Blood-Brain Barrier Molecular Trojan Horse Enables Imaging of Brain Uptake of Radioiodinated Recombinant Protein in the Rhesus Monkey

2013 ◽  
Vol 24 (10) ◽  
pp. 1741-1749 ◽  
Author(s):  
Ruben J. Boado ◽  
Eric K.-W. Hui ◽  
Jeff Zhiqiang Lu ◽  
Rachita K. Sumbria ◽  
William M. Pardridge
Keyword(s):  
Recombinant Protein ◽  
Rhesus Monkey ◽  
Blood Brain Barrier ◽  
Trojan Horse ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Blood Brain

scholarly journals Trojan Horse Transit Contributes to Blood-Brain Barrier Crossing of a Eukaryotic Pathogen

mBio ◽  
2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Felipe H. Santiago-Tirado ◽  
Michael D. Onken ◽  
John A. Cooper ◽  
Robyn S. Klein ◽  
Tamara L. Doering
Keyword(s):  
Experimental Evidence ◽  
Cryptococcus Neoformans ◽  
Blood Brain Barrier ◽  
Fungal Pathogen ◽  
Trojan Horse ◽  
Brain Barrier ◽  
Barrier Crossing ◽  
Blood Brain ◽  
The Brain

ABSTRACT 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. IMPORTANCE 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 to cryptococcal BBB crossing, and allows mutant fungi that cannot enter alone to invade the brain. IMPORTANCE 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 to cryptococcal BBB crossing, and allows mutant fungi that cannot enter alone to invade the brain.

scholarly journals Functional NHE1 expression is critical to blood brain barrier integrity and sumatriptan blood to brain uptake

PLoS ONE ◽  
2020 ◽  
Vol 15 (5) ◽  
pp. e0227463 ◽  
Author(s):  
Erika Liktor-Busa ◽  
Kiera T. Blawn ◽  
Kathryn L. Kellohen ◽  
Beth M. Wiese ◽  
Vani Verkhovsky ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity

Metabolic fuel and amino acid transport into the brain in experimental hypothyroidism

1990 ◽  
Vol 122 (2) ◽  
pp. 156-162 ◽  
Author(s):  
Arshag D. Mooradian
Keyword(s):  
Amino Acids ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Transport Systems ◽  
Brain Uptake ◽  
Acid Transport ◽  
Brain Extraction ◽  
Blood Brain ◽  
Brain Uptake Index ◽  
The Brain

Abstract The effect of hypothyroidism in the adult rat on blood-brain barrier and muscle transport of hexoses, neutral amino acids, basic amino acids, monocarboxylic acids, and ketone bodies was examined using single arterial injection-tissue sampling technique. The cerebral blood flow and brain extraction of 3H2O (internal reference substance) was not altered in 3-month-old hypothyroid rats maintained on methimazole, 0.025% in the drinking water, for 7 weeks. The brain uptake index of D-β-hydroxybutyrate was significantly reduced in hypothyroid rats (2.4 ± 0.3 vs 4.6 ± 0.6% p<0.001). Hypothyroid rats given thyroid hormone replacement therapy had normal brain uptake of D-β-hydroxybutyrate (4.4 ± 0.8%). The brain uptake index of butyrate was also significantly reduced in hypothyroid rats (39.3 ± 2.1 vs 47.2 ± 0.74%, p<0.001). The brain uptake index of other test substances and muscle uptake of nutrients examined were not altered in hypothyroid rats. These studies indicate that of the four transport systems examined in two tissues, the blood-brain barrier monocarboxylic acid transport system is most susceptible to the hypothyroidism-induced changes.

Blood–Brain Barrier Permeability and Brain Uptake Mechanism of Kainic Acid and Dihydrokainic Acid

2014 ◽  
Vol 40 (3) ◽  
pp. 542-549 ◽  
Author(s):  
Mikko Gynther ◽  
Aleksanteri Petsalo ◽  
Steen H. Hansen ◽  
Lennart Bunch ◽  
Darryl S. Pickering
Keyword(s):  
Kainic Acid ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Uptake Mechanism ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Blood Brain ◽  
Brain Barrier Permeability ◽  
Dihydrokainic Acid

Plasma proteins have a ticket to ride the blood-brain barrier

2020 ◽  
Vol 12 (552) ◽  
pp. eabd3610
Author(s):  
Albert A. Davis
Keyword(s):  
Blood Brain Barrier ◽  
Plasma Proteins ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Blood Brain

Analysis of labeled plasma proteins reveals a shift from receptor-mediated brain uptake to less specific transcytosis that occurs with aging.

scholarly journals Impact of P-Glycoprotein Inhibition and Lipopolysaccharide Administration on Blood-Brain Barrier Transport of Colistin in Mice

2010 ◽  
Vol 55 (2) ◽  
pp. 502-507 ◽  
Author(s):  
Liang Jin ◽  
Jian Li ◽  
Roger L. Nation ◽  
Joseph A. Nicolazzo
Keyword(s):  
Blood Brain Barrier ◽  
Systemic Inflammation ◽  
Brain Barrier ◽  
Brain Uptake ◽  
P Glycoprotein ◽  
Blood Brain ◽  
Colistin Sulfate ◽  
The Brain ◽  
Concentration Ratios

ABSTRACTThe aim of this study was to investigate the factors limiting the blood-brain barrier (BBB) transport of colistin in healthy mice and to assess the impact of systemic inflammation on the transport of this antibiotic across the BBB. Colistin sulfate (40 mg/kg) was administered subcutaneously to Swiss outbred mice as single and multiple doses to determine any relationship between brain uptake and plasma concentrations of colistin. To assess the effect of P-glycoprotein (P-gp) on BBB transport, colistin sulfate (5 mg/kg) was concomitantly administered intravenously with PSC833 or GF120918 (10 mg/kg). Systemic inflammation was induced by three intraperitoneal injections of lipopolysaccharide (LPS; 3 mg/kg), and BBB transport of colistin was subsequently measured following subcutaneous administration and by anin situbrain perfusion. The brain uptake of colistin was low following single and multiple subcutaneous doses, with brain-to-plasma concentration ratios ranging between 0.021 and 0.037, and this was not significantly enhanced by coadministration of GF120918 or PSC833 (P> 0.05). LPS significantly increased the brain uptake of subcutaneously administered colistin with area under the brain concentration time curve (AUCbrain) values of 11.7 ± 2.7 μg·h/g and 4.0 ± 0.3 μg·h/g for LPS- and saline-treated mice, respectively (mean ± standard deviation). Similarly,in situperfusion of colistin led to higher antibiotic brain concentrations in LPS-treated animals than in saline-treated animals, with colistin brain-to-perfusate concentration ratios of 0.019 ± 0.001 and 0.014 ± 0.001, respectively. This study demonstrates that the BBB transport of colistin is negligible in healthy mice; however, brain concentrations of colistin can be significantly enhanced during systemic inflammation, as might be observed in infected patients.

Comparison of lipid-mediated blood-brain-barrier penetrability in neonates and adults

1982 ◽  
Vol 243 (3) ◽  
pp. C161-C168 ◽  
Author(s):  
E. M. Cornford ◽  
L. D. Braun ◽  
W. H. Oldendorf ◽  
M. A. Hill
Keyword(s):  
Rat Brain ◽  
Blood Brain Barrier ◽  
Partition Coefficients ◽  
Brain Barrier ◽  
Facilitated Diffusion ◽  
Brain Uptake ◽  
Adult Rat ◽  
Newborn Rabbit ◽  
Blood Brain ◽  
Adult Rat Brain

The permeability of compounds that penetrate brain capillaries by virtue of their lipoidal solubilities was studied in vivo after a single capillary transit by the intracarotid injection technique. Brain permeabilities of 14C-labeled test isotopes were measured relative to that of tritiated water, a highly diffusible reference substance, with correction for any test isotope remaining in the cerebral vasculature. The brain uptake indices of acetamide, antipyrine, benzyl alcohol, butanol, caffeine, cytosine, diphenyl hydantoin, ethanol, ethylene glycol, heroin, mannitol, methanol, phenobarbital, propylene glycol, thiourea, and urea were measured in ether-anesthetized newborn rabbits. A highly significant correlation (r = 0.86) between brain uptake indices and octanol-saline partition coefficients of these compounds was observed. An almost identical relationship was derived in the adult rat blood-brain barrier where brain uptakes and partition coefficients of some 48 compounds could be correlated (r = 0.86). The similarities in slope-intercept relationships indicate that newborn rabbit and adult rat brain endothelia are functionally similar with respect to lipid-mediated permeability [in contrast to previous studies that have established dramatic differences in selective permeabilities of metabolites transported by saturable, carrier-mediated ("facilitated diffusion") mechanisms]. Permeability-surface area products were also derived; these data confirmed no differences in permeability could be detected between newborn and adult blood-brain-barrier capillaries. A relationship between hydrogen bond number (an alternative indicator of hydrophobic properties( and brain uptake indices derived for the adult rat brain could not be confirmed in the case of the newborn rabbit.

scholarly journals [11C]Flumazenil brain uptake is influenced by the blood-brain barrier efflux transporter P-glycoprotein

2012 ◽  
Vol 2 (1) ◽  
pp. 12 ◽  
Author(s):  
Femke E Froklage ◽  
Stina Syvänen ◽  
N Harry Hendrikse ◽  
Marc C Huisman ◽  
Carla FM Molthoff ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Uptake ◽  
Efflux Transporter ◽  
P Glycoprotein ◽  
Blood Brain

Blood-brain barrier tight junctions are altered during a 72-h exposure to λ-carrageenan-induced inflammatory pain

2002 ◽  
Vol 283 (4) ◽  
pp. H1531-H1537 ◽  
Author(s):  
J. D. Huber ◽  
V. S. Hau ◽  
L. Borg ◽  
C. R. Campos ◽  
R. D. Egleton ◽  
...  
Keyword(s):  
Western Blot ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Inflammatory Pain ◽  
Brain Perfusion ◽  
Brain Barrier ◽  
Brain Uptake ◽  
In Situ Brain Perfusion ◽  
Blood Brain

In this study, we examined the effect of λ-carrageenan-induced inflammatory pain on the functional and structural properties of the rat blood-brain barrier (BBB) over a 72-h time period. Systemic inflammation was induced by an intraplantar injection of 3% λ-carrageenan into the right hind paw of female Sprague-Dawley rats. In situ brain perfusion and Western blot analyses were performed at 1, 3, 6, 12, 24, 48, and 72 h. In situ brain perfusion showed λ-carrageenan significantly increased brain uptake of [14C]sucrose at 1, 3, 6, and 48 h (139 ± 9%, 166 ± 19%, 138 ± 13%, and 146 ± 7% compared with control, respectively). Capillary depletion analysis insured the increased brain uptake was due to increased BBB permeability and not vascular trapping. Western blot analyses for zonula occludens-1 (ZO-1) and occludin were performed on isolated cerebral microvessels. ZO-1 expression was significantly increased at 1, 3, and 6 h and returned to control expression levels by 12 h. Total occludin expression was significantly reduced at 1, 3, 6, 12, and 48 h. This investigation demonstrated that λ-carrageenan-induced inflammatory pain elicits a biphasic increase in BBB permeability with the first phase occurring from 1–6 h and the second phase occuring at 48 h. Furthermore, changes in BBB function are correlated with altered tight junctional protein expression of occludin and ZO-1. Changes in the structure of tight junctions may have important clinical ramifications concerning central nervous system homeostasis and therapeutic drug delivery.

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