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  • 1
    Electronic Resource
    Electronic Resource
    A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 89 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Although tight-junctions (TJs) at the blood–brain barrier (BBB) are important to prevent non-specific entry of compounds into the CNS, molecular mechanisms regulating TJ maintenance remain still unclear. The purpose of this study was therefore to identify molecules, which regulate occludin expression, derived from astrocytes and pericytes that ensheathe brain microvessels by using conditionally immortalized adult rat brain capillary endothelial (TR-BBB13), type II astrocyte (TR-AST4) and brain pericyte (TR-PCT1) cell lines. Transfilter co-culture with TR-AST4 cells, and exposure to conditioned medium of TR-AST4 cells (AST-CM) or TR-PCT1 cells (PCT-CM) increased occludin mRNA in TR-BBB13 cells. PCT-CM-induced occludin up-regulation was significantly inhibited by an angiopoietin-1-neutralizing antibody, whereas the up-regulation by AST-CM was not. Immunoprecipitation and western blot analyses confirmed that multimeric angiopoietin-1 is secreted from TR-PCT1 cells, and induces occludin mRNA, acting through tyrosine phosphorylation of Tie-2 in TR-BBB13 cells. A fractionated AST-CM study revealed that factors in the molecular weight range of 30–100 kDa led to occludin induction. Conversely, occludin mRNA was reduced by transforming growth factor β1, the mRNA of which was up-regulated in TR-AST4 cells following hypoxic treatment. In conclusion, in vitro BBB model studies revealed that the pericyte-derived multimeric angiopoietin-1/Tie-2 pathway induces occludin expression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02343.x
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  • 2
    Electronic Resource
    Electronic Resource
    Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood–retinal barrier (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 89 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The purpose of this study was to elucidate the mechanisms of blood-to-retina creatine transport across the blood–retinal barrier (BRB) in vivo and in vitro, and to identify the responsible transporter(s). The creatine transport across the BRB in vivo and creatine uptake in an in vitro model of the inner BRB (TR-iBRB2 cells) were examined using [14C]creatine. Identification and localization of the creatine transporter (CRT) were carried out by RT-PCR, western blot, and immunoperoxidase electron microscopic analyses. An in vivo intravenous administration study suggested that [14C]creatine is transported from the blood to the retina against the creatine concentration gradient that exists between the retina and blood. [14C]Creatine uptake by TR-iBRB2 cells was saturable, Na+- and Cl–-dependent and inhibited by CRT inhibitors, suggesting that CRT is involved in creatine transport at the inner BRB. RT-PCR and western blot analyses demonstrated that CRT is expressed in rat retina and TR-iBRB2 cells. Moreover, using an immunoperoxidase electron microscopic analysis, CRT immunoreactivity was found at both the luminal and abluminal membranes of the rat retinal capillary endothelial cells. In conclusion, CRT is expressed at the inner BRB and plays a role in blood-to-retina creatine transport across the inner BRB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02437.x
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  • 3
    Electronic Resource
    Electronic Resource
    Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 90 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Organic anion transporting polypeptide 3 (oatp3) transports various CNS-acting endogenous compounds, including thyroid hormones and prostaglandin E2, between extra- and intracellular spaces, suggesting a possible role in CNS function. The purpose of this study was to clarify the expression and localization of oatp3 in the mouse brain. RT-PCR analysis revealed that oatp3 mRNA is expressed in brain capillary-rich fraction, conditionally immortalized brain capillary endothelial cells, choroid plexus, brain and lung, but not in liver or kidney, where oatp1, 2 and 5 mRNAs were detected. Immunohistochemical analysis with anti-oatp3 antibody suggests that oatp3 protein is localized at the brush-border membrane of mouse choroid plexus epithelial cells. Furthermore, intense immunoreactivity was detected in neural cells in the border region between hypothalamus and thalamus, and in the olfactory bulb. Immunoreactivity was also detected in brain capillary endothelial cells in the cerebral cortex. These localizations in the mouse brain suggest that oatp3 plays roles in blood–brainand –cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02549.x
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  • 4
    Electronic Resource
    Electronic Resource
    The l-isomer-selective transport of aspartic acid is mediated by ASCT2 at the blood–brain barrier (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 87 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Aspartic acid (Asp) undergoes l-isomer-selective efflux transport across the blood–brain barrier (BBB). This transport system appears to play an important role in regulating l- and d-Asp levels in the brain. The purpose of this study was to identify the responsible transporters and elucidate the mechanism for l-isomer-selective Asp transport at the BBB. The l-isomer-selective uptake of Asp by conditionally immortalized mouse brain capillary endothelial cells used as an in vitro model of the BBB took place in an Na+- and pH-dependent manner. This process was inhibited by system ASC substrates such as l-alanine and l-serine, suggesting that system ASC transporters, ASCT1 and ASCT2, are involved in the l-isomer selective transport. Indeed, l-Asp uptake by oocytes injected with either ASCT1 or ASCT2 cRNA took place in a similar manner to that in cultured BBB cells, whereas no significant d-Asp uptake occurred. Although both ASCT1 and ASCT2 mRNA were expressed in the cultured BBB cells, the expression of ASCT2 mRNA was 6.7-fold greater than that of ASCT1. Moreover, immunohistochemical analysis suggests that ASCT2 is localized at the abluminal side of the mouse BBB. These results suggest that ASCT2 plays a key role in l-isomer-selective Asp efflux transport at the BBB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.02063.x
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  • 5
    Electronic Resource
    Electronic Resource
    Application of magnetically isolated rat retinal vascular endothelial cells for the determination of transporter gene expression levels at the inner blood–retinal barrier (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 91 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The purpose of the present study was to quantify transporter gene levels at the inner blood–retinal barrier (inner BRB) using a combination of magnetic isolation method for rat retinal vascular endothelial cells (RVEC) and real-time quantitative PCR analysis. The transcript levels of CD31, Tie-2, claudin-5, occludin, Jam-1, mdr1a, oatp2, and oatp14 in the RVEC fraction were more than 100-fold greater than those in the non-RVEC fraction, suggesting that these genes are predominantly expressed at the inner BRB. The transcript levels of GLUT1 and MCT1 in the RVEC fraction were the most abundant in the respective transporter family, suggesting that GLUT1 and MCT1 play a predominant role in d-glucose and monocarboxylate transport, respectively, at the inner BRB. In conclusion, application of magnetically isolated RVEC is able to determine transporter gene levels at the inner BRB thereby increasing our understanding of inner BRB functions at a molecular level.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02842.x
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  • 6
    Electronic Resource
    Electronic Resource
    Blood-Brain Barrier Produces Significant Efflux of L-Aspartic Acid but Not D-Aspartic Acid (1999)
    Oxford UK : Blackwell Science Ltd
    Journal of neurochemistry 73 (1999), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract : The brain efflux index method has been used to clarify the mechanism of efflux transport of acidic amino acids such as L-aspartic acid (L-Asp), L-glutamic acid (L-Glu), and D-aspartic acid (D-Asp) across the blood-brain barrier (BBB). About 85% of L-[3H]Asp and 40% of L-[3H]Glu was eliminated from the ipsilateral cerebrum within, respectively, 10 and 20 min of microinjection into the brain. The efflux rate constant of L-[3H]Asp and L-[3H]Glu was 0.207 and 0.0346 min-1, respectively. However, D-[3H]Asp was not eliminated from brain over a 20-min period. The efflux of L-[3H]Asp and L-[3H]Glu was inhibited in the presence of excess unlabeled L-Asp and L-Glu, whereas D-Asp did not inhibit either form of efflux transport. Aspartic acid efflux across the BBB appears to be stereospecific. Using a combination of TLC and the bioimaging analysis, attempts were made to detect the metabolities of L-[3H]Asp and L-[3H]Glu in the ipsilateral cerebrum and jugular vein plasma following a microinjection into parietal cortex, area 2. Significant amounts of intact L-[3H]Asp and L-[3H]Glu were found in all samples examined, including jugular vein plasma, providing direct evidence that at least a part of the L-Asp and L-Glu in the brain interstitial fluid is transported across the BBB in the intact form. To compare the transport of acidic amino acids using brain parenchymal cells, brain slice uptake studies were performed. Although the slice-to-medium ratio of D-[3H]Asp was the highest, followed by L-[3H]Glu and L-[3H]Asp, the initial uptake rate did not differ for both L-[3H]Asp and D-[3H]Asp, suggesting that the uptake of aspartic acid in brain parenchymal cells is not stereospecific. These results provide evidence that the BBB may act as an efflux pump for L-Asp and L-Glu to reduce the brain interstitial fluid concentration and act as a static wall for D-Asp.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1999.0731206.x
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  • 7
    Electronic Resource
    Electronic Resource
    Blood—Brain Barrier Is Involved in the Efflux Transport of a Neuroactive Steroid, Dehydroepiandrosterone Sulfate, via Organic Anion Transporting Polypeptide 2 (2000)
    Oxford UK : Blackwell Science Ltd.
    Journal of neurochemistry 75 (2000), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We have investigated the transport characteristics of dehydroepiandrosterone sulfate (DHEAS), a neuroactive steroid, at the blood—brain barrier (BBB) in a series of functional in vivo and in vitro studies. The apparent BBB efflux rate constant of [3H]DHEAS evaluated by the brain efflux index method was 2.68 × 10-2 min-1. DHEAS efflux transport was a saturable process with a Michaelis constant (Km) of 32.6 μM. Significant amounts of [3H]DHEAS were determined in the jugular venous plasma by HPLC, providing direct evidence that most of the DHEAS is transported in intact form from brain to the circulating blood across the BBB. This efflux transport of [3H]DHEAS was significantly inhibited by common rat organic anion-transporting polypeptide (oatp) substrates such as taurocholate, cholate, sulfobromophthalein, and estrone-3-sulfate. Moreover, the apparent efflux clearance of [3H]DHEAS across the BBB (118 μl/min-g of brain) was 10.4-fold greater than its influx clearance estimated by the in situ brain perfusion technique (11.4 μl/min-g of brain), suggesting that DHEAS is predominantly transported from the brain to blood across the BBB. In cellular uptake studies using a conditionally immortalized mouse brain capillary endothelial cell line (TM-BBB4), [3H]DHEAS uptake by TM-BBB4 cells exhibited a concentration dependence with a Km of 34.4 μM and was significantly inhibited by the oatp2-specific substrate digoxin. Conversely, [3H]digoxin uptake by TM-BBB4 cells was significantly inhibited by DHEAS. Moreover, the net uptake of [3H]DHEAS at 30 min was significantly increased under ATP-depleted conditions, suggesting that an energy-dependent efflux process may also be involved in TM-BBB4. RT-PCR and sequence analysis suggest that an oatp2 is expressed in TM-BBB4 cells. In conclusion, DHEAS efflux transport takes place across the BBB, and studies involving in vitro DHEAS uptake and RT-PCR suggest that there is oatp2-mediated DHEAS transport at the BBB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2000.0751907.x
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  • 8
    Electronic Resource
    Electronic Resource
    Blood–brain barrier transport of a novel µ1-specific opioid peptide, H-Tyr-d-Arg-Phe-β-Ala-OH (TAPA) (2003)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 84 (2003), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The purpose of this study was to clarify the mechanism of the blood–brain barrier (BBB) transport of H-Tyr-d-Arg-Phe-β-Ala-OH (TAPA), which is a novel dermorphin analog with high affinity for the µ1-opioid receptor. The in vivo BBB permeation influx rate of [125I]TAPA after an i.v. bolus injection (7.3 pmol/g body weight) into mice was estimated to be 0.265 ± 0.025µL/(min · g of brain). The influx rate of [125I]TAPA was reduced 70% by the coadministration of unlabeled TAPA (33 nmol/g of brain), suggesting the existence of a specific transport system for TAPA at the BBB. In order to elucidate the BBB transport mechanism of TAPA, a conditionally immortalized mouse brain capillary endothelial cell line (TM-BBB4) was used as an in vitro model of the BBB. The acid-resistant binding of [125I]TAPA, which represents the internalization of the peptide into cells, was temperature- and concentration-dependent with a half-saturation constant of 10.0 ± 1.7 µm. The acid-resistant binding of TAPA was significantly inhibited by 2,4-dinitrophenol, dansylcadaverine (an endocytosis inhibitor) and poly-l-lysine and protamine (polycations). These results suggest that TAPA is transported through the BBB by adsorptive-mediated endocytosis, which is triggered by binding of the peptide to negatively charged sites on the surface of brain capillary endothelial cells. Blood–brain barrier transport via adsorptive-mediated endocytosis plays a key role in the expression of the potent opioid activity of TAPA in the CNS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2003.01582.x
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  • 9
    Electronic Resource
    Electronic Resource
    Regulation of taurine transport at the blood–brain barrier by tumor necrosis factor-α, taurine and hypertonicity (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 83 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Taurine is the abundant sulfur-containing β-amino acid in brain where it exerts a neuroprotective effect. Although it is known that the blood–brain barrier (BBB) mediates taurine transport, the regulation of taurine transport have not been clarified yet. A conditionally immortalized rat brain capillary endothelial cells (TR-BBB13), an in vitro model of the BBB, exhibited [3H]taurine uptake, which was dependent on both Na+ and Cl–, and inhibited by β-alanine. Taurine transporter (TAUT) mRNA was detected in TR-BBB13 cells, and TAUT protein was also expressed at 70 kDa. TR-BBB13 cells exposed to 20 ng/mL TNF-α and under hypertonic conditions showed a 1.7-fold and 3.2-fold increase in [3H]taurine uptake, respectively. In contrast, lipopolysaccharide and diethyl maleate did not significantly affect taurine uptake. The taurine uptake was reduced by pre-treatment with excess taurine (50 mm). The mRNA level of the TAUT in TNF-α and following hypertonic treatment was greater than that in control cells, whereas that under excess taurine conditions was lower than in controls. Therefore, taurine transport activity at the BBB appears to be regulated at the transcriptional level by cell damage, osmolality and taurine in the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01223.x
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  • 10
    Electronic Resource
    Electronic Resource
    Role of blood–brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain (2002)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 83 (2002), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Renal impairment is associated with CNS dysfunctions and the accumulation of uremic toxins, such as indoxyl sulfate, in blood. To evaluate the relevance of indoxyl sulfate to CNS dysfunctions, we investigated the brain-to-blood transport of indoxyl sulfate at the blood–brain barrier (BBB) using the Brain Efflux Index method. [3H]Indoxyl sulfate undergoes efflux transport with an efflux transport rate of 1.08 × 10−2/min, and the process is saturable with a Km of 298 µm. This process is inhibited by para-aminohippuric acid, probenecid, benzylpenicillin, cimetidine and uremic toxinins, such as hippuric acidand 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid. RT–PCR revealed that an OAT3 mRNA is expressed in conditionally immortalized rat brain capillary endothelial cell lines and rat brain capillary fraction. Xenopus oocytes expressing OAT3 were found to exhibit [3H]indoxyl sulfate uptake, which was significantly inhibited by neurotransmitter metabolites, such as homovanillic acid and 3-methoxy-4-hydroxymandelic acid, and by acyclovir, cefazolin, baclofen, 6-mercaptopurine, benzoic acid, and ketoprofen. These results suggest that OAT3 mediates the brain-to-blood transport of indoxyl sulfate, and is also involved in the efflux transport of neurotransmitter metabolites and drugs. Therefore, inhibition of the brain-to-blood transport involving OAT3 would occur in uremia and lead to the accumulation of neurotransmitter metabolites and drugs in the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.2002.01108.x
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