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Brain Microvessel Endothelial Cell Culture Systems

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Models for Assessing Drug Absorption and Metabolism

Part of the book series: Pharmaceutical Biotechnology ((PBIO,volume 8))

Abstract

The cellular basis of the blood-brain barrier (BBB) was defined as the endothelial lining of the brain microvessels in the late 1960s (Reese and Karnovsky, 1967; Brightman and Reese, 1969). This unique endothelial lining was recognized as the sole restrictive permeability barrier to the passage of nutrients, drugs, and metabolic waste products between the blood and the central nervous system. Consequently, investigations on the BBB have focused on developing an understanding of the transport and functional properties of this specialized endothelium (Bradbury, 1993).

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References

  • Adson, A., Raub, T. J., Burton, P. S., Barshun, C. L., Hilgers, A. R., Audus, K. L., and Ho, N. F. H., 1994, Quantitative approaches to delineate paracellular diffusion in cultured epithelial monolayers, J. Pharm. Sci. 83:1529–1536.

    Article  PubMed  CAS  Google Scholar 

  • Audus, K. L., and Borchardt, R. T., 1986, Characterization of an in vitro blood-brain barrier model system for studying drug transport and metabolism, Pharm. Res. 3:81–87.

    Article  CAS  Google Scholar 

  • Audus, K. L., and Borchardt, R. T., 1987, Bovine brain microvessel endothelial cell monolayers as a model system for the blood-brain barrier, Ann. N. Y. Acad. Sci. 507:9–18.

    Article  PubMed  CAS  Google Scholar 

  • Audus, K. L., and Borchardt, R. T., 1991, Transport of macromolecules across the capillary endothelium, Handb. Exp. Pharmacol. 100:43–70.

    Article  CAS  Google Scholar 

  • Audus, K. L., and Raub, T. J., 1993, Lysosomes of brain and other vascular endothelia, in: The Blood-Brain Barrier (W. M. Pardridge, ed.) Raven Press, New York, pp. 201–227.

    Google Scholar 

  • Audus, K. L., Chikhale, P. J., Miller, D. W., Thompson, S. E., and Borchardt, R. T., 1992, Brain uptake of drugs: The influence of chemical and biological factors, Adv. Drug Res. 23:1–64.

    CAS  Google Scholar 

  • Baranczyk-Kuzma, A., and Audus, K. L., 1987, Characteristics of aminopeptidase activity from bovine brain microvessel endothelium, J. Cereb. Blood Flow Metab. 7:801–805.

    Article  PubMed  CAS  Google Scholar 

  • Baranczyk-Kuzma, A., Audus, K. L., and Borchardt, R. T., 1989a, Substrate specificity of phenol sulfotransferase from primary cultures of bovine brain microvessel endothelium, J. Neurochem. 46:1956–1960.

    Article  Google Scholar 

  • Baranczyk-Kuzma, A., Raub, T. J., and Audus, K. L., 1989b, Demonstration of acid hydrolase activity in primary cultures of bovine brain microvessel endothelium, Neurochem. Res. 14:689–691.

    Article  PubMed  CAS  Google Scholar 

  • Borges, N., Shi, F., Azevedo, I., and Audus, K. L., 1994, Changes in brain microvessel endothelial cell monolayer permeability induced by adrenergic drugs, Eur. J. Pharmacol. 269:243–248.

    Article  PubMed  CAS  Google Scholar 

  • Bowman, P. D., Ennis, S. R., Rarey, K. E., Betz, A. L., and Goldstein, G. W., 1983, Brain microvessel endothelial cells in tissue culture: A model for study of blood-brain barrier permeability, Ann. Neurol. 14:396–402.

    Article  PubMed  CAS  Google Scholar 

  • Bradbury, M. W. B., 1993, The blood-brain barrier, Exp. Physiol. 78:453–472.

    PubMed  CAS  Google Scholar 

  • Brightman, M. W., and Reese, T. S., 1969, Junctions between intimately opposed cell membranes in the vertebrate brain, J. Cell Biol. 40:648–677.

    Article  PubMed  CAS  Google Scholar 

  • Caspers, M. L., and Diglio, C. A., 1984, Expression of gamma-glutamyl transpeptidase in a transformed rat cerebral endothelial cell line, Biochim. Biophys. Acta 803:1–6.

    Article  PubMed  CAS  Google Scholar 

  • Chikhale, E. G., Ng, K.-Y., Burton, P. S., and Borchardt, R. T., 1994, Hydrogen bonding potential as a determinant of the in vitro and in situ blood-brain barrier permeability of peptides, Pharm. Res. 11:412–419.

    Article  PubMed  CAS  Google Scholar 

  • DeBault, L. E., 1981, γ-glutamyltranspeptidase induction mediated by glial foot process-to-endothelium contact in co-culture, Brain Res. 220:432–435.

    Article  PubMed  CAS  Google Scholar 

  • DeBault, L. E., and Cancilla, P. A., 1980, Gamma-glutamyl transpeptidase in isolated brain endothelial cell: Induction by glial cells in vitro, Science 207:653–655.

    Article  PubMed  CAS  Google Scholar 

  • DeBault, L. E., Henriquez, E., Hart, M. N., and Cancilla, P. A., 1981, Cerebral microvessels and derived cells in tissue culture: Establishment, identification, and preliminary characterization of an endothelial cell line, in vitro 15:480–494.

    Article  Google Scholar 

  • Dehouck, M.-P., Jolliet-Riant, P., Bree, F., Fruchart, J.-C., Cecchelli, R., and Tillement, J.-P, 1992, Drug transfer across the blood-brain barrier: Correlation between in vitro and in vivo models, J. Neurochem. 58:1790–1797.

    Article  PubMed  CAS  Google Scholar 

  • Diglio, C. A., Wolfe, D. E., and Meyers, P., 1983, Transformation of rat cerebral endothelial cells by Rous sarcoma virus, J. Cell Biol. 97:15–21.

    Article  PubMed  CAS  Google Scholar 

  • Durieu-Trautmann, O., Foignant, N., Strosberg, A. D., and Couraud, P. O., 1991, Coexpression of 1-and 2-adrenergic receptors on bovine brain capillary endothelial cells in culture, J. Neurochem. 56: 775–781.

    Article  PubMed  CAS  Google Scholar 

  • Fukuta, M., Okada, H., Iinuma, S., Yanai, S., and Toguchi, H., 1994, Insulin fragments as a carrier for peptide delivery across the blood-brain barrier, Pharm. Res. 11:1681–1688.

    Article  PubMed  CAS  Google Scholar 

  • Guillot, F. L., and Audus, K. L., 1991, Angiotensin peptide regulation of bovine brain microvessel endothelial cell monolayer permeability, J. Cardiovasc. Pharmacol. 18:212–218.

    Article  PubMed  CAS  Google Scholar 

  • Guillot, F. L., Misslin, P., and Lemaire, M., 1993, Comparison of fluvastatin and lovastatin blood-brain barrier transfer using in vitro and in vivo methods, J. Cardiovasc. Pharmacol. 21:339–346.

    Article  PubMed  CAS  Google Scholar 

  • Ho, N. F., Raub, T. J., Burton, P., Barsuhn, C. L., Adson, A., Audus, K. L., and Borchardt, R. T., 1996, Quantitative approaches to delineate passive transport mechanisms in cell culture monolayers, in: Transport Processes in Pharmaceutical Systems (K. J. Himmelstein, G. L. Amidon, and P. I. Lee, eds.), Marcel Dekker, New York, in press.

    Google Scholar 

  • Hurwitz, A. A., Berman, J. W., and Lyman, W. D., 1994, The role of the blood-brain barrier in HIV infection of the central nervous system, Adv. Neuroimmunol. 4:249–256.

    Article  PubMed  CAS  Google Scholar 

  • Jaehde, U., Goto, T., de Boer, A. G., and Breimer, D. D., 1993, Blood-brain barrier transport rate of quinolone antibacterials evaluated in cerebrovascular endothelial cell cultures, Eur. J. Pharm. Sci. 1:49–55.

    Article  Google Scholar 

  • Joo, F., 1985, The blood-brain barrier in vitro: Ten years of research on microvessels isolated from the brain, Neurochem. Int. 7:1–25.

    Article  PubMed  CAS  Google Scholar 

  • Joo, F., 1992, The cerebral microvessels in culture, an update, J. Neurochem. 58:1–17.

    Article  PubMed  CAS  Google Scholar 

  • Joo, F., 1993, The blood-brain barrier in vitro: The second decade, Neurochem. Int. 23:499–521.

    Article  PubMed  CAS  Google Scholar 

  • Lasbennes, F., and Gayet, J., 1984, Capacity for energy metabolism in microvessels isolated from rat brain, Neurochem. Res. 9:1–10.

    Article  PubMed  CAS  Google Scholar 

  • Masereeuw, R., Jaehde, U., Langemeijer, M. W. E., de Boer, A. G., and Breimer, D. D., 1994, in vitro and in vivo transport of zidovudine (AZT) across the blood-brain barrier and the effect of transport inhibitors, Pharm. Res. 11:324–330.

    Article  PubMed  CAS  Google Scholar 

  • McCall, A. L., Valente, J., Cordero, R., Ruderman, N. B., and Tornheim, K., 1988, Metabolic characterization of isolated cerebral microvessels: ATP and ADP concentrations, Microvasc. Res. 35:325–333.

    Article  PubMed  CAS  Google Scholar 

  • Miller, D. W., Audus, K. L., and Borchardt, R. T., 1992, Application of cultured endothelial cells of the brain microvasculature in the study of the blood-brain barrier, J. Tissue Cult. Methods 14:217–224.

    Article  Google Scholar 

  • Milton, S. G., and Knutson, V. P., 1990, Comparison of the function of the tight junctions of endothelial cells and epithelial cells in regulating the movement of electrolytes and macromolecules across the cell monolayer, J. Cell. Physiol. 144:498–504.

    Article  PubMed  CAS  Google Scholar 

  • Minikawa, T., Bready, J., Berliner, J., Fisher, M., and Cancilla, P. A., 1991, in vitro interaction of astrocytes and pericytes with capillary-like structures of brain microvessel endothelium, Lab. Invest. 65:32–40.

    Google Scholar 

  • Ng, K., Grass, G., Lane, H., and Borchardt, R. T., 1993, Characterization of the unstirred water layer in cultured brain microvessel endothelial cells, In Vitro Cell. Dev. Biol. 29A:627–629.

    Article  CAS  Google Scholar 

  • Oleson, S. P., and Crone, C., 1986, Substances that rapidly augment ionic conductance of endothelium in cerebral venules, Acta Physiol. Scand. 127:233–241.

    Article  Google Scholar 

  • Panula, P., Joo, F., and Rechardt, L., 1978, Evidence for the presence of viable endothelial cells in cultures derived from dissociated rat brain, Experientia 34:95–97.

    Article  PubMed  CAS  Google Scholar 

  • Pardridge, W. M., Triguero, D., Yang, J., and Cancilla, P. A., 1990, Comparison of in vitro and in vivo models of drug transcytosis through the blood-brain barrier, J. Pharm. Exp. Ther. 253:884–891.

    CAS  Google Scholar 

  • Pirro, J. P., Di Rocco, R. J., Narra, R. K., and Nunn, A. D., 1994, The relationship between in vitro trans-endothelial permeability and in vivo single-pass brain extraction of several SPECT imaging agents, J. Nucl. Med. 35:1514–1519.

    PubMed  CAS  Google Scholar 

  • Raub, T. J., and Audus, K. L., 1990, Adsorptive endocytosis and membrane recycling by cultured primary bovine brain microvessel endothelial cell monolayers, J. Cell Sci. 97:127–138.

    PubMed  CAS  Google Scholar 

  • Raub, T. J., and Newton, C. R., 1991, Recycling kinetics and transcytosis of transferrin in primary cultures of bovine brain microvessel endothelial cells, J. Cell. Physiol. 149:141–151.

    Article  PubMed  CAS  Google Scholar 

  • Raub, T. J., Kuentzel, S. L., and Sawada, G. A., 1992, Permeability of bovine brain microvessel endothelial cells in vitro: Barrier tightening by a factor released from astroglioma cells, Exp. Cell Res. 199:330–340.

    Article  PubMed  CAS  Google Scholar 

  • Reardon, P. M., and Audus, K. L., 1993, Applications of primary cultures of brain microvessel endothelial cell monolayers in the study of vasoactive peptide interaction with the blood-brain barrier, S.T.P Pharm. Sci. 3:63–68.

    CAS  Google Scholar 

  • Reese, T. S., and Karnovsky, M. J., 1967, Structural localization of a blood-brain barrier to exogenous peroxidase, J. Cell Biol. 34:207–217.

    Article  PubMed  CAS  Google Scholar 

  • Robinson, R. A., TenEyck, C. J., and Hart, M. N., 1986, Establishment and preliminary growth characteristics of a transformed mouse cerebral microvessel endothelial cell line, Lab. Invest. 54:579–588.

    PubMed  CAS  Google Scholar 

  • Saheki, A., Terasaki, T., Tamai, I., and Tsuji, A., 1994, in vivo and in vitro blood-brain barrier transport of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, Pharm. Res. 11:305–311.

    Article  PubMed  CAS  Google Scholar 

  • Scriba, G. K., and Borchardt, R. T., 1989a, Metabolism of catecholamine esters by cultured bovine brain microvascular endothelium, J. Neurochem. 53:610–615.

    Article  PubMed  CAS  Google Scholar 

  • Scriba, G. K., and Borchardt, R. T., 1989b, Metabolism of l-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) by bovine brain microvessel endothelial cells, Brain Res. 501:175–178.

    Article  PubMed  CAS  Google Scholar 

  • Shi, F., and Audus, K. L., 1994, Biochemical characteristics of primary and passaged cultures of primate brain microvessel endothelial cells, Neurochem. Res. 19:427–433.

    Article  PubMed  CAS  Google Scholar 

  • Shi, F, Bailey, C., Malick, A. W., and Audus, K. L., 1993a, Biotin uptake and transport across bovine brain microvessel endothelial cell monolayers, Pharm. Res. 10:282–288.

    Article  PubMed  CAS  Google Scholar 

  • Shi, F., Cavitt, J. L., Bailey, C., Malick, A. W., and Audus, K. L., 1993b, Characterization of dextromethorphan and dextrorphan uptake by a putative glutamic acid carrier and passive diffusion across brain microvessel endothelium, Drug Deliv. 1:113–118.

    Article  CAS  Google Scholar 

  • Smith, K. R., and Borchardt, R. T., 1989, Permeability and mechanism of albumin, cationized albumin, and glycosylated albumin transcellular transport across monolayers of cultured bovine brain capillary endothelial cells, Pharm. Res. 6:466–473.

    Article  PubMed  CAS  Google Scholar 

  • Sussman, I., Carson, M. P., McCall, A. L., Shulz, V., Ruderman, N. B., and Tornheim, K., 1988, Energy state of bovine cerebral microvessels: Comparison of isolation methods, Microvasc. Res. 35:167–178.

    Article  PubMed  CAS  Google Scholar 

  • Takakura, Y., Audus, K. L., and Borchardt, R. T., 1991a, Blood-brain barrier: Transport studies in isolated brain capillaries and in cultured brain endothelial cells, Adv. Pharmacol. 22:137–165.

    Article  PubMed  CAS  Google Scholar 

  • Takakura, Y., Trammel, A. M., Kuentzel, S. L., Raub, T. J., Davies, A., Baldwin, S. A., and Borchardt, R. T., 1991b, Hexose uptake in primary cultures of bovine brain microvessel endothelial cells. I. Basic characteristics and effects of D-glucose and insulin, Biochim. Biophys. Acta 1070:1–10.

    Article  PubMed  CAS  Google Scholar 

  • Thompson, S. E., and Audus, K. L., 1994a, Leucine enkephalin metabolism by bovine brain microvessel endothelial cells, Peptides 15:109–116.

    Article  PubMed  CAS  Google Scholar 

  • Thompson, S. E., and Audus, K. L., 1994b, Leucine enkephalin effects on brain microvessel endothelial cell monolayer permeability, Pharm. Res. 11:1367–1370.

    Google Scholar 

  • Thompson, S. E., Cavitt, J., and Audus, K. L., 1994, Leucine enkephalin effects on endocytosis, membrane structure, tight junction integrity and passive permeability in brain microvessel endothelial cells, J. Cardiovasc. Pharmacol. 24:818–825.

    Article  PubMed  CAS  Google Scholar 

  • Tontsch, U., and Bauer, H. C., 1991, Glial cells and neurons induce blood/brain barrier related enzymes in cultured cerebral endothelial cells, Brain Res. 539:247–253.

    Article  PubMed  CAS  Google Scholar 

  • Tsuji, A., Terasaki, T., Takabatake, Y., Tenda, Y., Tamai, I., Yamashima, T., Moritani, S., Tsuruo, T., and Yamashita, J., 1992, P-Glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells, Life Sci. 51:1427–1437.

    Article  PubMed  CAS  Google Scholar 

  • Tunkel, A. R., Rosser, S. W., Hansen, E. J., and Scheid, W. M., 1991, Blood-brain barrier alterations in bacterial meningitis: Development of an in vitro model and observations on the effects of lipopolysaccharide, In Vitro Cell. Dev. Biol. 27A:113–120.

    Article  PubMed  CAS  Google Scholar 

  • Vorbrodt, A. W., and Trowbridge, R. S., 1991a, Ultracytochemical characteristics of cultured sheep brain microvascular endothelial cells, J. Histochem. Cytochem. 39:1555–1563.

    Article  PubMed  CAS  Google Scholar 

  • Vorbrodt, A. W., and Trowbridge, R. S., 1991b, Ultrastructural study of transcellular transport of native and cationized albumin in cultured sheep brain microvascular endothelium, J. Neurocytol 20:998–1006.

    Article  PubMed  CAS  Google Scholar 

  • Weber, S. J., Abbruscato, T. J., Brownson, E. A., Lipkowski, A. W., Polt, R., Misicka, A., Haaseth, R. C., Bartosz, H., Hruby, V. J., and Davis, T. P., 1993, Assessment of an in vitro blood-brain barrier model using several [Met5]enkephalin opioid analogs, J. Pharmacol. Exp. Ther. 266:1649–1655.

    PubMed  CAS  Google Scholar 

  • Williams, S. K., Gillis, J. F., Matthews, M. A., Wagner, R. C., and Bitensky, M. W., 1980, Isolation and characterization of brain endothelial cells: Morphology and enzyme activity, J. Neurochem. 35: 374–381.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, 66045, USA

    Kenneth L. Audus, Lawrence Ng, Wen Wang & Ronald T. Borchardt

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  1. Kenneth L. Audus
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  2. Lawrence Ng
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  3. Wen Wang
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  4. Ronald T. Borchardt
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Editors and Affiliations

  1. The University of Kansas, Lawrence, Kansas, USA

    Ronald T. Borchardt

  2. SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA

    Philip L. Smith

  3. Tacora Corporation, Seattle, Washington, USA

    Glynn Wilson

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Audus, K.L., Ng, L., Wang, W., Borchardt, R.T. (1996). Brain Microvessel Endothelial Cell Culture Systems. In: Borchardt, R.T., Smith, P.L., Wilson, G. (eds) Models for Assessing Drug Absorption and Metabolism. Pharmaceutical Biotechnology, vol 8. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-1863-5_13

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  • DOI: https://doi.org/10.1007/978-1-4899-1863-5_13

  • Publisher Name: Springer, Boston, MA

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