Bidirectional saturable transport of LHRH across the blood-brain barrier

1991 ◽  
Vol 261 (3) ◽  
pp. E312-E318 ◽  
Author(s):  
C. M. Barrera ◽  
A. J. Kastin ◽  
M. B. Fasold ◽  
W. A. Banks
Keyword(s):  
Blood Brain Barrier ◽  
Ovarian Function ◽  
Brain Barrier ◽  
Multiple Time ◽  
Blood Brain ◽  
Permeability Surface ◽  
Cerebrovascular Permeability ◽  
The Difference ◽  
Single Time Point ◽  
Time Point

Systemic administration of luteinizing hormone-releasing hormone (LHRH) in rats has been found to influence behavior independently of pituitary or ovarian function. A previous study has shown that LHRH can cross the blood-brain barrier in one direction, but it was not known whether this was due to a saturable transport system. The rate of entry of 125I-labeled LHRH from blood to brain was determined by two different single-pass methods of carotid perfusion. The first, a multiple time point method, measures Ki from the slope of the linear regression when brain-to-blood ratios of radioiodinated LHRH are plotted against time. Saturable transport was determined by the difference between the Ki of rats perfused with 125I-LHRH (12.51 X 10(-3) mg.g-1.min-1) vs. rats perfused with 125I-LHRH and unlabeled LHRH (10 nmol/ml; 2.20 X 10(-3) ml.g-1.min-1). The inhibition by the unlabeled peptide was statistically significant (P less than 0.001). The second method, a single time point technique, measures the cerebrovascular permeability-surface area coefficient (PA). Saturable transport was determined in rats by the competition of unlabeled LHRH with 125I-LHRH. The PA value for 125I-LHRH (20.00 X 10(-3) ml.g-1.min-1) was significantly greater (P less than 0.05) than for 125I-LHRH with the addition of 10 nmol/ml unlabeled LHRH (4.14 X 10(-3) ml.g-1.min-1). Saturable transport of LHRH from brain to blood in mice was also determined.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Transport of D-Glucose and 2-Fluorodeoxyglucose across the Blood-Brain Barrier in Humans

1996 ◽  
Vol 16 (4) ◽  
pp. 659-666 ◽  
Author(s):  
Steen G. Hasselbalch ◽  
Gitte M. Knudsen ◽  
Søren Holm ◽  
L. Pinborg Hageman ◽  
Brunella Capaldo ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Initial Distribution ◽  
Brain Barrier ◽  
Transport Parameters ◽  
Indicator Method ◽  
Blood Brain ◽  
The Difference ◽  
Regional Cerebral Glucose Metabolism ◽  
The Brain

The deoxyglucose method for calculation of regional cerebral glucose metabolism by PET using 18F-2-fluoro-2-deoxy-d-glucose (FDG) requires knowledge of the lumped constant, which corrects for differences in the blood–brain barrier (BBB) transport and phosphorylation of FDG and glucose. The BBB transport rates of FDG and glucose have not previously been determined in humans. In the present study these transport rates were measured with the intravenous double-indicator method in 24 healthy subjects during normoglycemia (5.2 ± 0.7 m M). Nine subjects were restudied during moderate hypoglycemia (3.4 ± 0.4 m M) and five subjects were studied once during hyperglycemia (15.0 ± 0.7 m M). The global ratio between the unidirectional clearances of FDG and glucose (K1*/K1) was similar in normoglycemia (1.48 ± 0.22), moderate hypoglycemia (1.41 ± 0.23), and hyperglycemia (1.44 ± 0.20). This ratio is comparable to what has been obtained in rats. We argue that the global ratio is constant throughout the brain and may be applied for the regional determination of LC. We also determined the transport parameters of the two hexoses from brain back to blood and, assuming symmetrical transport across the BBB, we found evidence of a larger initial distribution volume of FDG in brain (0.329 ± 0.236) as compared with that of glucose (0.162 ± 0.098, p < 0.005). The difference can be explained by the very short experimental time, in which FDG may distribute both intra- and extracellularly, whereas glucose remains in a volume comparable to the interstitial fluid of the brain.

scholarly journals Mechanisms of Brain Ion Homeostasis during Acute and Chronic Variations of Plasma Potassium

1995 ◽  
Vol 15 (2) ◽  
pp. 336-344 ◽  
Author(s):  
Walter Stummer ◽  
A. Lorris Betz ◽  
Richard F. Keep
Keyword(s):  
Blood Brain Barrier ◽  
Ion Homeostasis ◽  
Plasma Potassium ◽  
Brain Barrier ◽  
Intracellular Space ◽  
Blood Brain ◽  
Permeability Surface ◽  
Ion Contents ◽  
Potassium Influx ◽  
Parenchymal Cells

Brain and CSF potassium concentrations are well regulated during acute and chronic alterations of plasma potassium. In a previous study, we have shown that during chronic perturbations, regulation is achieved by appropriate adaptation of potassium influx, but that the degree of such adaptation during acute perturbations is much less. To elucidate further potential regulatory mechanisms, rats were rendered acutely or chronically hyper- or hypokalemic (range 2.7–7.6 m M). Measurements were made of brain and CSF water and ion contents to examine whether regulation occurred by modulation of K+ uptake into parenchymal cells. Furthermore, the permeability-surface area products (PSs) of 22Na+ were determined, because changes in K+ efflux via Na+,K+-ATPase on the brain-facing side of the blood–brain barrier might be reflected in modified Na+ permeability. Brain and CSF K+ concentrations and Na PS were all independent of chronic changes in plasma K+ and acute hypokalemia, suggesting that neither modulation of parenchymal K+ uptake nor K+ efflux via the Na+,K+-ATPase is involved in extracellular K+ regulation in these conditions. In contrast, Na PSs were increased by 40% (p < 0.05) in acute hyperkalemia. This was accompanied by a slight loss of tissue K+ and water from the intracellular space. These results suggest that increased potassium influx in acute hyperkalemia is compensated by stimulation of K+ efflux via Na+,K+-ATPase. A slight degree of overstimulation, as indicated by a net loss of tissue K+, leads us to hypothesize that other factors, apart from the kinetic characteristics of Na+,K+-ATPase, may regulate this enzyme at the blood–brain barrier.

Blood-brain barrier permeability to sucrose and dextran after osmotic opening

1984 ◽  
Vol 247 (4) ◽  
pp. R634-R638 ◽  
Author(s):  
Y. Z. Ziylan ◽  
P. J. Robinson ◽  
S. I. Rapoport
Keyword(s):  
Blood Brain Barrier ◽  
Brain Regions ◽  
Brain Barrier ◽  
Differential Rate ◽  
Barrier Permeability ◽  
Blood Brain Barrier Permeability ◽  
Size Dependent ◽  
Blood Brain ◽  
Permeability Surface ◽  
Brain Barrier Permeability

Regional cerebrovascular permeability-surface area (PA) products were calculated for two nonelectrolyte tracers differing considerably in molecular weight and size [( 14C]sucrose: mol wt 340 daltons, radius 5 A; and [3H]dextran: mol wt approximately 79,000 daltons, radius approximately 65 A) in control (uninfused) rats and in rats 6, 35, and 55 min after the blood-brain barrier was opened by a 30-s infusion of 1.8 molal L(+)-arabinose into a carotid artery. In control brain regions, mean PA for [14C]sucrose was 10(-5) s-1, whereas PA was not measurable for [3H]dextran. Six minutes after arabinose infusion, PA for both substances increased dramatically to 10(-4) s-1 or more; PA then declined at 35 and 55 min after arabinose infusion, but more markedly for [3H]dextran than for [14C]sucrose. The results demonstrate a size-dependent, differential rate of closure of the blood-brain barrier after osmotic opening. This is shown to be consistent with a pore model with bulk flow for blood-brain barrier permeability after osmotic opening.

scholarly journals Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation

2020 ◽  
Vol 21 (12) ◽  
pp. 4407 ◽  
Author(s):  
William A. Banks ◽  
Priyanka Sharma ◽  
Kristin M. Bullock ◽  
Kim M. Hansen ◽  
Nils Ludwig ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Extracellular Vesicles ◽  
Surface Proteins ◽  
Brain Barrier ◽  
Multiple Time ◽  
Blood Brain ◽  
Cancerous Cell ◽  
Wheatgerm Agglutinin ◽  
Mannose 6 Phosphate

Extracellular vesicles can cross the blood–brain barrier (BBB), but little is known about passage. Here, we used multiple-time regression analysis to examine the ability of 10 exosome populations derived from mouse, human, cancerous, and non-cancerous cell lines to cross the BBB. All crossed the BBB, but rates varied over 10-fold. Lipopolysaccharide (LPS), an activator of the innate immune system, enhanced uptake independently of BBB disruption for six exosomes and decreased uptake for one. Wheatgerm agglutinin (WGA) modulated transport of five exosome populations, suggesting passage by adsorptive transcytosis. Mannose 6-phosphate inhibited uptake of J774A.1, demonstrating that its BBB transporter is the mannose 6-phosphate receptor. Uptake rates, patterns, and effects of LPS or WGA were not predicted by exosome source (mouse vs. human) or cancer status of the cell lines. The cell surface proteins CD46, AVβ6, AVβ3, and ICAM-1 were variably expressed but not predictive of transport rate nor responses to LPS or WGA. A brain-to-blood efflux mechanism variably affected CNS retention and explains how CNS-derived exosomes enter blood. In summary, all exosomes tested here readily crossed the BBB, but at varying rates and by a variety of vesicular-mediated mechanisms involving specific transporters, adsorptive transcytosis, and a brain-to-blood efflux system.

scholarly journals Virulence Factors of Meningitis-Causing Bacteria: Enabling Brain Entry across the Blood–Brain Barrier

2019 ◽  
Vol 20 (21) ◽  
pp. 5393 ◽  
Author(s):  
Herold ◽  
Schroten ◽  
Schwerk
Keyword(s):  
Blood Brain Barrier ◽  
Virulence Factors ◽  
Host Cells ◽  
Brain Barrier ◽  
Host Cell Signaling ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Difference ◽  
Multiple Pathogens ◽  
The Brain

Infections of the central nervous system (CNS) are still a major cause of morbidity and mortality worldwide. Traversal of the barriers protecting the brain by pathogens is a prerequisite for the development of meningitis. Bacteria have developed a variety of different strategies to cross these barriers and reach the CNS. To this end, they use a variety of different virulence factors that enable them to attach to and traverse these barriers. These virulence factors mediate adhesion to and invasion into host cells, intracellular survival, induction of host cell signaling and inflammatory response, and affect barrier function. While some of these mechanisms differ, others are shared by multiple pathogens. Further understanding of these processes, with special emphasis on the difference between the blood–brain barrier and the blood–cerebrospinal fluid barrier, as well as virulence factors used by the pathogens, is still needed.

Quantitative aspects of reversible osmotic opening of the blood-brain barrier

1980 ◽  
Vol 238 (5) ◽  
pp. R421-R431 ◽  
Author(s):  
S. I. Rapoport ◽  
W. R. Fredericks ◽  
K. Ohno ◽  
K. D. Pettigrew
Keyword(s):  
Blood Brain Barrier ◽  
Time Course ◽  
External Carotid Artery ◽  
Brain Barrier ◽  
External Carotid ◽  
Blood Brain ◽  
Experimental Pharmacology ◽  
Cerebrovascular Permeability ◽  
Barrier Opening ◽  
The Right

Retrograde infusion of a hypertonic arabinose solution into the right external carotid artery of rats reversibly increases cerebrovascular permeability to [14C]sucrose in the right cerebral hemisphere. PA ([14C]sucrose permeability x capillary surface area) rises from a control mean of 11 x 10(-6) S-1 to above 200 x 10(-6) S-1. The rise correlates with an increased staining of the brain by intravascular Evans blue, and is followed by a transient, 1-1.5% increase in brain water content. At least 20 s of infusion is required for 1.6 M arabinose solution to effectively open the blood-brain barrier. The increase in cerebrovascular permeability is temporary, however, because PA remains slightly elevated 1-2 h after infusion and is normal 6 h after infusion. It is suggested that osmotic barrier opening is mediated by cerebrovascular dilatation as well as by shrinkage of the vascular endothelium. By quantitatively defining thresholds of infusate concentration and infusion time for osmotic barrier opening, and by characterizing the time course of increased PA, the experiments establish criteria for applying the osmotic method to experimental pharmacology of the central nervous system.

scholarly journals Nicotine Raises the Influx of Permeable Solutes across the Rat Blood—Brain Barrier with Little or No Capillary Recruitment

1995 ◽  
Vol 15 (4) ◽  
pp. 687-698 ◽  
Author(s):  
J.-L. Chen ◽  
L. Wei ◽  
D. Bereczki ◽  
F.-J. Hans ◽  
T. Otsuka ◽  
...  
Keyword(s):  
Blood Flow ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Brain Areas ◽  
Nicotine Treatment ◽  
Influx Rate ◽  
Capillary Recruitment ◽  
Blood Brain ◽  
Solute Uptake ◽  
Permeability Surface

Nicotine (1.75 mg/kg s.c.) was administered to rats to raise local CBF (lCBF) in various parts of the brain, test the capillary recruitment hypothesis, and determine the effects of this increase in lCBF on local solute uptake by brain. lCBF as well as the local influx rate constants ( K1) and permeability-surface area ( PS) products of [14C]antipyrine and [14C]-3- O-methyl-d-glucose (30MG) were estimated by quantitative autoradiography in 44 brain areas. For this testing, the finding of significantly increased PS products supports the capillary recruitment hypothesis. In 17 of 44 areas, nicotine treatment increased lCBF by 30–150%, K1 of antipyrine by 7–40%, K1 of 30MG by 5–27%, PS product of antipyrine by 0–20% (mean 7%), and PS product of 30MG by 0–23% (mean 8%). Nicotine had no effect on blood flow or influx in the remaining 27 areas. The increases in lCBF and K1 of antipyrine were significant, whereas those in K1 of 30MG and in PS for both antipyrine and 30MG were not statistically significant. The lack of significant changes in PS products implies that in brain areas where nicotine increased blood flow: (a) essentially no additional capillaries were recruited and (b) blood flow within brain capillary beds rises by elevating linear velocity. The K1 results indicate that the flow increase generated by nicotine will greatly raise the influx and washout rates of highly permeable materials, modestly elevate those of moderately permeable substances, and negligibly change those of solutes with extraction fractions of <0.2, thereby preserving the barrier function of the blood–brain barrier.

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