Blood-Brain Barrier In Vitro Models and Their Application in Toxicology: The Report and Recommendations of ECVAM Workshop 49 1,2

Anon. (1994). ECVAM News & Views. ATLA 22, 7–11.

Anon. (2001). White Paper on a Strategy for a Future Chemicals Policy (COM(2001)88 final), 32 pp. Brussels, Belgium: European Commission. Website http://europa.eu.int/comm/enterprise/chemicals/chempol/whitepaper/reach.htm (Accessed 18.11.03).

Anon. (2003). Directive 2003/15/EC of the European Parliament and of the Council of 27 February 2003 amending Council Directive 76/768/EEC on the approximation of the laws of the Member States relating to cosmetic products (Text with EEA relevance). Official Journal of the European Union L66, 26–35.

Kusuhara H. , & Sugiyama Y. (2001). Efflux transport systems for drugs at the blood–brain barrier and blood–cerebrospinal fluid barrier (part 1). Drug Discovery Today 6, 150–156.

Feng M.R. (2002). Assessment of blood–brain barrier penetration: in silico, in vitro and in vivo. Current Drug Metabolism 3, 647–657.

Nitz T. , Eisenblätter T. , Haselbach M. , & Galla H-J. (2001). Recent advances in the development of cell culture models for the blood–brain- and blood–CSF-barrier. In Blood–Brain Barrier Delivery and Brain Pathology (ed. Kluwer J.L. ), pp. 45–62. New York, NJ, USA: Plenum Press.

Haselbach M. , Wegener J. , Decker S. , Engelbertz C. , & Galla H-J. (2001). Porcine choroid plexus epithelial cells in culture: regulation of barrier properties and transport processes. Microscopy Research and Technique 52, 137–152.

Strazielle N. , & Ghersi-Egea J-F. (1999). Demonstration of a couplet metabolism–efflux process at the choroid plexus as a mechanism of brain protection towards xenobiotics. Journal of Neuroscience 19, 6275–6289.

Savettieri G. , Di Liegro I. , Catania C. , Licata L. , Pitarresi G.L. , D'Agostino S. , Schiera G. , De Caro V. , Giandalia G. , Giannola L.I. , & Cestelli A. (2000). Neurons and ECM regulate occluding localization in brain endothelial cells. Molecular Neuroreceptors 11, 1081–1084.

Bauer H.C. , & Bauer H. (2000). Neural induction of the blood–brain barrier: still an enigma. Cell and Molecular Neurobiology 20, 13–28.

de Vries H.E. , Kuiper J. , de Boer A.G. , van Berkel J.C. , & Breimer D.D. (1997). The blood–brain barrier in neuroinflammatory diseases. Pharmacological Reviews 49, 143–155.

Grant G.A. , Abbott N.J. , & Janigro D. (1998). Understanding the physiology of the blood–brain barrier: in vitro models. News in Physiological Sciences 13, 287–293.

Andersen M.E. (1991). Physiological modelling of organic compounds. Annals of Occupational Hygiene 35, 309–321.

Poulin P. , & Krishnan K. (1996). A tissue composition-based algorithm for predicting tissue: air partition coefficients of organic chemicals. Toxicology and Applied Pharmacology 136, 126–130.

DeJongh J. , Verhaar H.J. , & Hermens J.L. (1998). Role of kinetics in acute lethality of nonreactive volatile organic compounds (VOCs). Toxicological Sciences 45, 26–32.

Meulenberg C.J. , & Vijverberg H.P. (2000). Empirical relations predicting human and rat tissue: air partition coefficients of volatile organic compounds. Toxicology and Applied Pharmacology 165, 206–216.

Worth A.P. , & Balls M. eds (2002). Alternative (Nonanimal) Methods for Chemicals Testing: Current Status and Future Prospects. A report prepared by ECVAM and the ECVAM working group on chemicals. ATLA 30, Suppl. 1, 1–125.

Forsby A. , Pilli F. , Bianchi V. , & Walum E. (1995). Determination of critical cellular neurotoxic concentrations in human neuroblastoma (SH-SY5Y) cell cultures. ATLA 23, 800–811.

DeJongh J. , Forsby A. , Houston J.B. , Beckman M. , Combes R. , & Blaauboer B.J. (1999). An integrated approach to the prediction of systemic toxicity using computer-based biokinetic models and biological in vitro test methods: overview of a prevalidation study based on the ECITTS project. Toxicology in Vitro 13, 549–554.

Rubin L.L. , & Staddon J.M. (1999). The cell biology of the blood–brain barrier. Annual Review of Neuroscience 22, 11–23.

Garberg P. (1998). In vitro models of the blood–brain barrier. ATLA 26, 821–847.

de Boer A.G. , & Gaillard P.J. (2002). In vitro models of the blood–brain barrier: when to use which? Current Medicinal Chemistry — Central Nervous System Agents 2, 203–209.

Méresse S. , Dehouck M.P. , Delorme P. , Bensaid M. , Tauber J.P. , Delbart C. , Fruchart J.C. , & Cecchelli R. (1989). Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. Journal of Neurochemistry 53, 1363–1371.

Dehouck M.P. , Méresse S. , Delorme P. , Fruchart J-C. , & Cecchelli R. (1990). An easier, reproducible, and mass-production method to study the blood–brain barrier in vitro. Journal of Neurochemistry 54, 1798–1801.

Dehouck M.P. , Dehouck B. , Schluep C. , Fruchart J.C. , Lemaire M. , & Cecchelli R. (1995). Drug transport to the brain: comparison between in vitro and in vivo models of the blood–brain barrier. European Journal of Pharmaceutical Sciences 3, 357–365.

Fenart L. , Buée-Scherrer V. , Descamps L. , Duhem C. , Poullain M.G. , Cecchelli R. , & Dehouck M.P. (1998). Inhibition of P-glycoprotein at the blood–brain barrier level: in vitro studies of its implication in blood–brain barrier integrity and in drug transport to the brain by an in vitro model of the blood–brain barrier. Pharmaceutical Research 15, 993–1000.

Dehouck M.P. , Vigne P. , Torpier G. , Breittmayer J.P. , Cecchelli R. , & Frelin C. (1997). Endothelin-I as a mediator of endothelial cell–pericyte interactions in bovine brain capillaries. Journal of Cerebral Blood Flow and Metabolism 17, 464–469.

Descamps L. , Dehouck M.P. , Torpier G. , & Cecchelli R. (1996). Receptor-mediated transcytosis of transferrin through blood–brain barrier endothelial cells. American Journal of Physiology–Heart and Circulatory Physiology 270, 1149–1158.

Fillebeen C. , Descamps L. , Dehouck M.P. , Fenart L. , Benaissa M. , Spick G. , Cecchelli R. , & Pierce A. (1999). Receptor mediated transcytosis of lactoferrin through the blood–brain barrier. Journal of Biological Chemistry 274, 7011–7017.

Cecchelli R. , Dehouck B. , Descamps L. , Fenart L. , Buée-Scherrer V. , Duhem C. , Lundquist S. , Rentfel M. , Torpier G. , & Dehouck M.P. (1999). In vitro model for evaluating drug transport across the blood–brain barrier. Advanced Drug Delivery Reviews 36, 165–178.

Lundquist S. , Renftel M. , Brillault J. , Fenart L. , Cecchelli R. , & Dehouck M.P. (2002). Prediction of drug transport through the blood–brain barrier in vivo: a comparison between two in vitro cell models. Pharmaceutical Research 7, 976–981.

Hoheisel D. , Nitz T. , Franke H. , Wegener J. , Hakvoort A. , Tilling T. , & Galla H-J. (1998). Hydrocortisone reinforces the blood–brain barrier properties in a serum-free cell culture system. Biochemical and Biophysical Research Communications 244, 231–316.

Lohmann C. , Hüwel S. , & Galla H-J. (2002). Predicting blood–brain barrier permeability of drugs: evaluation of different in vitro assays. Journal of Drug Targeting 10, 263–276.

Eisenblätter T. , Hüwel S. , & Galla H-J. (2003). Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood–brain barrier. Brain Research 971, 221–231.

Nitz T. , Eisenblätter T. , Psathaki K. , & Galla H-J. (2003). Serum-derived factors weaken the barrier properties of cultured porcine brain capillary endothelial cells in vitro. Brain Research 981, 30–40.

Gaillard P.J. , van der Meide P.H. , de Boer A.G. , & Breimer D.D. (2001). Glucocorticoid and type I interferon interactions at the blood–brain barrier: relevance for drug therapies for multiple sclerosis. NeuroReport 12, 2189–2193.

Uyttendaele H. , Closson V. , Wu G. , Roux F. , Weinmaster G. , & Kitajewski J. (2000). Notch4 and Jagged-1 induce microvessel differentiation of rat brain endothelial cells. Microvascular Research 60, 91–103.

Drexler H.G. , Quentmeier H. , Dirks W.G. , & MacLeod R.A. (2002). Bladder carcinoma cell line ECV304 is not a model system for endothelial cells. In Vitro Cellular and Developmental Biology — Animal 38, 185–186.

Dirks W.G. , MacLeod R.A. , & Drexler H.G. (1999). ECV304 (endothelial) is really T24 (bladder carcinoma): cell line cross-contamination at source. In Vitro Cellular and Developmental Biology — Animal 35, 558–559.

Lundquist S. , Renftel M. , Brillault J. , Fenart L. , Cecchelli R. , & Dehouck M.P. (2002). Prediction of drug transport through the blood–brain barrier in vivo: a comparison between two in vitro cell models. Pharmaceutical Research 19, 976–981.

Gaillard P.J. , Voorwinden L.H. , Nielsen J.L. , Ivanov A. , Atsumi R. , Engman H. , Ringbom C. , de Boer A.G. , & Breimer D.D. (2001). Establishment and functional characterizarion of an in vitro model of the blood–brain barrier, comprising a co-culture of brain capillary endothelial cells and astrocytes. European Journal of Pharmacuetical Sciences 12, 215–222.

Kramer S.D. , Schutz Y.B. , Wunderli-Allenspach H. , Abbott N.J. , & Begley D.J. (2002). Lipids in blood–brain barrier models in vitro. II. Influence of glial cells on lipid classes and lipid fatty acids. In Vitro Cellular and Developmental Biology — Animal 38, 566–571.

Tilling T.H. , Engelbertz C.H. , Decker S.T. , Korte D. , Hüwel S. , & Galla H-J. (2002). Expression and adhesive properties of basement membrane proteins in cerebral capillary endothelial cell cultures. Cell and Tissue Research 310, 19–29.

Lohmann C. , Krischke M. , Wegener J. , & Galla H-J. (2004). Tyrosine phosphatase inhibition induces loss of blood–brain barrier integrity by matrix metalloproteinase-dependent and independent pathways. Brain Research 995, 184–196.

Tähti H. , Nevala H. , & Toimela T. (2003). Refining in vitro neurotoxicity testing — the development of blood–brain barrier models. ATLA 31, 273–276.

Toimela T. , Mäenpää H. , Mannerström M. , & Tähti H. (2004). Development of an in vitro blood–brain barrier model — cytotoxicity of mercury and aluminum. Toxicology and Applied Pharmacology 195, 73–82.

Blaauboer B.J. (2003). Biokinetic and toxicodynamic modelling and its role in toxicological research and risk assessment. ATLA 31, 277–281.

DeJongh J. , Nordin-Andersson M. , Ploeger B. , & Forsby A. (1999). Estimation of systemic toxicity of acrylamide by integration of in vitro toxicity data with kinetic simulations. Toxicology and Applied Pharmacology 158, 261–268.

Poulin P. , & Krishnan K. (1996). A tissue composition-based algorithm for predicting tissue: air partition coefficients of organic chemicals. Toxicology and Applied Pharmacology 136, 126–130.

DeJongh J. , Verhaar H.J. , & Hermens J.L.M. (1997). A quantitative property–property relationship (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans. Archives of Toxicology 72, 17–25.

Lee G. , Dallas S. , Hong M. , & Bendayan R. (2001). Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacological Reviews 53, 569–596.

Sun H. , Dai H. , Shaik N. , & Elmquist W.F. (2003). Drug efflux transporters in the CNS. Advanced Drug Delivery Reviews 55, 83–105.

Gaillard P.J. , de Boer A.G. , & Breimer D.D. (2003). Pharmacological investigations on lipopolysaccharide-induced permeability changes in the blood–brain barrier in vitro. Microvascular Research 65, 24–31.

Ghersi-Egea J.F. , & Strazielle N. (2002). Choroid plexus transporters for drugs and other xenobiotics. Journal of Drug Targeting 10, 353–357.

Roux F. , Durieu-Trautmann O. , Chaverot N. , Claire M. , Mailly P. , Bourre J.M. , Strosberg A.D. , & Couraud P.O. (1994). Regulation of gamma-glutamyl transpeptidase and alkaline phosphatase activities in immortalized rat brain microvessel endothelial cells. Journal of Cellular Physiology 159, 101–113.

Greenwood J. , Pryce G. , Devine L. , Male D.K. , dos Santos W.L. , Calder V.L. , & Adamson P. (1996). SV40 large T immortalised cell lines of the rat blood–brain and blood–retinal barriers retain their phenotypic and immunological characteristics. Journal of Neuroimmunology 71, 51–63.

Terasaki T. , & Hosoya K. (2001). Conditionally immortalized cell lines as a new in vitro model for the study of barrier functions. Biological and Pharmaceutical Bulletin 24, 111–118.

Blasig I.E. , Giese H. , Schroeter M.L. , Sporbert A. , Utepbergenov D.I. , Buchwalow I.B. , Neubert K. , Schonfelder G. , Freyer D. , Schimke I. , Siems W.E. , Paul M. , Haseloff R.F. , & Blasig R. (2001). NO and oxyradical metabolism in new cell lines of rat brain capillary endothelial cells forming the blood–brain barrier. Microvascular Research 62, 114–127.

Lechardeur D. , Schwartz B. , Paulin D. , & Scherman D. (1995). Induction of blood–brain barrier differentiation in a rat brain-derived endothelial cell line. Experimental Cell Research 220, 161–170.

Kido Y. , Tamai I. , Okamoto M. , Suzuki F. , & Tsuji A. (2000). Functional clarification of MCT1-mediated transport of monocarboxylic acids at the blood–brain barrier using in vitro cultured cells and in vivo BUI studies. Pharmaceutical Research 17, 55–62.

Mooradian D.L. , & Diglio C.A. (1991). Production of a transforming growth factor-beta-like growth factor by RSV-transformed rat cerebral microvascular endothelial cells. Tumour Biology 12, 171–183.

Xu J. , Qu Z.X. , Moore S.A. , Hsu C.Y. , & Hogan E.L. (1992). Receptor-linked hydrolysis of phosphoinositides and production of prostacyclin in cerebral endothelial cells. Journal of Neurochemistry 58, 1930–1935.

Asaba H. , Hosoya K. , Takanaga H. , Ohtsuki S. , Tamura E. , Takizawa T. , & Terasaki T. (2000). Blood–brain barrier is involved in the efflux transport of a neuroactive steroid, dehydroepiandrosterone sulfate, via organic anion transporting polypeptide 2. Journal of Neurochemistry 75, 1907–1916.

Wijsman J.A. , & Shivers R.R. (1998). Immortalized mouse brain endothelial cells are ultrastructurally similar to endothelial cells and respond to astrocyteconditioned medium. In Vitro Cellular and Developmental Biology — Animal 34, 777–784.

Tatsuta T. , Naito M. , Oh-hara T. , Sugawara I. , & Tsuruo T. (1992). Functional involvement of P-glycoprotein in blood–brain barrier. Journal of Biological Chemistry 267, 20383–20391.

Sobue K. , Yamamoto N. , Yoneda K. , Hodgson M.E. , Yamashiro K. , Tsuruoka N. , Tsuda T. , Katsuya H. , Miura Y. , Asai K. , & Kato T. (1999). Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neuroscience Research 35, 155–164.

Durieu-Trautmann O. , Foignant-Chaverot N. , Perdomo J. , Gounon P. , Strosberg A.D. , & Couraud P.O. (1991). Immortalization of brain capillary endothelial cells with maintenance of structural characteristics of the blood–brain barrier endothelium. In Vitro Cellular and Developmental Biology — Animal 27, 771–778.

Stins M.F. , Prasadarao N.V. , Zhou J. , Arditi M. , & Kim K.S. (1997). Bovine brain microvascular endothelial cells transfected with SV40-large T antigen: development of an immortalized cell line to study pathophysiology of CNS disease. In Vitro Cellular and Developmental Biology — Animal 33, 243–247.

Teifel M. , & Friedl P. (1996). Establishment of the permanent microvascular endothelial cell line PBMEC/C1-2 from porcine brains. Experimental Cell Research 228, 50–57.

Muruganandam A. , Herx L.M. , Monette R. , Durkin J.P. , & Stanimirovic D.B. (1997). Development of immortalized cerebromicrovascular endothelial cell line as an in vitro model of the human blood–brain barrier. FASEB Journal 11, 1187–1197.

Xiao L. , Yang C. , Dorovini-Zis K. , Tandon N.N. , Ades E. , Lal A.A. , & Udhayakumar V. (1996). Plasmodium falciparum: involvement of additional receptors in the cytoadherence of infected erythrocytes to microvascular endothelial cells. Experimental Parasitology 84, 42–55.

Prudhomme J.G. , Sherman I.W. , Land K.M. , Moses A.V. , Stenglein S. , & Nelson J.A. (1996). Studies of Plasmodium falciparum cytoadherence using immortalized human brain capillary endothelial cells. International Journal of Parasitology 26, 647–655.

Kallmann B.A. , Wagner S. , Hummel V. , Buttmann M. , Bayas A. , Tonn J.C. , & Rieckmann P. (2002). Characteristic gene expression profile of primary human cerebral endothelial cells. FASEB Journal 16, 589–591.

Drexler H.G. , Quentmeier H. , Dirks W.G. , & MacLeod R.A. (2002). Bladder carcinoma cell line ECV304 is not a model system for endothelial cells. In Vitro Cellular and Developmental Biology — Animal 38, 185–186.

Veronesi B. (1996). Characterization of the MDCK cell line for screening neurotoxicants. Neurotoxicology 17, 433–443.

Smith B.J. , Doran A.C. , McLean S. , Tingley F.D. III , O'Neill B.T. , & Kajiji S.M. (2001). P-glycoprotein efflux at the blood–brain barrier mediates differences in brain disposition and pharmacodynamics between two structurally related neurokinin-1 receptor antagonists. Journal of Pharmacology and Experimental Therapeutics 298, 1252–1259.

Batrakova E.V. , Miller D.W. , Li S. , Alakhov V.Y. , Kabanov A.V. , & Elmquist W.F. (2001). Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies. Journal of Pharmacology and Experimental Therapeutics 296, 551–557.