Blood–Brain Barrier Controls Carnitine Level in the Brain: A Study on a Model System with RBE4 Cells

Mroczkowska, Joanna E.; Roux, F.; Nałȩcz, Maciej J.; Nałęcz, Katarzyna A.

doi:10.1006/bbrc.1999.1923

Cited by 25 publications

(22 citation statements)

References 29 publications

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“…RBE4 cells, RBEC1 and TR-BBB cells have been used to demonstrate that transporters such as organic cation transporter/carnitine transporter (OCTN2) (Friedrich et al, 2003;Kido et al, 2001a;Mroczkowska et al, 2000), serotonin transporter , and the ATA2 system A isoform are expressed in rat brain endothelium (Tables V-VI). However, in vitro data obtained in RBE cell lines have to be confirmed by in vivo experiments or mRNA/protein expression analysis in freshly isolated RBE cells, since over-expression of nonspecific genes such as mdr1b, mdr2, and multidrug resistance-associated protein-1 (Mrp1) has been observed in RBE cell lines or primary cultures, compared with brain endothelium in situ Regina et al, 1998;Tamai et al, 2000).…”

Section: Use Of Immortalized Rbe Cell Lines For the Study Of Blood-brmentioning

confidence: 99%

“…(1) Mroczkowska et al, 2000; (2) Kido et al, 2001a; (3) Friedrich et al, 2003 Carnitine/organic cation Na + dependence; same Km as the rat intestine or placenta OCTN2 RBE4/RBEC1: characterization studies-conclusion that the carnitine/organic cation transporter is functionally expressed in the brain endothelium (1) Karlstedt et al, 1999 Histamine Sensibility to inhibitory agents (impromidine) Requirement of external Na + RBE4: characterization and regulation studies-expression of H1 and H2 receptors (1) Down-regulation of H1 and H2 receptor mRNA expression by dexamethasone (1) Histamine uptake…”

Section: Octn2mentioning

confidence: 99%

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Rat Brain Endothelial Cell Lines for the Study of Blood–Brain Barrier Permeability and Transport Functions

2005

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(1) In vitro models of the BBB have been developed from cocultures between bovine, porcine, rodent or human brain capillary endothelial cells with rodent or human astrocytes. Since most in vivo BBB studies have been performed with small laboratory animals, especially rats, it is important to establish a rat brain endothelial (RBE) cell culture system that will allow correlations between in vitro and in vivo results. The present review will constitute a brief description of the best characterized RBE cell lines (RBE4, GP8/3.9, GPNT, RBEC1, TR-BBBs and rBCEC4 cell lines) and will summarize their recent and important contribution to our current knowledge of the BBB transport functions and permeability to blood-borne solutes, drugs, and cells. (2) In most cases, primary cultures of RBE cells were transduced with an immortalizing gene (SV40 or polyoma virus large T-antigen or adenovirus E1A), either by transfection of plasmid DNA or by infection using retroviral vectors. In one case however, the conditionally immortalized TR-BBB cell line was derived from primary cultures of brain endothelial cells of SV40-T-expressing transgenic rats. (3) All cell lines appear to have an endothelial morphology. The absence of foci formation would mean that the cells are not transformed. The endothelial origin is shown by the expression of Factor VIII-related antigen. Immortalized RBE cells express all the enzymes and transporters that are considered as specific for the blood-brain barrier endothelium, with similar characteristics to those expected from in vivo analyses, but at a significantly lower level. Some RBE cell lines are responsive to astroglial factors, such as RBE4 cells, rBEC4, and TR-BBB cells. None of the immortalized RBE cell lines appear to generate the necessary restrictive paracellular barrier properties that would allow to use them in transendothelial permeability screening. (4) RBE cell lines have been used to demonstrate that transporters such as organic cation transporter/carnitine transporter, serotonin transporter, and the ATA2 system A isoform are expressed in rat brain endothelium. When the transporter is shown to be expressed with the same properties in the immortalized RBE cells as in vivo, regulation studies may be initiated even if the transporter is down-regulated. Pharmacological applications have been proposed with well-characterized transporters such as monocarboxylic acid transporter-1, large neutral amino acid tansporter-1, nucleoside carrier systems, and P-glycoprotein. RBE cell monolayers have also been used to investigate the mechanism of the transendothelial transport of large molecules, such as immunoliposomes or nanoparticles, potentially useful as drug delivery vectors to the brain. (5) RBE4 and GP8 cell lines have been extensively used to demonstrate that intercellular adhesion molecule-1 (ICAM-1) engagement in brain endothelial cells triggers multiple signal transduction pathways. Using functional assays, it was established that ICAM-1 signaling is intimately and actively involved in facili...

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Section: Use Of Immortalized Rbe Cell Lines For the Study Of Blood-brmentioning

confidence: 99%

Section: Octn2mentioning

confidence: 99%

Rat Brain Endothelial Cell Lines for the Study of Blood–Brain Barrier Permeability and Transport Functions

2005

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“…Although RBE4 cells have been extensively used as an in vitro model for the blood-brain barrier (Chishty et al, 2002;Lagrange et al, 1999;Mroczkowska et al, 2000), relatively little data are available concerning their motility properties. Since we were interested in several distinct processes involved in angiogenesis, we first characterized the adhesive and migratory properties of these cells on various purified ECM proteins.…”

Section: Dependency Of Rbe4 Cell Adhesion and Migration On Substratementioning

confidence: 99%

Inhibition of Angiogenic Properties of Brain Endothelial Cells by Platelet-Derived Sphingosine-1-Phosphate

Pilorget

Annabi

Bouzeghrane

et al. 2005

J Cereb Blood Flow Metab

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The platelet-derived lysophospholipid sphingosine-1-phosphate (S1P) is present in blood plasma and is one of the most potent growth factors displaying proangiogenic activity towards endothelial cells (EC) derived from various tissues. The paracrine regulation of brain angiogenesis by plateletderived growth factors is, however, poorly understood. In the present study, we assessed the role of S1P on brain EC migration and tubulogenesis, using rat brain-derived (RBE4) EC as an in vitro model. We show that S1P inhibits brain EC migration and tubulogenesis, while it displays proangiogenic activity towards noncerebral EC. Overexpression of the S1P receptor S1P-1 in RBE4 cells potentiated all of the S1P-mediated events. We also show that the lack of expression of MT1-MMP, a membrane-bound matrix metalloproteinase that is thought to cooperate with S1P in tubulogenic processes, may explain the antiangiogenic activity of S1P on brain vasculature. Altogether our results support the hypothesis of a tissue-specific, antiangiogenic role of S1P in the brain, which may help to stabilize the cerebral vasculature and thus have crucial impact on the setting and regulation of normal brain vascularization.

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“…Experiments performed with the suspension of brain capillary endothelial cells demonstrated that carnitine uptake can be inhibited by butyrobetaine (an OCTN2 substrate) as well as by leucine and 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BCH) Mroczkowska et al, 2000) and functioning of B 0;þ at the basolateral side has been postulated . In order to approach a physiological situation representing carnitine flux through the bloodbrain barrier, a model of endothelial cells grown on filters was applied, moreover, the cells were grown in the presence of astrocytes what allows to keep their proper phenotype (Cecchelli et al, 1999).…”

Section: Transport Of Carnitine In the Brainmentioning

confidence: 99%

“…In the postnatal period the fatty acid oxidation develops rapidly, what is correlated with the increased activity of palmitoylCoA synthetase and carnitine palmitoyltransferase (Warshaw and Terry, 1976), the process of fatty acid b-oxidation is, however, relatively low in neurons from adult brain. Carnitine accumulates in the brain (Bresolin et al, 1982), it is transported through the blood-brain barrier, released from the brain capillary endothelial cells as free carnitine (Mroczkowska et al, , 2000 and taken up by neural cells Wawrze nczyk et al, 2001). Primary carnitine deficiency (On-line Mendelian Inheritance in Man 212140) is a recessive inherited disorder caused by defective carnitine transport and can result in hypoketotic hypoglycemia, hepatic encephalopathy (Rey'e-like syndrome), sudden infant death in younger children or in skeletal or cardiac myopathy.…”

Section: Introductionmentioning

confidence: 99%

Carnitine: transport and physiological functions in the brain

Nałęcz

Miecz

Bérézowski

et al. 2004

Molecular Aspects of Medicine

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Blood–Brain Barrier Controls Carnitine Level in the Brain: A Study on a Model System with RBE4 Cells

Cited by 25 publications

References 29 publications

Rat Brain Endothelial Cell Lines for the Study of Blood–Brain Barrier Permeability and Transport Functions

Rat Brain Endothelial Cell Lines for the Study of Blood–Brain Barrier Permeability and Transport Functions

Inhibition of Angiogenic Properties of Brain Endothelial Cells by Platelet-Derived Sphingosine-1-Phosphate

Carnitine: transport and physiological functions in the brain

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