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.

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.

Understanding the Physiology of the Blood-Brain Barrier: In Vitro Models

Physiology ◽  
1998 ◽  
Vol 13 (6) ◽  
pp. 287-293 ◽  
Author(s):  
Gerald A. Grant ◽  
N. Joan Abbott ◽  
Damir Janigro
Keyword(s):  
Central Nervous System ◽  
Tissue Culture ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
In Vitro Models ◽  
Brain Barrier ◽  
Blood Brain ◽  
Brain Tissue Culture ◽  
The Brain

Endothelial cells exposed to inductive central nervous system factors differentiate into a blood-brain barrier phenotype. The blood-brain barrier frequently obstructs the passage of chemotherapeutics into the brain. Tissue culture systems have been developed to reproduce key properties of the intact blood-brain barrier and to allow for testing of mechanisms of transendothelial drug permeation.

scholarly journals Blood-brain barrier behavior during temporary concussion

1960 ◽  
Vol 198 (6) ◽  
pp. 1296-1298 ◽  
Author(s):  
Benedict Cassen ◽  
Richard Neff
Keyword(s):  
Central Nervous System ◽  
Blood Brain Barrier ◽  
Normal Activity ◽  
Brain Barrier ◽  
Electrolyte Balance ◽  
Barrier Membranes ◽  
Phosphate Ions ◽  
Blood Brain ◽  
The Central Nervous System ◽  
The Brain

Experimental evidence is obtained that, coincident with a state of not too severe concussion, the blood-brain barrier system becomes more permeable to phosphate ions. The permeability returns to normal when the animal recovers and shows normal activity. Arguments are presented in favor of the hypothesis that dysfunction of the central nervous system during concussion is related to a disturbed electrolyte balance in the fluids of the brain caused by a piezochemical disturbance of the blood-brain barrier membranes (presumably the astropods of the astrocytic cells).

scholarly journals Age-Associated Changes in the Immune System and Blood–Brain Barrier Functions

2019 ◽  
Vol 20 (7) ◽  
pp. 1632 ◽  
Author(s):  
Michelle Erickson ◽  
William Banks
Keyword(s):  
Central Nervous System ◽  
Immune System ◽  
Blood Brain Barrier ◽  
Neurological Disorders ◽  
Brain Barrier ◽  
Immune Functions ◽  
Blood Brain ◽  
The Brain ◽  
Brain Barriers

Age is associated with altered immune functions that may affect the brain. Brain barriers, including the blood–brain barrier (BBB) and blood–CSF barrier (BCSFB), are important interfaces for neuroimmune communication, and are affected by aging. In this review, we explore novel mechanisms by which the aging immune system alters central nervous system functions and neuroimmune responses, with a focus on brain barriers. Specific emphasis will be on recent works that have identified novel mechanisms by which BBB/BCSFB functions change with age, interactions of the BBB with age-associated immune factors, and contributions of the BBB to age-associated neurological disorders. Understanding how age alters BBB functions and responses to pathological insults could provide important insight on the role of the BBB in the progression of cognitive decline and neurodegenerative disease.

Glial induction of blood-brain barrier-Like L-system amino acid transport in the ECV304 cell line

Glia ◽  
2002 ◽  
Vol 39 (2) ◽  
pp. 99-104 ◽  
Author(s):  
M. Chishty ◽  
A. Reichel ◽  
D.J. Begley ◽  
N.J. Abbott
Keyword(s):  
Amino Acid ◽  
Cell Line ◽  
Blood Brain Barrier ◽  
Amino Acid Transport ◽  
Brain Barrier ◽  
Acid Transport ◽  
Blood Brain ◽  
L System ◽  
Ecv304 Cell

scholarly journals Tembusu Virus entering the central nervous system caused nonsuppurative encephalitis without disrupting the blood-brain barrier

2021 ◽  
Author(s):  
Sheng Yang ◽  
Yufei Huang ◽  
Yonghong Shi ◽  
Xuebing Bai ◽  
Ping Yang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Blood Brain Barrier ◽  
Neurological Symptoms ◽  
Brain Barrier ◽  
Poultry Industry ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Tembusu Virus ◽  
The Brain

Tembusu Virus (TMUV) is an emerging and re-emerging zoonotic pathogen that adversely affects poultry industry in recent years. TMUV disease is characterized by nonsuppurative encephalitis in ducklings. The duckling infection model was established to study the mechanism of TMUV crossing the blood-brain barrier (BBB) into the central nervous system (CNS). Here, we showed that no obvious clinical symptoms and enhancement of BBB permeability occurred at the early stage of infection (3∼5 dpi). While simultaneously virus particles were observed by transmission electron microscopy in the brain, inducing the accumulation of inflammatory cytokines. Neurological symptoms and disruption of BBB appeared at the intermediate stage of infection (7∼9 dpi). It was confirmed that TMUV could survive and propagate in brain microvascular endothelial cells (BMECs), but did not affect the permeability of BBB in vivo and in vitro at an early date. In conclusion, TMUV enters the CNS then causes encephalitis, and finally destruct the BBB, which may be due to the direct effect of TMUV on BMECs and the subsequent response of “inflammatory storm”. IMPORTANCE The TMUV disease has caused huge losses to the poultry industry in Asia, which is potentially harmful to public health. Neurological symptoms and their sequelae are the main characters of this disease. However, the mechanism of how this virus enters the brain and causes encephalitis is unclear. In this study, we confirmed that the virus entered the CNS and then massively destroyed BBB and the BBB damage was closely associated with the subsequent outbreak of inflammation. TMUV may enter the CNS through the transcellular and “Trojan horse” pathways. These findings can fill the knowledge gap in the pathogenesis of TMUV-infected poultry and be benefit for the treatment of TMUV disease. What’s more, TMUV is a representative to study the infection of avian flavivirus. Therefore, our studies have significances both for understanding of the full scope of mechanisms of TMUV and other flavivirus infection, and conceivably, for therapeutics.

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 Modulation of Sialic Acid Dependence Influences the Central Nervous System Transduction Profile of Adeno-associated Viruses

2019 ◽  
Vol 93 (11) ◽  
Author(s):  
Blake H. Albright ◽  
Katherine E. Simon ◽  
Minakshi Pillai ◽  
Garth W. Devlin ◽  
Aravind Asokan
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Sialic Acid ◽  
Blood Brain Barrier ◽  
Viral Vectors ◽  
Variable Region ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Brain

ABSTRACT Central nervous system (CNS) transduction by systemically administered recombinant adeno-associated viral (AAV) vectors requires crossing the blood-brain barrier (BBB). We recently mapped a structural footprint on the AAVrh.10 capsid, which, when grafted onto the AAV1 capsid (AAV1RX), enables viral transport across the BBB; however, the underlying mechanisms remain unknown. Here, we establish through structural modeling that this footprint overlaps in part the sialic acid (SIA) footprint on AAV1. We hypothesized that altered SIA-capsid interactions may influence the ability of AAV1RX to transduce the CNS. Using AAV1 variants with altered SIA footprints, we map functional attributes of these capsids to their relative SIA dependence. Specifically, capsids with ablated SIA binding can penetrate and transduce the CNS with low to moderate efficiency. In contrast, AAV1 shows strong SIA dependency and does not transduce the CNS after systemic administration and, instead, transduces the vasculature and the liver. The AAV1RX variant, which shows an intermediate SIA binding phenotype, effectively enters the brain parenchyma and transduces neurons at levels comparable to the level of AAVrh.10. In corollary, the reciprocal swap of the AAV1RX footprint onto AAVrh.10 (AAVRX1) attenuated CNS transduction relative to that of AAVrh.10. We conclude that the composition of residues within the capsid variable region 1 (VR1) of AAV1 and AAVrh.10 profoundly influences tropism, with altered SIA interactions playing a partial role in this phenotype. Further, we postulate a Goldilocks model, wherein optimal glycan interactions can influence the CNS transduction profile of AAV capsids. IMPORTANCE Understanding how viruses cross the blood-brain barrier can provide insight into new approaches to block infection by pathogens or the ability to exploit these pathways for designing new recombinant viral vectors for gene therapy. In this regard, modulation of virus-carbohydrate interactions by mutating the virion shell can influence the ability of recombinant viruses to cross the vascular barrier, enter the brain, and enable efficient gene transfer to neurons.

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