left internal carotid artery bifurcation or sham operation. The rats were treated with deferoxamine (DFX) or vehicle (100mg/kg) for a maximum of 7 days. Brain edema, BBB...

  19. Quantitative and Mechanistic Understanding of AZD1775 Penetration across Human Blood-Brain Barrier in Glioblastoma Patients using an IVIVE-PBPK Modeling Approach.

    Science.gov (United States)

    Li, Jing; Wu, Jianmei; Bao, Xun; Honea, Norissa; Xie, Youming; Kim, Seongho; Sparreboom, Alex; Sanai, Nader

    2017-09-19

    AZD1775, a first-in-class, small molecule inhibitor of the Wee1 tyrosine kinase, is under evaluation as a potential chemo- and radio-sensitizer for treating glioblastoma. This study was to prospectively, quantitatively, and mechanistically investigate the penetration of AZD1775 across human blood-brain barrier (BBB). AZD1775 plasma and tumor pharmacokinetics were evaluated in 20 glioblastoma patients. The drug metabolism, transcellular passive permeability, and interactions with efflux and uptake transporters were determined using human derived in vitro systems. A whole-body physiologically based pharmacokinetic (PBPK) model integrated with a 4-compartment permeability-limited brain model was developed for predicting the kinetics of AZD1775 BBB penetration and assessing the factors modulating this process. AZD1775 exhibited good tumor penetration in glioblastoma patients, with the unbound tumor-to-plasma concentration ratio ranging from 1.3 to 24.4 (median, 3.2). It was a substrate for ABCB1, ABCG2, and OATP1A2, but not for OATP2B1 or OAT3. AZD1775 transcellular passive permeability and active efflux clearance across MDCKII-ABCB1 or MDCKII-ABCG2 cell monolayers were dependent on the basolateral pH. The PBPK model well predicted observed drug plasma and tumor concentrations in patients. The extent and rate of drug BBB penetration were influenced by BBB integrity, efflux and uptake active transporter activity, and drug binding to brain tissue. In the relatively acidic tumor microenvironment where ABCB1/ABCG2 transporter-mediated efflux clearance is reduced, OATP1A2-mediated active uptake becomes dominant driving AZD1775 penetration into brain tumor. Variations in the brain tumor regional pH, transporter expression/activity, and BBB integrity collectively contribute to the heterogeneity of AZD1775 penetration into brain tumors. Copyright ©2017, American Association for Cancer Research.

  20. Changes in cerebral blood flow and blood brain barrier in the gerbil hippocampal CA1 region following repeated brief cerebral ischemia.

    Science.gov (United States)

    Jingtao, J.; Sato, S.; Yamanaka, N.

    1999-12-01

    Neuronal damage and changes in cerebral blood flow (CBF) and the permeability of the blood-brain barrier (BBB) following repeated brief periods of ischemia were studied in Mongolian gerbils. The cerebral ischemia was produced by three repeated occlusions of bilateral common carotid arteries for 3 min at 1-h intervals. CBF and permeability of the BBB were examined with tracers (China ink and silver nitrate) at 1, 3, and 7 days post ischemia using light and electron microscopy. Three days after the reperfusion, significant extravasation of tracers, consequential reduction of CBF, extensive neuronal destruction, and intravascular platelet aggregation were observed. Such vascular changes in the CA1 region were more severe than those in the frontal cortex. These findings strongly support the view that microcirculatory disturbance may be a mechanism responsible for delayed neuronal death in the CA1 region of the hippocampus.

  1. CD146 coordinates brain endothelial cell-pericyte communication for blood-brain barrier development.

    Science.gov (United States)

    Chen, Jianan; Luo, Yongting; Hui, Hui; Cai, Tanxi; Huang, Hongxin; Yang, Fuquan; Feng, Jing; Zhang, Jingjing; Yan, Xiyun

    2017-09-05

    The blood-brain barrier (BBB) establishes a protective interface between the central neuronal system and peripheral blood circulation and is crucial for homeostasis of the CNS. BBB formation starts when the endothelial cells (ECs) invade the CNS and pericytes are recruited to the nascent vessels during embryogenesis. Despite the essential function of pericyte-EC interaction during BBB development, the molecular mechanisms coordinating the pericyte-EC behavior and communication remain incompletely understood. Here, we report a single cell receptor, CD146, that presents dynamic expression patterns in the cerebrovasculature at the stages of BBB induction and maturation, coordinates the interplay of ECs and pericytes, and orchestrates BBB development spatiotemporally. In mouse brain, CD146 is first expressed in the cerebrovascular ECs of immature capillaries without pericyte coverage; with increased coverage of pericytes, CD146 could only be detected in pericytes, but not in cerebrovascular ECs. Specific deletion of Cd146 in mice ECs resulted in reduced brain endothelial claudin-5 expression and BBB breakdown. By analyzing mice with specific deletion of Cd146 in pericytes, which have defects in pericyte coverage and BBB integrity, we demonstrate that CD146 functions as a coreceptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular ECs. Moreover, we found that the attached pericytes in turn down-regulate endothelial CD146 by secreting TGF-β1 to promote further BBB maturation. These results reveal that the dynamic expression of CD146 controls the behavior of ECs and pericytes, thereby coordinating the formation of a mature and stable BBB.

  2. The joint power of sex and stress to modulate brain-gut-microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome.

    Science.gov (United States)

    Pigrau, M; Rodiño-Janeiro, B K; Casado-Bedmar, M; Lobo, B; Vicario, M; Santos, J; Alonso-Cotoner, C

    2016-04-01

    Intestinal homeostasis is a dynamic process that takes place at the interface between the lumen and the mucosa of the gastrointestinal tract, where a constant scrutiny for antigens and toxins derived from food and microorganisms is carried out by the vast gut-associated immune system. Intestinal homeostasis is preserved by the ability of the mucus layer and the mucosal barrier to keep the passage of small-sized and antigenic molecules across the epithelium highly selective. When combined and preserved, immune surveillance and barrier's selective permeability, the host capacity of preventing the development of intestinal inflammation is optimized, and viceversa. In addition, the brain-gut-microbiome axis, a multidirectional communication system that integrates distant and local regulatory networks through neural, immunological, metabolic, and hormonal signaling pathways, also regulates intestinal function. Dysfunction of the brain-gut-microbiome axis may induce the loss of gut mucosal homeostasis, leading to uncontrolled permeation of toxins and immunogenic particles, increasing the risk of appearance of intestinal inflammation, mucosal damage, and gut disorders. Irritable bowel syndrome is prevalent stress-sensitive gastrointestinal disorder that shows a female predominance. Interestingly, the role of stress, sex and gonadal hormones in the regulation of intestinal mucosal and the brain-gut-microbiome axis functioning is being increasingly recognized. We aim to critically review the evidence linking sex, and stress to intestinal barrier and brain-gut-microbiome axis dysfunction and the implications for irritable bowel syndrome. © 2015 John Wiley & Sons Ltd.

  3. Communication from the periphery to the hypothalamus through the blood-brain barrier: An in vitro platform.

    Science.gov (United States)

    Martins, João Pedro; Alves, Cecília Juliana; Neto, Estrela; Lamghari, Meriem

    2016-02-29

    One of the major routes of communication from the peripheral systems to the hypothalamus, the core structure of body homeostasis, is the humoral transmission through the blood-brain barrier (BBB). The BBB cultures are the in vitro model of choice to depict the mechanisms behind blood-brain interplay. Still, this strategy excludes the integration of the brain tissue response and, therefore, the resulting output might be limited. In this study, two in vitro assays were established: BBB coculture model and hypothalamic organotypic cultures. The combination of these two assays was used as a platform to address the two critical steps in the humoral transmission through the BBB to the brain: blood-BBB/BBB-brain. The in vitro model of the BBB was performed according to a coculture system using a brain microvascular endothelial cell line (bEnd.3) and primary astrocytes. The expression of junctional molecules as claudin-5, ZO-1, occludin and VE-cadherin was observed in the bEnd.3 cell-cell contact, confirming the BBB phenotype of these endothelial cells. Moreover, the transendothelial electrical resistance (TEER) values (71.1±9.4Ω× cm(2)) and the permeability coefficients (Pe) obtained in the transendothelial flux test (3.3±0.11×10(-6)cm/sec) support high integrity of the established barrier. The hypothalamic organotypic cultures were prepared from 8-days-old C57Bl/6 mice brains, based on the air-medium interface culture method. High cell viability (82±9.6%) and a dense neuronal network were achieved. The stimulation with dexamethasone resulted in an increased neuropeptide (NPY) expression, confirming the responsiveness of the neuronal system of these organotypic cultures. After optimization and characterization of each assay, the functionality of the platform was validated through the evaluation of the hypothalamic response to deep wound encompassing skin and muscle in mice. Results allowed to identify increased NPY activity in hypothalamic slices in response to

  4. Glutamate Efflux at the Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Cederberg-Helms, Hans Christian; Uhd-Nielsen, Carsten; Brodin, Birger

    2014-01-01

    L-Glutamate is considered the most important excitatory amino acid in the mammalian brain. Strict control of its concentration in the brain interstitial fluid is important to maintain neurotransmission and avoid excitotoxicity. The role of astrocytes in handling L-glutamate transport and metaboli...

  5. Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

    Energy Technology Data Exchange (ETDEWEB)

    Eum, Sung Yong, E-mail: seum@miami.edu; Jaraki, Dima; András, Ibolya E.; Toborek, Michal

    2015-09-15

    Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24 h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs. - Highlights: • PCB153 disturbed human brain endothelial barrier through disruption of occludin. • Lipid raft-associated PP

  6. Resuscitation of Hypotensive Traumatic Brain Injured Animals With Spray-Dried Plasma Does Not Adversely Alter Physiology and Improves Blood-Brain Barrier Function.

    Science.gov (United States)

    McDaniel, Steven; Golla, Stephanie; Moore, Anthony N; DaCorta, Joe; Bode, Arthur; Pati, Shibani; Dash, Pramod K; Zhao, Jing

    2017-07-01

    According to the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Center, the number of soldiers who have sustained a traumatic brain injury (TBI) has risen dramatically over the past decade. Studies have shown that brain damage can be exacerbated if blood loss occurs (often occurring in polytrauma). As blood supply is critical for brain function and survival, TBI patients must be properly resuscitated to maintain blood volume, blood pressure, and cerebral perfusion. Recent studies have suggested that blood loss can damage the vascular endothelium and enhance blood-brain barrier (BBB) permeability. Brain endothelial cells and the tight junctions between them are key structural components of the BBB. As the BBB is critical for isolating the brain from potential pathogens and for regulating the influx of molecules into the brain, evaluation of resuscitation fluids for their efficacy to improve BBB function has clinical relevance. Although whole blood and fresh frozen plasma (FFP) contain the essential coagulation factors, ions, and other factors, the transport and storage of these products in remote, austere environments can be challenging. The use of spray-dried plasma (SDP) has several advantages including storage at ambient temperature, can be readily reconstituted before use, and infectious materials can be inactivated during the drying process. In this study, we compared FFP and SDP for their effects on blood pressure, cerebral blood flow, BBB integrity, and markers of endothelial cells and tight junction proteins, in TBI animals with blood loss. All procedures were reviewed and approved by the UTHealth animal welfare committee. Sprague Dawley rats received controlled cortical impact brain injury followed by removal of 25% blood volume. Animals were resuscitated 40 minutes later with either FFP or concentrated SDP (Resusix) Heart rate and blood pressure were monitored continuously using catheters implanted into the femoral artery

  7. Low permeability to oxygen of a new barrier film prevents butyric acid bacteria spore formation in farm corn silage.

    Science.gov (United States)

    Borreani, G; Tabacco, E

    2008-11-01

    The outgrowth of Clostridium spore-forming bacteria causes late blowing in cheeses. Recently, the role of air diffusion during storage and feed-out and the role of aerobic deterioration has been shown to indirectly favor butyric acid bacteria (BAB) growth and to determine the presence of high concentrations of BAB spores in farm tank milk. A new oxygen barrier (OB) film was tested and compared with conventional polyethylene (ST). The objective was to verify whether the OB film could prevent BAB spore formation in whole-crop corn silage during storage on 2 commercial farms with different potential silage spoilage risks. Two bunkers (farms 1 and 2) were divided into 2 parts along the length so that half the feed-out face would be covered with ST film and the other half with OB film. Plastic net bags with freshly chopped corn were buried in the upper layer and in the central part (CORE) of the bunkers. The silos were opened in summer and fed out at different removal rates (19 vs. 33 cm/d). Herbage at ensiling, silage at unloading, and silage after air exposure (6 and 15 d) were analyzed for pH, nitrate, BAB spores, yeasts, and molds. The BAB spores in herbages at ensiling were 2.84 log(10) most probable number (MPN)/g, with no differences between treatments or farms. Nitrate was below the detection limit on farm 1 and exceeded 2,300 mg/kg of fresh matter on farm 2. At unloading, the BAB spores in the ST silage on farm 1 were greater than 5 log(10) MPN/g, whereas in the CORE and the OB silages, they were approximately 2 log(10) MPN/g. The ST silage had the greatest pH (5.89), the greatest mold count (5.07 log(10) cfu/g), and the greatest difference between silage temperature and ambient temperature (dT(section-ambient)). On farm 2, the ST silage had the greatest concentration of BAB spores (2.19 log(10) MPN/g), the greatest pH (4.05), and the least nitrate concentration compared with the CORE and the OB silages. Pooled data on BAB spores collected from aerobically

  8. Blood brain barrier and Alzheimer's disease: Similarity and dissimilarity of molecular alerts.

    Science.gov (United States)

    Toropova, Alla P; Toropov, Andrey A; Begum, S; Achary, P G R

    2017-10-16

    Blood brain barrier and Alzheimer's disease are interrelated. This interrelation is detected by physicochemical methods, pharmacological and electrophysiological analyses. Nature of the phenomenon is extremely complex. The description of this interrelation in mathematical terms is very important task. The systematization of facts, which are described in the literature and related to interaction between processes, which influence on Alzheimer's disease and blood brain barrier is object of this work. In addition, the establishing of correlations between molecular features and endpoints, which are related to treatment of Alzheimer's disease and blood brain barrier using the CORAL software are objects study in this work. The logically structural analysis of information available in the literature; and building up quantitative structure - activity relationships (QSARs) by the Monte Carlo method has been used to solve the task of systematization of facts related to "treatment Alzheimer's disease vs. blood brain barrier". Comparison of agreements and disagreements of available published papers together with the statistical quality of built up QSARs are results of this work. The facts from published papers; and technical details of QSAR built up in this study give possibility to formulate the following rules: (i) there are molecular alerts, which are promoters of increase of blood brain barrier and therapeutic activity of anti-Alzheimer disease agents; (ii) there are molecular alerts, which contradict each other. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. In vitro screening of nanomedicines through the blood brain barrier: A critical review.

    Science.gov (United States)

    Aparicio-Blanco, Juan; Martín-Sabroso, Cristina; Torres-Suárez, Ana-Isabel

    2016-10-01

    The blood-brain barrier accounts for the high attrition rate of the treatments of most brain disorders, which therefore remain one of the greatest health-care challenges of the twenty first century. Against this background of hindrance to brain delivery, nanomedicine takes advantage of the assembly at the nanoscale of available biomaterials to provide a delivery platform with potential to raising brain levels of either imaging or therapeutic agents. Nevertheless, to prevent later failure due to ineffective drug levels at the target site, researchers have been endeavoring to develop a battery of in vitro screening procedures that can predict earlier in the drug discovery process the ability of these cutting-edge drug delivery platforms to cross the blood-brain barrier for biomedical purposes. This review provides an in-depth analysis of the currently available in vitro blood-brain barrier models (both cell-based and non-cell-based) with the focus on their suitability for understanding the biological brain distribution of forthcoming nanomedicines. The relationship between experimental factors and underlying physiological assumptions that would ultimately lead to a more predictive capacity of their in vivo performance, and those methods already assayed for the evaluation of the brain distribution of nanomedicines are comprehensively discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. The role of shear stress in Blood-Brain Barrier endothelial physiology

    Directory of Open Access Journals (Sweden)

    Puvenna Vikram

    2011-05-01

    Full Text Available Abstract Background One of the most important and often neglected physiological stimuli contributing to the differentiation of vascular endothelial cells (ECs into a blood-brain barrier (BBB phenotype is shear stress (SS. With the use of a well established humanized dynamic in vitro BBB model and cDNA microarrays, we have profiled the effect of SS in the induction/suppression of ECs genes and related functions. Results Specifically, we found a significant upregulation of tight and adherens junctions proteins and genes. Trans-endothelial electrical resistance (TEER and permeability measurements to know substances have shown that SS promoted the formation of a tight and highly selective BBB. SS also increased the RNA level of multidrug resistance transporters, ion channels, and several p450 enzymes. The RNA level of a number of specialized carrier-mediated transport systems (e.g., glucose, monocarboxylic acid, etc. was also upregulated. RNA levels of modulatory enzymes of the glycolytic pathway (e.g., lactate dehydrogenase were downregulated by SS while those involved in the Krebs cycle (e.g., lactate and other dehydrogenases were upregulated. Measurements of glucose consumption versus lactate production showed that SS negatively modulated the glycolytic bioenergetic pathways of glucose metabolism in favor of the more efficient aerobic respiration. BBB ECs are responsive to inflammatory stimuli. Our data showed that SS increased the RNA levels of integrins and vascular adhesion molecules. SS also inhibited endothelial cell cycle via regulation of BTG family proteins encoding genes. This was paralleled by significant increase in the cytoskeletal protein content while that of membrane, cytosol, and nuclear sub-cellular fractions decreased. Furthermore, analysis of 2D gel electrophoresis (which allows identifying a large number of proteins per sample of EC proteins extracted from membrane sub-cellular endothelial fractions showed that SS increased

  11. The blood-brain barrier in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, L.; Tfelt-Hansen, P.

    2008-01-01

    Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access...... vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy Udgivelsesdato: 2008/12...

  12. Contamination movement around a permeable reactive barrier at Solid Waste Management Unit 12, Naval Weapons Station Charleston, North Charleston, South Carolina, 2009

    Science.gov (United States)

    Vroblesky, Don A.; Petkewich, Matthew D.; Conlon, Kevin J.

    2010-01-01

    The U.S. Geological Survey and the Naval Facilities Engineering Command Southeast investigated natural and engineered remediation of chlorinated volatile organic compound groundwater contamination at Solid Waste Management Unit 12 at the Naval Weapons Station Charleston, North Charleston, South Carolina, beginning in 2000. In early 2004, groundwater contaminants began moving around the southern end of a permeable reactive barrier (PRB) installed by a consultant in December 2002. The PRB is a 130-foot-long and 3-foot-wide barrier consisting of varying amounts of zero-valent iron with or without sand mixture. Contamination moving around the PRB probably has been transported at least 75 feet downgradient from the PRB at a rate of about 15 to 29 feet per year.

  13. Andrographolide-loaded nanoparticles for brain delivery: Formulation, characterisation and in vitro permeability using hCMEC/D3 cell line.

    Science.gov (United States)

    Guccione, Clizia; Oufir, Mouhssin; Piazzini, Vieri; Eigenmann, Daniela Elisabeth; Jähne, Evelyn Andrea; Zabela, Volha; Faleschini, Maria Teresa; Bergonzi, Maria Camilla; Smiesko, Martin; Hamburger, Matthias; Bilia, Anna Rita

    2017-10-01

    Andrographolide (AG) is a major diterpenoid of the Asian medicinal plant Andrographis paniculata which has shown exciting pharmacological potential for the treatment of inflammation-related pathologies including neurodegenerative disorders. Conversely, the low bioavailability of AG still represents a limiting factor for its use. To overcome these limitations, AG was loaded into human serum albumin based nanoparticles (HSA NPs) and poly ethylcyanoacrylate nanoparticles (PECA NPs). HSA NPs were prepared by thermal (HSAT AG NPs) and chemical cross-linking (HSAC AG NPs), while PECA AG NPs were produced by emulsion-polymerization. NPs were characterized in terms of size, zeta (ζ)-potential, polydispersity, and release studies of AG. In addition, the ability of free AG and AG-loaded in PECA and HSAT NPs to cross the blood-brain barrier (BBB) was assessed using an in vitro BBB model based on human cerebral microvascular endothelial cell line (hCMEC/D3). For BBB drug permeability assays, a quantitative UPLC-MS/MS method for AG in Ringer HEPES buffer was developed and validated according to international regulatory guidelines for industry. Free AG did not permeate the BBB model, as also predicted by in silico studies. HSAT NPs improved by two-fold the permeation of AG while maintaining the integrity of the cell layer, while PECA NPs temporarily disrupted BBB integrity. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Diabetic and sympathetic influences on the water permeability barrier function of human skin as measured using transepidermal water loss: A case-control study.

    Science.gov (United States)

    Han, Seung Hoon; Park, Ji Woong

    2017-11-01

    The presence of long-standing hyperglycemic conditions has been suggested to lead to many skin problems associated with an impaired skin barrier function. However, the relationship between impaired skin barrier status and altered peripheral nervous system function has not yet been determined. The purpose of this study was to investigate the water evaporation rate as a measure of the permeability barrier function of diabetic skin and its relationship to diabetic sensorimotor polyneuropathy (DSPN) and peripheral autonomic neuropathy (PAN) using well-controlled confounding variables.This case-control study included 42 participants with chronic diabetes and 43 matched healthy controls. The diabetic group underwent a nerve conduction study and sympathetic skin response (SSR) test to confirm the presence of DSPN and PAN, respectively. Different skin regions were analyzed using the noninvasive Tewameter instrument (Courage + Khazaka Electronic GmbH, Cologne, Germany). The impacts of PAN, DSPN, age, and diabetes duration on the values of transepidermal water loss (TEWL) were each analyzed and compared between the groups.Regardless of the presence of DSPN or PAN, the TEWL values as measured on the distal extremities were significantly lower in the diabetic group than in the control group. In the diabetic group, participants with abnormal SSR test results showed decreased TEWL values in the finger, sole, and first toe, as compared with participants with normal SSR test results. In the control group, age showed a negative correlation with the TEWL values with respect to some measured regions. However, in the diabetic group, there was no significant correlation between either patient age or diabetes duration and TEWL values.The presence of a long-term hyperglycemic state can reduce the permeability barrier function of the skin, a phenomenon that might be related to the presence of an impaired peripheral sympathetic nervous system, rather than peripheral sensorimotor

  15. TNAP and EHD1 are over-expressed in bovine brain capillary endothelial cells after the re-induction of blood-brain barrier properties.

    Directory of Open Access Journals (Sweden)

    Barbara Deracinois

    Full Text Available Although the physiological properties of the blood-brain barrier (BBB are relatively well known, the phenotype of the component brain capillary endothelial cells (BCECs has yet to be described in detail. Likewise, the molecular mechanisms that govern the establishment and maintenance of the BBB are largely unknown. Proteomics can be used to assess quantitative changes in protein levels and identify proteins involved in the molecular pathways responsible for cellular differentiation. Using the well-established in vitro BBB model developed in our laboratory, we performed a differential nano-LC MALDI-TOF/TOF-MS study of Triton X-100-soluble protein species from bovine BCECs displaying either limited BBB functions or BBB functions re-induced by glial cells. Due to the heterogeneity of the crude extract, we increased identification yields by applying a repeatable, reproducible fractionation process based on the proteins' relative hydrophobicity. We present proteomic and biochemical evidence to show that tissue non-specific alkaline phosphatase (TNAP and Eps15 homology domain-containing protein 1(EDH1 are over-expressed by bovine BCECs after the re-induction of BBB properties. We discuss the impact of these findings on current knowledge of endothelial and BBB permeability.

  16. Initial contact of glioblastoma cells with existing normal brain endothelial cells strengthen the barrier function via fibroblast growth factor 2 secretion: a new in vitro blood-brain barrier model.

    Science.gov (United States)

    Toyoda, Keisuke; Tanaka, Kunihiko; Nakagawa, Shinsuke; Thuy, Dinh Ha Duy; Ujifuku, Kenta; Kamada, Kensaku; Hayashi, Kentaro; Matsuo, Takayuki; Nagata, Izumi; Niwa, Masami

    2013-05-01

    Glioblastoma multiforme (GBM) cells invade along the existing normal capillaries in brain. Normal capillary endothelial cells function as the blood-brain barrier (BBB) that limits permeability of chemicals into the brain. To investigate whether GBM cells modulate the BBB function of normal endothelial cells, we developed a new in vitro BBB model with primary cultures of rat brain endothelial cells (RBECs), pericytes, and astrocytes. Cells were plated on a membrane with 8 μm pores, either as a monolayer or as a BBB model with triple layer culture. The BBB model consisted of RBEC on the luminal side as a bottom, and pericytes and astrocytes on the abluminal side as a top of the chamber. Human GBM cell line, LN-18 cells, or lung cancer cell line, NCI-H1299 cells, placed on either the RBEC monolayer or the BBB model increased the transendothelial electrical resistance (TEER) values against the model, which peaked within 72 h after the tumor cell application. The TEER value gradually returned to baseline with LN-18 cells, whereas the value quickly dropped to the baseline in 24 h with NCI-H1299 cells. NCI-H1299 cells invaded into the RBEC layer through the membrane, but LN-18 cells did not. Fibroblast growth factor 2 (FGF-2) strengthens the endothelial cell BBB function by increased occludin and ZO-1 expression. In our model, LN-18 and NCI-H1299 cells secreted FGF-2, and a neutralization antibody to FGF-2 inhibited LN-18 cells enhanced BBB function. These results suggest that FGF-2 would be a novel therapeutic target for GBM in the perivascular invasive front.

  17. New frontiers in translational research in neuro-oncology and the blood-brain barrier: report of the tenth annual Blood-Brain Barrier Disruption Consortium Meeting.

    Science.gov (United States)

    Doolittle, Nancy D; Abrey, Lauren E; Bleyer, W Archie; Brem, Steven; Davis, Thomas P; Dore-Duffy, Paula; Drewes, Lester R; Hall, Walter A; Hoffman, John M; Korfel, Agnieszka; Martuza, Robert; Muldoon, Leslie L; Peereboom, David; Peterson, Darryl R; Rabkin, Samuel D; Smith, Quentin; Stevens, Glen H J; Neuwelt, Edward A

    2005-01-15

    The blood-brain barrier (BBB) presents a major obstacle to the treatment of malignant brain tumors and other central nervous system (CNS) diseases. For this reason, a meeting partially funded by an NIH R13 grant was convened to discuss recent advances and future directions in translational research in neuro-oncology and the BBB. Cell biology and transport across the BBB, delivery of agents to the CNS, neuroimaging, angiogenesis, immunotherapy, and gene therapy, as well as glioma, primary CNS lymphoma, and metastases to the CNS were discussed. Transport across the BBB relates to the neurovascular unit, which consists not only of endothelial cells but also of pericyte, glia, and neuronal elements.

  18. Modeling the ischemic blood-brain barrier; the effects of oxygen-glucose deprivation (OGD) on endothelial cells in culture

    DEFF Research Database (Denmark)

    Tornabene, Erica; Helms, Hans Christian Cederberg; Berndt, Philipp

    Introduction - The blood-brain barrier (BBB) is a physical, transport and metabolic barrier which plays a key role in preventing uncontrolled exchanges between blood and brain, ensuring an optimal environment for neurons activity. This extent interface is created by the endothelial cells forming...... pathways across the barrier in ischemic and postischemic brain endothelium is important for developing new medical therapies capable to exploit the barrier changes occurring during/after ischemia to permeate in the brain and treat this devastating disease. Materials and Methods - Primary cultures...

  19. Effects of casein glycomacropeptide supplementation on growth performance, intestinal morphology, intestinal barrier permeability and inflammatory responses in Escherichia coli K88 challenged piglets

    Directory of Open Access Journals (Sweden)

    Yili Rong

    2015-06-01

    Full Text Available Casein glycomacropeptide (CGMP is a bioactive peptide derived from milk with multiple functions. This study was aimed at evaluating the effects of CGMP as a potential feed additive on growth performance, intestinal morphology, intestinal barrier permeability and inflammatory responses of Escherichia coli K88 (E. coli K88 challenged piglets. Eighteen weaning piglets were randomly assigned to three groups. Control group and K88 challenged group received a basal diet, and CGMP treated group received the basal diet supplemented with 1% of CGMP powder. The trail lasted for 12 days, K88 was orally administered to the piglets of K88 challenged group and CGMP treated group on days 8–10. The results showed that the diet containing 1% CGMP significantly alleviated the decrease in average daily gain (P  0.05 and barrier permeability damage (P < 0.05, and acute inflammatory response (P < 0.05 induced by E. coli K88 infection. In conclusion, CGMP supplementation in the diet protected the weaning piglets against E. coli K88 infection.

  20. Uptake mechanism of ApoE-modified nanoparticles on brain capillary endothelial cells as a blood-brain barrier model.

    Science.gov (United States)

    Wagner, Sylvia; Zensi, Anja; Wien, Sascha L; Tschickardt, Sabrina E; Maier, Wladislaw; Vogel, Tikva; Worek, Franz; Pietrzik, Claus U; Kreuter, Jörg; von Briesen, Hagen

    2012-01-01

    The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor. This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier.

  1. Trojan Horse Transit Contributes to Blood-Brain Barrier Crossing of a Eukaryotic Pathogen.

    Science.gov (United States)

    Santiago-Tirado, Felipe H; Onken, Michael D; Cooper, John A; Klein, Robyn S; Doering, Tamara L

    2017-01-31

    The blood-brain barrier (BBB) protects the central nervous system (CNS) by restricting the passage of molecules and microorganisms. Despite this barrier, however, the fungal pathogen Cryptococcus neoformans invades the brain, causing a meningoencephalitis that is estimated to kill over 600,000 people annually. Cryptococcal infection begins in the lung, and experimental evidence suggests that host phagocytes play a role in subsequent dissemination, although this role remains ill defined. Additionally, the disparate experimental approaches that have been used to probe various potential routes of BBB transit make it impossible to assess their relative contributions, confounding any integrated understanding of cryptococcal brain entry. Here we used an in vitro model BBB to show that a "Trojan horse" mechanism contributes significantly to fungal barrier crossing and that host factors regulate this process independently of free fungal transit. We also, for the first time, directly imaged C. neoformans-containing phagocytes crossing the BBB, showing that they do so via transendothelial pores. Finally, we found that Trojan horse crossing enables CNS entry of fungal mutants that cannot otherwise traverse the BBB, and we demonstrate additional intercellular interactions that may contribute to brain entry. Our work elucidates the mechanism of cryptococcal brain invasion and offers approaches to study other neuropathogens. The fungal pathogen Cryptococcus neoformans invades the brain, causing a meningoencephalitis that kills hundreds of thousands of people each year. One route that has been proposed for this brain entry is a Trojan horse mechanism, whereby the fungus crosses the blood-brain barrier (BBB) as a passenger inside host phagocytes. Although indirect experimental evidence supports this intriguing mechanism, it has never been directly visualized. Here we directly image Trojan horse transit and show that it is regulated independently of free fungal entry, contributes

  2. Iron transport across the blood-brain barrier; Development, neurovascular regulation and cerebral amyloid angiopathy

    Science.gov (United States)

    McCarthy, Ryan C; Kosman, Daniel J

    2014-01-01

    There are two barriers for iron entry into the brain: 1) the brain-cerebrospinal fluid (CSF) barrier and 2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease. PMID:25355056

  3. Potential Use of Nanomedicine for Drug Delivery Across the Blood-Brain Barrier in Healthy and Diseased Brain.

    Science.gov (United States)

    Ruozi, Barbara; Belletti, Daniela; Pederzoli, Francesca; Forni, Flavio; Vandelli, Maria Angela; Tosi, Giovanni

    2016-01-01

    The research of efficacious non-invasive therapies for the treatment of brain diseases represents a huge challenge, as people affected by disorders of the central nervous system (CNS) will significantly increase. Moreover, the blood-brain barrier is a key factor in hampering a number of effective drugs to reach the CNS. This review is therefore focusing on possible interventions of nanomedicine-based approaches in selected diseases affecting the CNS. A wide overview of the most outstanding results on preclinical evaluations of the potential of nanomedicine in brain diseases (i.e. brain tumor, Alzheimer, Parkinson, epilepsy and others) is given, with highlights on the data with relevant interest and real possibility in translation from bench-to-bedside. Moreover, a critical evaluation on the rationale in planning nanosystems to target specific brain pathologies is described, opening the path to a more structured and pathology-tailored design of nanocarriers.

  4. FIELD TEST INSTRUCTION 100-NR-2 OPERABLE UNIT DESIGN OPTIMIZATION STUDY FOR SEQUESTRATION OF SR-90 SATURATED ZONE APATITE PERMEABLE REACTIVE BARRIER EXTENSION

    Energy Technology Data Exchange (ETDEWEB)

    BOWLES NA

    2010-10-06

    The objective of this field test instruction is to provide technical guidance for aqueous injection emplacement of an extension apatite permeable reactive barrier (PRE) for the sequestration of strontium-90 (Sr-90) using a high concentration amendment formulation. These field activities will be conducted according to the guidelines established in DOE/RL-2010-29, 100-NR-2 Design Optimization Study, hereafter referred to as the DOS. The DOS supports the Federal Facility Agreement Consent Order (EPA et al., 1989), Milestone M-16-06-01, and 'Complete Construction of a Permeable Reactive Barrier at 100-N.' Injections of apatite precursor chemicals will occur at an equal distance intervals on each end of the existing PRE to extend the PRB from the existing 91 m (300 ft) to at least 274 m (900 ft). Field testing at the 100-N Area Apatite Treatability Test Site, as depicted on Figure 1, shows that the barrier is categorized by two general hydrologic conceptual models based on overall well capacity and contrast between the Hanford and Ringold hydraulic conductivities. The upstream portion of the original barrier, shown on Figure 1, is characterized by relatively low overall well specific capacity. This is estimated from well development data and a lower contrast in hydraulic conductivity between the Hanford formation and Ringold Formations. Comparison of test results from these two locations indicate that permeability contrast between the Hanford formation and Ringold Formation is significantly less over the upstream one-third of the barrier. The estimated hydraulic conductivity for the Hanford formation and Ringold Formation over the upstream portion of the barrier based on observations during emplacement of the existing 91 m (300 ft) PRB is approximately 12 and 10 m/day (39 and 32 ft/day), respectively (PNNL-17429). However, these estimates should be used as a rough guideline only, as significant variability in hydraulic conductivity is likely to be observed in

  5. The effect of aging on brain barriers and the consequences for Alzheimer's disease development.

    Science.gov (United States)

    Gorlé, Nina; Van Cauwenberghe, Caroline; Libert, Claude; Vandenbroucke, Roosmarijn E

    2016-08-01

    Life expectancy has increased in most developed countries, which has led to an increase in the proportion of elderly people in the world's population. However, this increase in life expectancy is not accompanied by a lengthening of the health span since aging is characterized with progressive deterioration in cellular and organ functions. The brain is particularly vulnerable to disease, and this is reflected in the onset of age-related neurodegenerative diseases such as Alzheimer's disease. Research shows that dysfunction of two barriers in the central nervous system (CNS), the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB), plays an important role in the progression of these neurodegenerative diseases. The BBB is formed by the endothelial cells of the blood capillaries, whereas the BCSFB is formed by the epithelial cells of the choroid plexus (CP), both of which are affected during aging. Here, we give an overview of how these barriers undergo changes during aging and in Alzheimer's disease, thereby disturbing brain homeostasis. Studying these changes is needed in order to gain a better understanding of the mechanisms of aging at the brain barriers, which might lead to the development of new therapies to lengthen the health span (including mental health) and reduce the chances of developing Alzheimer's disease.

  6. The blood-brain barrier in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, L; Tfelt-Hansen, P

    2008-01-01

    Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access...... to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized...... with special emphasize on the triptans and calcitonin gene-related peptide (CGRP). The human experimental headache model, especially the use of glycerol trinitrate (the nitric oxide model), and experiences with CGRP administrations utilize the systemic administration of the agonists with effects on other...

  7. Permeability surface area product analysis in malignant brain edema prediction - A pilot study.

    Science.gov (United States)

    Volny, O; Cimflova, P; Lee, T-Y; Menon, B K; d'Esterre, C D

    2017-05-15

    Using an extended CT perfusion acquisition (150s), we sought to determine the association between perfusion parameters and malignant edema after ischemic stroke. Patients (from prospective study PROVE-IT, NCT02184936) with terminal internal carotid artery±proximal middle cerebral occlusion were involved. CTA was assessed for clot location and status of leptomeningeal collaterals. The following CTP parameters were calculated within the ischemic territory and contralaterally: permeability surface area product (PS), cerebral blood flow (CBF) and cerebral blood volume (CBV). PS was calculated using the adiabatic approximation to the Johnson and Wilson model. Outcome was evaluated by midline shift and infarction volume on follow-up imaging. Of 200 patients enrolled, 7 patients (3.5%) had midline shift≥5mm (2 excluded for poor-quality scans). Five patients with midline shift and 5 matched controls were analysed. There was no significant difference in mean PS, CBF and CBV within the ischemic territory between the two groups. A CBV threshold of 1.7ml/100g had the highest AUC=0.72, 95% CI=0.54-0.90 for early midline shift prediction, sensitivity and specificity were 0.83 and 0.67 respectively. Our preliminary results did not show significant differences in permeability surface area analysis if analysed for complete ischemic region. CBV parameter had the highest accuracy and there was a trend for the mean PS values for midline shift prediction. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. The permeability of the posterior blood ocular barrier after xenon photocoagulation: a study using fluorescein labelled dextrans.

    OpenAIRE

    McNaught, E I; Foulds, W S; Johnson, N. F.

    1981-01-01

    Xenon photocoagulation burns in the rabbit fundus were studied angiographically with fluorescein labelled dextrans of molecular weights in the range 3000 to 150 000. Recent photocoagulation burns showed dye leakage to all molecular weights used. Angiograms 2 days after burns had been produced showed leakage of dextrans of molecular weights up to and including 70 000 but no leakage of dextran of 150 000 molecular weight. At 7 days after photocoagulation healed burns remained permeable to dextr...

  9. Restraint stress-induced morphological changes at the blood-brain barrier in adult rats

    Directory of Open Access Journals (Sweden)

    Petra eSántha

    2016-01-01

    Full Text Available Stress is well known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognised in the development of neurodegenerative disorders, such as Alzheimer’s disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3 and 21 days were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occludin and glucose transporter-1 and astroglia (GFAP. Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, one-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5 and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes

  10. Astrocytes and pericytes differentially modulate blood–brain barrier characteristics during development and hypoxic insult

    OpenAIRE

    Al Ahmad, A; Taboada, C B; Gassmann, M.; Ogunshola, O O

    2010-01-01

    Understanding regulation of blood-brain barrier (BBB) is crucial to reduce/prevent its disruption during injury. As high brain complexity makes interpretation of in vivo data challenging, BBB studies are frequently performed using simplified in vitro models. However, many models fail to address the three-dimensional (3D) cellular interactions that occur in vivo, an important feature that may explain discrepancies in translation of in vitro data to the in vivo situation. We have designed and c...

  11. Physiologic and anatomic characterization of the brain surface glia barrier of Drosophila.

    Science.gov (United States)

    DeSalvo, Michael K; Mayer, Nasima; Mayer, Fahima; Bainton, Roland J

    2011-09-01

    Central nervous system (CNS) physiology requires special chemical, metabolic, and cellular privileges for normal function, and blood-brain barrier (BBB) structures are the anatomic and physiologic constructs that arbitrate communication between the brain and body. In the vertebrate BBB, two primary cell types create CNS exclusion biology, a polarized vascular endothelium (VE), and a tightly associated single layer of astrocytic glia (AG). Examples of direct action by the BBB in CNS disease are constantly expanding, including key pathophysiologic roles in multiple sclerosis, stroke, and cancer. In addition, its role as a pharmacologic treatment obstacle to the brain is long standing; thus, molecular model systems that can parse BBB functions and understand the complex integration of sophisticated cellular anatomy and highly polarized chemical protection physiology are desperately needed. Compound barrier structures that use two primary cell types (i.e., functional bicellularity) are common to other humoral/CNS barrier structures. For example, invertebrates use two cell layers of glia, perineurial and subperineurial, to control chemical access to the brain, and analogous glial layers, fenestrated and pseudocartridge, to maintain the blood-eye barrier. In this article, we summarize our current understanding of brain-barrier glial anatomy in Drosophila, demonstrate the power of live imaging as a screening methodology for identifying physiologic characteristics of BBB glia, and compare the physiologies of Drosophila barrier layers to the VE/AG interface of vertebrates. We conclude that many unique BBB physiologies are conserved across phyla and suggest new methods for modeling CNS physiology and disease. Copyright © 2011 Wiley-Liss, Inc.

  12. What is the blood-brain barrier? A molecular perspective. Cerebral vascular biology.

    Science.gov (United States)

    Drewes, L R

    1999-01-01

    The term "blood-brain barrier" was coined over one hundred years ago as a result of the observation that vital dyes introduced into the circulation quickly penetrated and stained nearly all organs and tissues of the mammalian body except the brain which retained its pale creamy appearance. Advances in microscopy revealed that, in contrast to other vascular beds, the brain endothelial cells lining the vascular wall are tightly linked with junctional complexes that eliminate gaps or spaces between cells and prevent any free diffusion of blood-borne substances into the brain parenchymal space. The endothelial cells, situated at the interface between blood and brain, therefore, play a critical role in performing essential biological functions including transport of micro- and macronutrients, receptor-mediated signaling, leukocyte trafficking, and osmoregulation. A number of molecular components responsible for some of these unique properties have now been identified and are being characterized under physiological and disease conditions. These include the proteins involved in formation and assembly of tight junctions; the plasma membrane-embedded proteins that are responsible for transport of brain energy substrates and nutrients (glucose, monocarboxylic acids, nucleosides, amino acids, others); the multi-drug transporter protein, p-glycoprotein, and other drug-rejecting proteins that protect the brain from foreign, potentially disruptive chemicals. These and other recent findings, taken as a whole, reveal the brain endothelium as a complex and dynamic biological system, in contrast to the simple, inert and rigid barrier initially perceived.

  13. Contribution of thrombin-reactive brain pericytes to blood-brain barrier dysfunction in an in vivo mouse model of obesity-associated diabetes and an in vitro rat model.

    Directory of Open Access Journals (Sweden)

    Takashi Machida

    Full Text Available Diabetic complications are characterized by the dysfunction of pericytes located around microvascular endothelial cells. The blood-brain barrier (BBB exhibits hyperpermeability with progression of diabetes. Therefore, brain pericytes at the BBB may be involved in diabetic complications of the central nervous system (CNS. We hypothesized that brain pericytes respond to increased brain thrombin levels in diabetes, leading to BBB dysfunction and diabetic CNS complications. Mice were fed a high-fat diet (HFD for 2 or 8 weeks to induce obesity. Transport of i.v.-administered sodium fluorescein and 125I-thrombin across the BBB were measured. We evaluated brain endothelial permeability and expression of tight junction proteins in the presence of thrombin-treated brain pericytes using a BBB model of co-cultured rat brain endothelial cells and pericytes. Mice fed a HFD for 8 weeks showed both increased weight gain and impaired glucose tolerance. In parallel, the brain influx rate of sodium fluorescein was significantly greater than that in mice fed a normal diet. HFD feeding inhibited the decline in brain thrombin levels occurring during 6 weeks of feeding. In the HFD fed mice, plasma thrombin levels were significantly increased, by up to 22%. 125I-thrombin was transported across the BBB in normal mice after i.v. injection, with uptake further enhanced by co-injection of unlabeled thrombin. Thrombin-treated brain pericytes increased brain endothelial permeability and caused decreased expression of zona occludens-1 (ZO-1 and occludin and morphological disorganization of ZO-1. Thrombin also increased mRNA expression of interleukin-1β and 6 and tumor necrosis factor-α in brain pericytes. Thrombin can be transported from circulating blood through the BBB, maintaining constant levels in the brain, where it can stimulate pericytes to induce BBB dysfunction. Thus, the brain pericyte-thrombin interaction may play a key role in causing BBB dysfunction in

  14. Enhanced brain distribution of carboplatin in a primate model after blood-brain barrier disruption using an implantable ultrasound device.

    Science.gov (United States)

    Goldwirt, Lauriane; Canney, Michael; Horodyckid, Catherine; Poupon, Joel; Mourah, Samia; Vignot, Alexandre; Chapelon, Jean-Yves; Carpentier, Alexandre

    2016-01-01

    Glioblastoma is both the most common and aggressive primary brain tumor in adults. Carboplatin chemotherapy has shown only modest efficacy in progressive high-grade gliomas. The limited clinical efficacy of carboplatin may be due to its low concentration in tissue when the drug is delivered intravenously. The aim of this study was to assess whether the tissue concentration of intravenously administered carboplatin could be enhanced by ultrasound-induced blood-brain disruption in a primate model. Carboplatin was administered intravenously for 60 min to a single primate following blood-brain barrier opening induced by an implantable ultrasound device. Blood and brain samples were collected after animal killing, which occurred 60 min after the end of carboplatin administration. Platinum quantification in ultrafiltrate plasma and brain samples was performed using inductively coupled plasma mass spectrometry. The brain concentration of platinum was highly enhanced (5.2×) in the 3.9 cm(3) region sonicated by the US beam, with a higher concentration in more vascularized anatomical structures. At 5 and 10 mm from the US beam axis, platinum concentrations were slightly enhanced (2.2× and 1.3× respectively). This study demonstrates that BBB opening using an implantable ultrasound transducer enhances the brain distribution of carboplatin in a loco-regional manner. Such a treatment approach is of significant interest for the treatment of primary brain tumors and is under current evaluation in a phase 1 clinical trial (NCT02253212).

  15. Blood-brain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkey.

    Science.gov (United States)

    Boado, Ruben J; Hui, Eric K-W; Lu, Jeff Zhiqiang; Sumbria, Rachita K; Pardridge, William M

    2013-10-16

    Recombinant proteins are large molecule drugs that do not cross the blood-brain barrier (BBB). However, BBB-penetration of protein therapeutics is enabled by re-engineering the recombinant protein as IgG fusion proteins. The IgG domain is a monoclonal antibody (mAb) against an endogenous BBB receptor-mediated transport system, such as the human insulin receptor (HIR), and acts as a molecular Trojan horse to ferry the fused protein across the BBB. In the present study, a recombinant lysosomal enzyme, iduronate 2-sulfatase (IDS), is fused to the HIRMAb, and BBB penetration of the IDS alone vs the HIRMAb-IDS fusion protein is compared in the Rhesus monkey. Recombinant IDS and the HIRMAb-IDS fusion protein were radiolabeled with indirect iodination with the [(125)I]-Bolton-Hunter reagent and with direct iodination with Iodogen/[(125)I]-idodine. IDS and the HIRMAb-IDS fusion protein have comparable plasma pharmacokinetics and uptake by peripheral organs. IDS does not cross the BBB. The HIRMAb-IDS fusion protein crosses the BBB and the brain uptake is 1% of injected dose/brain. Brain imaging shows HIRMAb-IDS penetration to all parts of brain, and immunoprecipitation of brain radioactivity shows intact fusion protein in brain. The use of BBB molecular Trojan horses enables brain imaging of recombinant proteins that are re-engineered for BBB transport.

  16. Increased flux of the plant sterols campesterol and sitosterol across a disrupted blood brain barrier.

    Science.gov (United States)

    Saeed, Ahmed A; Genové, Guillem; Li, Tian; Hülshorst, Frank; Betsholtz, Christer; Björkhem, Ingemar; Lütjohann, Dieter

    2015-07-01

    The intact blood-brain barrier in mammalians prevents exchange of cholesterol loaden particles between periphery and brain and thus nearly all cholesterol in this organ originates from de novo synthesis. Dietary cholesterol homologues from plants, campesterol and sitosterol, are known to get enriched to some extent in the mammalian brain. We recently showed that Pdgfb(ret)(/)(ret) mice, with a pericyte deficiency and a leaking blood-brain barrier phenotype, have significantly higher levels of plant sterols in the brain compared to their heterozygous Pdgfb(ret)(/)(+) controls keeping the integrity of the blood-brain barrier (BBB). In order to further study the protective functionality of the BBB we synthesized a mixture of [(2)H6]campesterol/sitosterol and fed it for 10-40days to genetically different types of animals. There was a significant enrichment of both deuterium stable isotope labeled plant sterols in the brain of both strains of mice, however, with a lower enrichment in the controls. As expected, the percentage and absolute enrichment was higher for [(2)H6]campesterol than for the more lipophilic [(2)H6]sitosterol. The results confirm that a leaking BBB causes increased flux of plant sterols into the brain. The significant flux of the labeled plant sterols into the brain of the control mice illustrates that the presence of an alkyl group in the 24-position of the steroid side chain markedly increases the ability of cholesterol to pass an intact BBB. We discuss the possibility that there is a specific transport mechanism involved in the flux of alkylated cholesterol species across the BBB. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Does sumatriptan cross the blood-brain barrier in animals and man?

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer

    2010-01-01

    Sumatriptan, a relatively hydrophilic triptan, based on several animal studies has been regarded to be unable to cross the blood-brain barrier (BBB). In more recent animal studies there are strong indications that sumatriptan to some extent can cross the BBB. The CNS adverse events of sumatriptan...

  18. Protective effects of monomethyl fumarate at the inflamed blood-brain barrier

    NARCIS (Netherlands)

    Lim, J.L.; van der Pol, S.M.A.; Di Dio, F.; van het Hof, B.; Kooij, G.; de Vries, H.E.; van Horssen, J.

    2015-01-01

    Background: Reactive oxygen species play a key role in the pathogenesis of multiple sclerosis as they induce blood-brain barrier disruption and enhance transendothelial leukocyte migration. Thus, therapeutic compounds with antioxidant and anti-inflammatory potential could have clinical value in

  19. Microfluidic organ-on-chip technology for blood-brain barrier research

    NARCIS (Netherlands)

    van der Helm, Marieke Willemijn; van der Meer, Andries Dirk; Eijkel, Jan C.T.; van den Berg, Albert; Segerink, Loes Irene

    Organs-on-chips are a new class of microengineered laboratory models that combine several of the advantages of current in vivo and in vitro models. In this review, we summarize the advances that have been made in the development of organ-on-chip models of the blood-brain barrier (BBBs-on-chips) and

  20. Microfluidic organ-on-chip technology for blood-brain barrier research

    NARCIS (Netherlands)

    van der Helm, Marieke Willemijn; van der Meer, Andries Dirk; Eijkel, Jan C.T.; van den Berg, Albert; Segerink, Loes Irene

    2016-01-01

    Organs-on-chips are a new class of microengineered laboratory models that combine several of the advantages of current in vivo and in vitro models. In this review, we summarize the advances that have been made in the development of organ-on-chip models of the blood-brain barrier (BBBs-on-chips) and

  1. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II : Potential mechanisms

    NARCIS (Netherlands)

    van Vliet, Erwin A; Otte, Wim M; Wadman, Wytse J; Aronica, Eleonora; Kooij, Gijs; de Vries, Helga E; Dijkhuizen, Rick M; Gorter, Jan A

    OBJECTIVE: Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure

  2. Theranastic USPIO-loaded microbubbles for mediating and monitoring blood-brain barrier permeation

    NARCIS (Netherlands)

    Lammers, Twan Gerardus Gertudis Maria; Koczera, Patrick; Fokong, Stanley; Gremse, Felix; Ehling, Josef; Vogt, Michael; Pich, Andrij; Storm, Gerrit; van Zandvoort, Marc; Kiessling, Fabian

    2015-01-01

    Efficient and safe drug delivery across the blood-brain barrier (BBB) remains one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO)

  3. Theranostic USPIO-loaded microbubbles for mediating and monitoring blood-brain barrier permeation

    NARCIS (Netherlands)

    Lammers, Twan|info:eu-repo/dai/nl/304824577; Koczera, Patrick; Fokong, Stanley; Gremse, Felix; Ehling, Josef; Vogt, Michael; Pich, Andrij; Storm, G|info:eu-repo/dai/nl/073356328; Van Zandvoort, Marc; Kiessling, Fabian

    2015-01-01

    Efficient and safe drug delivery across the blood-brain barrier (BBB) remains one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO)

  4. P-Glycoprotein Function at the Blood-Brain Barrier: Effects of Age and Gender

    NARCIS (Netherlands)

    van Assema, D.M.E.; Lubberink, J.M.; Boellaard, R.; Schuit, R.C.; Windhorst, A.D.; Scheltens, P.; Lammertsma, A.A.; van Berckel, B.N.M.

    2012-01-01

    Purpose: P-glycoprotein (Pgp) is an efflux transporter involved in transport of several compounds across the blood-brain barrier (BBB). Loss of Pgp function with increasing age may be involved in the development of age-related disorders, but this may differ between males and females. Pgp function

  5. Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins.

    Science.gov (United States)

    Taevernier, Lien; Bracke, Nathalie; Veryser, Lieselotte; Wynendaele, Evelien; Gevaert, Bert; Peremans, Kathelijne; De Spiegeleer, Bart

    2016-09-06

    The cyclic depsipeptide mycotoxins beauvericin and enniatins are capable of reaching the systemic circulation through various routes of exposure and are hence capable of exerting central nervous system (CNS) effects, if they are able to pass the blood-brain barrier (BBB), which was the main objective of this study. Quantification of the mycotoxins was performed using an in-house developed and validated bio-analytical UHPLC-MS/MS method. Prior to the BBB experiments, the metabolic stability of the mycotoxins was evaluated in vitro in mouse serum and brain homogenate. The BBB permeation kinetics of beauvericin and enniatins were studied using an in vivo mice model, applying multiple time regression for studying the blood-to-brain influx. Additionally, capillary depletion was applied to obtain the fraction of the peptides really entering the brain parenchyma and the fraction loosely adhered to the brain capillary wall. Finally, also the brain-to-blood efflux transport kinetics was studied. Metabolic stability data indicated that the investigated mycotoxins were stable during the duration of the in vivo study. The brain influx study showed that beauvericin and enniatins are able to cross the blood-brain barrier in mice: using the Gjedde-Patlak biphasic model, it was shown that all investigated mycotoxins exert a high initial influx rate into the brain (K1 ranging from 11 to 53μL/(g×min)), rapidly reaching a plateau. After penetration, the mycotoxins reached the brain parenchyma (95%) with only a limited amount residing in the capillaries (5%). Negligible efflux (<0.005min(-1)) from the brain was observed in the 15min post-intracerebroventricular injection. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Intra-Arterial Delivery of AAV Vectors to the Mouse Brain After Mannitol Mediated Blood Brain Barrier Disruption

    Science.gov (United States)

    Santillan, Alejandro; Sondhi, Dolan; Dyke, Jonathan P.; Crystal, Ronald G.; Gobin, Y. Pierre; Ballon, Douglas J.

    2014-01-01

    The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single

  7. Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain.

    Science.gov (United States)

    Römermann, Kerstin; Fedrowitz, Maren; Hampel, Philip; Kaczmarek, Edith; Töllner, Kathrin; Erker, Thomas; Sweet, Douglas H; Löscher, Wolfgang

    2017-05-01

    There is accumulating evidence that bumetanide, which has been used over decades as a potent loop diuretic, also exerts effects on brain disorders, including autism, neonatal seizures, and epilepsy, which are not related to its effects on the kidney but rather mediated by inhibition of the neuronal Na-K-Cl cotransporter isoform NKCC1. However, following systemic administration, brain levels of bumetanide are typically below those needed to inhibit NKCC1, which critically limits its clinical use for treating brain disorders. Recently, active efflux transport at the blood-brain barrier (BBB) has been suggested as a process involved in the low brain:plasma ratio of bumetanide, but it is presently not clear which transporters are involved. Understanding the processes explaining the poor brain penetration of bumetanide is needed for developing strategies to improve the brain delivery of this drug. In the present study, we administered probenecid and more selective inhibitors of active transport carriers at the BBB directly into the brain of mice to minimize the contribution of peripheral effects on the brain penetration of bumetanide. Furthermore, in vitro experiments with mouse organic anion transporter 3 (Oat3)-overexpressing Chinese hamster ovary cells were performed to study the interaction of bumetanide, bumetanide derivatives, and several known inhibitors of Oats on Oat3-mediated transport. The in vivo experiments demonstrated that the uptake and efflux of bumetanide at the BBB is much more complex than previously thought. It seems that both restricted passive diffusion and active efflux transport, mediated by Oat3 but also organic anion-transporting polypeptide (Oatp) Oatp1a4 and multidrug resistance protein 4 explain the extremely low brain concentrations that are achieved after systemic administration of bumetanide, limiting the use of this drug for targeting abnormal expression of neuronal NKCC1 in brain diseases. Copyright © 2017 Elsevier Ltd. All rights

  8. Breaking down brain barrier breaches in cerebral malaria

    DEFF Research Database (Denmark)

    Petersen, Jens E V; Lavstsen, Thomas; Craig, Alister

    2016-01-01

    Recent findings have linked brain swelling to death in cerebral malaria (CM). These observations have prompted a number of investigations into the mechanisms of this pathology with the goal of identifying potential therapeutic targets. In this issue of the JCI, Gallego-Delgado and colleagues...... present evidence that implicates angiotensin receptors and the relocation of β-catenin to the endothelial cell nucleus in CM. This study provides a renewed focus on infected erythrocyte debris as the cause of endothelial damage and challenges previous work implicating direct effects of infected...

  9. The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Ruben J. Boado

    2011-01-01

    Full Text Available The application of blood-borne gene therapy protocols to the brain is limited by the presence of the blood-brain barrier (BBB. Viruses have been extensively used as gene delivery systems. However, their efficacy in brain is limited by the lack of transport across the BBB following intravenous (IV administration. Recent progress in the “Trojan Horse Liposome” (THL technology applied to transvascular non-viral gene therapy of the brain presents a promising solution to the trans-vascular brain gene delivery problem. THLs are comprised of immunoliposomes carrying nonviral gene expression plasmids. The tissue target specificity of the THL is provided by peptidomimetic monoclonal antibody (MAb component of the THL, which binds to specific endogenous receptors located on both the BBB and on brain cellular membranes, for example, insulin receptor and transferrin receptor. These MAbs mediate (a receptor-mediated transcytosis of the THL complex through the BBB, (b endocytosis into brain cells and (c transport to the brain cell nuclear compartment. The expression of the transgene in brain may be restricted using tissue/cell specific gene promoters. This manuscript presents an overview on the THL transport technology applied to brain disorders, including lysosomal storage disorders and Parkinson's disease.

  10. The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the Blood-Brain Barrier.

    Science.gov (United States)

    Boado, Ruben J; Pardridge, William M

    2011-01-01

    The application of blood-borne gene therapy protocols to the brain is limited by the presence of the blood-brain barrier (BBB). Viruses have been extensively used as gene delivery systems. However, their efficacy in brain is limited by the lack of transport across the BBB following intravenous (IV) administration. Recent progress in the "Trojan Horse Liposome" (THL) technology applied to transvascular non-viral gene therapy of the brain presents a promising solution to the trans-vascular brain gene delivery problem. THLs are comprised of immunoliposomes carrying nonviral gene expression plasmids. The tissue target specificity of the THL is provided by peptidomimetic monoclonal antibody (MAb) component of the THL, which binds to specific endogenous receptors located on both the BBB and on brain cellular membranes, for example, insulin receptor and transferrin receptor. These MAbs mediate (a) receptor-mediated transcytosis of the THL complex through the BBB, (b) endocytosis into brain cells and (c) transport to the brain cell nuclear compartment. The expression of the transgene in brain may b