A Reduction in the Transfer of Amino Acids Across the Blood-Brain Barrier Might Not be the Sole Mechanism by Which Vasopressin Affects Amino Acid Levels within the Brain

1996 ◽  
pp. 21-26
Author(s):  
A. Reichel ◽  
D. J. Begley ◽  
A. Ermisch
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
Amino Acid Levels ◽  
The Brain

scholarly journals Asymmetrical Transport of Amino Acids across the Blood—Brain Barrier in Humans

1990 ◽  
Vol 10 (5) ◽  
pp. 698-706 ◽  
Author(s):  
G. Moos Knudsen ◽  
K. D. Pettigrew ◽  
C. S. Patlak ◽  
M. M. Hertz ◽  
O. B. Paulson
Keyword(s):  
Amino Acids ◽  
Endothelial Cell ◽  
Amino Acid ◽  
Blood Brain Barrier ◽  
Extracellular Fluid ◽  
Brain Barrier ◽  
Reverse Direction ◽  
Single Membrane ◽  
Blood Brain ◽  
The Brain

Blood–brain barrier permeability to four large neutral and one basic amino acid was studied in 30 patients with the double indicator technique. The resultant 64 venous outflow curves were analyzed by means of two models that take tracer backflux and capillary heterogeneity into account. The first model considers the blood–brain barrier as a double membrane where amino acids from plasma enter the endothelial cell. When an endothelial cell volume of 0.001 ml/g was assumed, permeability from the blood into the endothelial cell was, for most amino acids, about 10–20 times larger than the permeability for the reverse direction. The second model assumes that the amino acids, after intracarotid injection, cross a single membrane barrier and enter a well-mixed compartment, the brain extracellular fluid, i.e., the endothelial cell is assumed to behave as a single membrane. With this model, for large neutral amino acids, the permeability out of the extracellular fluid space back to the blood was between 8 to 12 times higher than the permeability from the blood into the brain. Such a difference in permeabilities across the blood–brain barrier can almost entirely be ascribed to the effect of a nonlinear transport system combined with a relatively small brain amino acid metabolism. The significance of the possible presence of an energy-dependent A system at the abluminal side of the blood–brain barrier is discussed and related to the present findings. For both models, calculation of brain extraction by simple peak extraction values underestimates true unidirectional brain uptake by 17–40%. This raises methodological problems when estimating blood to brain transfer of amino acids with this traditional in vivo method.

scholarly journals Carrier-Mediated Delivery of Metabotropic Glutamate Receptor Ligands to the Central Nervous System: Structural Tolerance and Potential of the l-system Amino Acid Transporter at the Blood-Brain Barrier

2000 ◽  
Vol 20 (1) ◽  
pp. 168-174 ◽  
Author(s):  
Andreas Reichel ◽  
David J. Begley ◽  
N. Joan Abbott
Keyword(s):  
Central Nervous System ◽  
Amino Acid ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Side Chain ◽  
Large Neutral Amino Acid ◽  
Metabotropic Glutamate ◽  
Blood Brain ◽  
L System ◽  
The Brain

The brain endothelial large neutral amino acid carrier (l-system) is well suited for facilitated drug transport to the brain because of its high transport capacity and relatively broad structural substrate tolerance. The authors have examined the potential of this transporter for central nervous system (CNS) delivery of a new family of compounds derived from the large neutral amino acid phenylglycine. These compounds are highly selective for specific isoforms of metabotropic glutamate receptors (mGluRs) but will only become effective therapeutics for CNS diseases such as ischemic disorders, stroke, and epilepsy if they can effectively cross the blood-brain barrier. Using the immortalized rat brain endothelial cell line RBE4 as in vitro blood-brain barrier model, the authors have studied the interaction of phenylglycine and selected derivatives with the l-system-mediated transport of l-[3H]-histidine. The transport of l-histidine was characteristic of the l-system in vivo with the following kinetic parameters: Km 135 ± 18 μmol/L, Vmax 15.3 ± 1.13 nmol/min/mg protein, and KD 2.38 ± 0.84 μL/min/mg protein. The affinities of the l-system for phenylglycine and the derivatives investigated increased in the order S-4-carboxy-phenylglycine (Ki = 16 mmol/L) < R-phenylglycine (2.2 mmol/L) < S-3-hydroxy-phenylglycine (48 μmol/L) < S-phenylglycine (34 μmol/L), suggesting that a negative charge at the side chain or R-configuration is detrimental for carrier recognition, whereas neutral side chain substituents are well tolerated. The authors have further shown (1) that the mode of interaction with the l-system of S-phenylglycine and S-3-hydroxy-phenylglycine is competitive, and (2) that the transporter carries these two agents into the cell as shown by high-performance liquid chromatography (HPLC) analysis of the RBE4 cell contents. The study provides the first evidence for the potential of S-phenylglycine derivatives for carrier-mediated delivery to the CNS and outlines the substrate specificity of the l-system at the blood-brain barrier for this class of mGluR ligands. As the affinities of S-phenylglycine and S-3-hydroxy-phenylglycine for the l-system carrier are even higher than those of some natural substrates, these agents should efficiently enter CNS via this route. Possible strategies for a synergistic optimization of phenylglycine-derived therapeutics with respect to desired activity at the CNS target combined with carrier-mediated delivery to overcome the blood-brain barrier are discussed.

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.

Amino acid assignment to one of three blood-brain barrier amino acid carriers

1976 ◽  
Vol 230 (1) ◽  
pp. 94-98 ◽  
Author(s):  
WH Oldendorf ◽  
J Szabo
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Blood Brain Barrier ◽  
Internal Standard ◽  
Basic Amino Acid ◽  
Brain Barrier ◽  
Carrier System ◽  
Blood Brain ◽  
Cross Inhibition ◽  
Amino Acid Carrier

The percentages of 22 14C-labeled amino acids remaining in rat brain 15 s after carotid injection were measured relative to a simultaneously injected diffusible internal standard, 3HOH. The injected solution also contained a nondiffusible internal standard, [113mIn]EDTA to correct for incomplete brain blood compartment washout. Self-inhibition and cross-inhibition was demonstrated by inclusion of unlabeled amino acids and carboxylic acids. All amino acids tested, excluding proline, alanine, and glycine, could be assigned to one, and only one, blood-brain barrier carrier system. The neutral carrier system transported phenylalanine, leucine, tyrosine, isoleucine, methionine, tryptophane, valine, DOPA, cysteine, histidine, threonine, glutamine, asparagine, and serine. Affinity for a basic amino acid carrier system was demonstrated for arginine, ornithine, and lysine. A third, low-capacity independent carrier system transporting aspartic and glutamic acids was demonstrated.

scholarly journals The Emerging Role of Amino Acids of the Brain Microenvironment in the Process of Metastasis Formation

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2891
Author(s):  
Francesca Cutruzzolà ◽  
Amani Bouzidi ◽  
Francesca Romana Liberati ◽  
Sharon Spizzichino ◽  
Giovanna Boumis ◽  
...  
Keyword(s):  
Amino Acids ◽  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Metastasis Formation ◽  
Lung Cancers ◽  
Continuous Release ◽  
Blood Brain ◽  
The Brain

Brain metastases are the most severe clinical manifestation of aggressive tumors. Melanoma, breast, and lung cancers are the types that prefer the brain as a site of metastasis formation, even if the reasons for this phenomenon still remain to be clarified. One of the main characteristics that makes a cancer cell able to form metastases in the brain is the ability to interact with the endothelial cells of the microvasculature, cross the blood–brain barrier, and metabolically adapt to the nutrients available in the new microenvironment. In this review, we analyzed what makes the brain a suitable site for the development of metastases and how this microenvironment, through the continuous release of neurotransmitters and amino acids in the extracellular milieu, is able to support the metabolic needs of metastasizing cells. We also suggested a possible role for amino acids released by the brain through the endothelial cells of the blood–brain barrier into the bloodstream in triggering the process of extravasation/invasion of the brain parenchyma.

Na+-dependent transport of large neutral amino acids occurs at the abluminal membrane of the blood-brain barrier

2003 ◽  
Vol 285 (6) ◽  
pp. E1167-E1173 ◽  
Author(s):  
Robyn L. O'Kane ◽  
Richard A. Hawkins
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Blood Brain Barrier ◽  
Basement Membranes ◽  
Brain Barrier ◽  
Large Neutral Amino Acid ◽  
Large Neutral Amino Acids ◽  
Neutral Amino Acids ◽  
Blood Brain ◽  
Dependent Transport

Several Na+-dependent carriers of amino acids exist on the abluminal membrane of the blood-brain barrier (BBB). These Na+-dependent carriers are in a position to transfer amino acids from the extracellular fluid of brain to the endothelial cells and thence to the circulation. To date, carriers have been found that may remove nonessential, nitrogen-rich, or acidic (excitatory) amino acids, all of which may be detrimental to brain function. We describe here Na+-dependent transport of large neutral amino acids across the abluminal membrane of the BBB that cannot be ascribed to currently known systems. Fresh brains, from cows killed for food, were used. Microvessels were isolated, and contaminating fragments of basement membranes, astrocyte fragments, and pericytes were removed. Abluminal-enriched membrane fractions from these microvessels were prepared. Transport was Na+dependent, voltage sensitive, and inhibited by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, a particular inhibitor of the facilitative large neutral amino acid transporter 1 (LAT1) system. The carrier has a high affinity for leucine ( Km21 ± 7 μM) and is inhibited by other neutral amino acids, including glutamine, histidine, methionine, phenylalanine, serine, threonine, tryptophan, and tyrosine. Other established neutral amino acids may enter the brain by way of LAT1-type facilitative transport. The presence of a Na+-dependent carrier on the abluminal membrane capable of removing large neutral amino acids, most of which are essential, from brain indicates a more complex situation that has implications for the control of essential amino acid content of brain.

scholarly journals The Transport of Leucine and Aminocyclopentanecarboxylate across the Intact, Energy-Depleted Rat Blood—Brain Barrier

1989 ◽  
Vol 9 (2) ◽  
pp. 226-233 ◽  
Author(s):  
J. Greenwood ◽  
A. S. Hazell ◽  
O. E. Pratt
Keyword(s):  
Amino Acid ◽  
Blood Brain Barrier ◽  
Molecular Size ◽  
Brain Barrier ◽  
Large Neutral Amino Acid ◽  
Blood Brain ◽  
Order Of Magnitude ◽  
The Central Nervous System ◽  
The Brain

The transport across the blood-brain barrier of the large neutral amino acid leucine and the nonmetabolised aminocyclopentanecarboxylate (ACPC), of similar molecular size, was studied in the perfused, energy-depleted rat brain. It was found that when both leucine and ACPC were perfused for periods of up to 10 min their accumulation in the brain increased in a linear fashion. The ratio of perfusate radioactivity per milliliter and tissue radioactivity per gram (Rt/Rp) rose to above unity for both leucine and ACPC, indicating continued uptake against a concentration gradient of the radiolabel within the CNS. When the effect of increasing the concentration of the amino acid upon its influx into the brain was studied, it was found that under these conditions the kinetics of transport for both leucine and ACPC were of a similar order of magnitude to those reported previously in vivo. The values for the Michaelis constant for transport ( Km), maximum rate of transport ( Vmax), and the constant for the apparently linear, nonsaturable component ( Kd) for leucine into the cerebrum were 84.5 ± 29.0 μ M, 45.5 ± 1.5 nmole/min/g, and 2.62 ± 0.15 μl/min/g, respectively, and for ACPC 381 ± 64 μ M, 54.0 ± 1.5 nmole/min/g and 0.35 ± 0.10 μl/min/g, respectively. Comparing this data with previously reported values it is suggested that the transport of leucine into the central nervous system from a perfusate or bolus where no other competing amino acids are present, is flow dependent. Furthermore, ACPC enters the brain almost entirely by a carrier-mediated process, with little or no nonsaturable influx despite a similar oil/water partition coefficient as leucine.

scholarly journals Preferred Stereoselective Transport of the D-isomer of cis-4-[18F]fluoro-proline at the Blood–Brain Barrier

2005 ◽  
Vol 25 (5) ◽  
pp. 607-616 ◽  
Author(s):  
Karl-Josef Langen ◽  
Kurt Hamacher ◽  
Dagmar Bauer ◽  
Stefan Bröer ◽  
Dirk Pauleit ◽  
...  
Keyword(s):  
Amino Acids ◽  
Blood Brain Barrier ◽  
Mammalian Cells ◽  
Human Subjects ◽  
Standardized Uptake Value ◽  
Brain Barrier ◽  
Influx Rate ◽  
Blood Brain ◽  
Pet Tracer ◽  
The Brain

Generally, L-amino acids are preferably transported into mammalian cells compared with their D-isomers, and only L-amino acids are incorporated into proteins. Former studies, however, indicated that D-[H]proline is accumulated in the brain of mice after injection, while L-[3H]proline is not. We investigated the differential cerebral uptake of the D- and L-isomers of the PET tracer cis-4-[18F]fluoroproline (D-/L- cis-FPro) and of D-/L-[3H]proline (D-/L-Pro) in rats by dual tracer autoradiography and the uptake of D- cis-FPro in two human subjects by PET. The standardized uptake value (SUV) of D- cis-FPro in the cerebral cortex of rats 2 h p.i. was 3.05±1.18 ( n=9) versus 0.06±0.01 ( n=4) for L- cis-FPro ( P<0.001) and 1.29±0.27 ( n=4) for D-Pro versus 0.30±0.14 ( n=9) for L-Pro ( P<0.001). Analysis of the rat brain tissue after injection of D- cis-FPro ( n=3) revealed no radioactivity in the proteins but a relevant part in the form of L- trans-FPro. The PET studies yielded a four- to five-fold higher SUV and influx rate constant in the human cortex for D- cis-FPro than for L- cis-FPro. We conclude that D- cis-FPro and D-Pro are preferably transported at the blood–brain barrier compared with their L-isomers and isomerized to the L-form within the brain. Thus, D-Pro in the plasma might be a source of intracerebral L-proline, which has been shown to act as a modulator of excitatory neurotransmission.

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