Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Modelling of the blood–brain barrier in drug discovery and development

Key Points

  • The value of many promising drug candidates is diminished by the presence of barriers between blood and brain that possess both structural and enzymatic components at the level of the cerebral capillaries, the epithelia of the choroid plexuses and other circumventricular organs, and the arachnoid membranes.

  • Cerebral capillaries comprise approximately 95% of the total area of the barriers between blood and brain. They are the main entry route for molecules into the CNS as well as the major hurdle that impedes most neuropharmaceuticals from eliciting a desired pharmacological effect at an obtainable dose.

  • The blood–brain barrier (BBB) is implicated in pathologies such as neurodegenerative disorders, stroke and traumatic brain injury as well as in infectious processes and inflammatory pain. BBB dysfunction in these pathologies may result in compromised transport and permeability properties of the barrier as well as in alterations in cerebrovascular regulatory mechanisms of blood flow, with ensuing perturbed signalling between brain endothelium and associated cells, such as glia and neurons.

  • By modelling the BBB it is possible to make predictions about brain uptake of potential drug candidates and to study the effect of therapeutic interventions at the level of the cerebral capillaries. This provides not only powerful means to assess the risk for taking compounds further in the pharmaceutical development process, but also generates important information to allow for rational drug design.

  • To optimize drug design and develop therapies targeted at disease mechanisms involving the BBB or to improve drug delivery to the CNS, BBB models are required that adequately reflect in vivo conditions.

  • A shift from small molecules towards biopharmaceuticals in major pharmaceutical companies is likely to lead to increased efforts in developing and evaluating strategies to improve the delivery of large molecules to the brain. An integrative use of in vitro BBB models and in vivo techniques, together with advances in medicinal chemistry and tailor-made design of antibodies, proteins and peptides, are likely to be of key importance.

Abstract

The market for neuropharmaceuticals is potentially one of the largest sectors of the global pharmaceutical market owing to the increase in average life expectancy and the fact that many neurological disorders have been largely refractory to pharmacotherapy. The brain is a delicate organ that can efficiently protect itself from harmful compounds and precisely regulate its microenvironment. Unfortunately, the same mechanisms can also prove to be formidable hurdles in drug development. An improved understanding of the regulatory interfaces that exist between blood and brain may provide novel and more effective strategies to treat neurological disorders.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The blood–brain barrier.
Figure 2: Modelling the blood–brain barrier in vitro.
Figure 3: Specific response of brain capillary endothelial cells.
Figure 4: Chemical structure and BBB interaction.

References

  1. Ballabh, P., Braun, A. & Nedergaard M. The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol. Dis. 16, 1–13 (2004).

    CAS  PubMed  Google Scholar 

  2. Huber, J. D., Egleton R. D. & Davis, T. P. Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci. 12, 719–725 (2001).

    Google Scholar 

  3. Bradbury, M. The concept of a blood–brain barrier. (Wiley, New York, 1979).

    Google Scholar 

  4. Pardridge, W. M. Peptide drug delivery to the brain. (Raven Press, New York,1991).

    Google Scholar 

  5. Pardridge, W. M. et al. Comparison of in vitro and in vivo models of drug transcytosis through the blood–brain barrier. J. Pharmacol. Exp. Ther. 253, 884–891 (1990).

    CAS  PubMed  Google Scholar 

  6. Ghersi-Egea, J. F., Leninger-Muller, B., Suleman, G., Siest, G. & Minn, A. Localisation of drug-metabolizing enzyme activities to blood-brain interfaces and circumventricular organs. J. Neurochem. 62, 1089–1096 (1994).

    CAS  PubMed  Google Scholar 

  7. El-Bacha, R. S. & Minn, A. Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell. Mol. Biol. 45, 15–23 (1999).

    CAS  PubMed  Google Scholar 

  8. Fenstermacher, J. D. et al. Relationship of capillary density to glucose utilization and blood flow in white and grey matter of the rat brain. Microvasc. Res. 29, 219–220 (1985).

    Google Scholar 

  9. Sakurada, O. et al. Measurement of local cerebral blood flow with iodo[ 14C]antipyrine. Am. J. Physiol. 234, H59–H66 (1978).

    CAS  PubMed  Google Scholar 

  10. Craigie, E. H. On the relative vascularity of various parts of the central nervous system of the albino rat. J. Comp. Neurol. 31, 429–464 (1920).

    Google Scholar 

  11. Jones, E. G. On the mode of entry of blood vessels into the cerebral cortex. J. Anat. 106, 507–520 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Maynard, E. A. Electron microscopy of the vascular bed of rat cerebral cortex. Am. J. Anat. 100, 409–433 (1957).

    CAS  PubMed  Google Scholar 

  13. Simard, M., Arcuino, G., Takano, T., Liu, Q. S. & Nedergaard, M. Signalling at the gliovascular interface. J. Neurosci. 23, 9254–9262 (2003).

    CAS  PubMed  Google Scholar 

  14. Pellerin, L. & Magistretti, P. J. Food for thought: challenging the dogmas. J. Cereb. Blood Flow Metab. 23, 1282–1286 (2003).

    PubMed  Google Scholar 

  15. Newman, E. A. New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci. 26, 536–542 (2003).

    CAS  PubMed  Google Scholar 

  16. Edvinsson, L. & Hamel, E. Cerebral Blood Flow and Metabolism (eds Edvinsson, L. & Krause, D. N.) 43–67 (Lippincott, Williams and Wilkins, Philadelphia, 2002).

    Google Scholar 

  17. Wolburg, H. et al. Modulation of tight junction structure in blood–brain barrier endothelial cells: Effects of tissue culture, second messager and cocultured astrocytes. J. Cell Sci. 107, 1347–1357 (1994).

    CAS  PubMed  Google Scholar 

  18. Boado, R. J., Wang, L. & Pardridge, W. M. Enhanced expression of the blood–brain barrier GLUT1 glucose transporter gene by brain-derived factors. Brain Res. Mol. Brain Res. 22, 259–267 (1994).

    CAS  PubMed  Google Scholar 

  19. Raub, T. J. Signal transduction and glial cell modulation of cultured brain microvessel endothelial cell tight junctions. Am. J. Physiol. 271, C495–C503 (1996).

    CAS  PubMed  Google Scholar 

  20. Rist, R. J. et al. F-actin cytoskeleton and sucrose permeability of immortalised rat brain microvascular endothelial cell monolayers: Effects of cyclic AMP and astrocytic factors. Brain Res. 768, 10–18 (1997).

    CAS  PubMed  Google Scholar 

  21. Roux, F. et al. Regulation of γ-glutamyl transpeptidase and alkaline phosphatase activities in immortalized rat brain microvessel endothelial cell line. J. Cell Physiol. 159, 101–113 (1994).

    CAS  PubMed  Google Scholar 

  22. Dehouck, B., Dehouck, M. P., Fruchard, J. C. & Cecchelli, R. Upregulation of the low density lipoprotein receptor at the blood–brain barrier:Intercommunications between brain capillary endothelial cells and astrocytes. J. Cell. Biol. 126, 465–473 (1994).

    CAS  PubMed  Google Scholar 

  23. DeBault, L. E. & Cancilla, P. A. γ-Glutamyltranspeptidase in isolated brain endothelial cells: induction by glial cells in vitro. Science 207, 653–655 (1980).

    CAS  PubMed  Google Scholar 

  24. Hayashi, Y. et al. Induction of various blood–brain barrier properties in non-neuronal endothelial cells by close apposition to co-cultured astrocytes. Glia 19, 13–26 (1997).

    CAS  PubMed  Google Scholar 

  25. Sobue, K. et al. Induction of blood–brain barrier properties in immortalized bovine brain endothelial cells by astrocytic factors. Neurosci. Res. 35, 155–164 (1999).

    CAS  PubMed  Google Scholar 

  26. Abbott, N. J. Astrocyte-endothelial interactions and blood–brain barrier permeability. J. Anat. 200, 629–638 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Haseloff, R. F., Blasig, I. E., Bauer H. C. & Bauer, H. In search of the astrocytic factor(s) modulating blood–brain barrier functions in brain capillary endothelial cells in vitro. Cell. Mol. Neurobiol. 25, 25–39 (2005).

    CAS  PubMed  Google Scholar 

  28. Pardridge, W. M., Triguero, D., Buciak, J. & Yang, J. Evaluation of cationized rat albumin as a potential blood–brain barrier drug transport vector. Exp. Neurol. 255, 893–899 (1990).

    CAS  Google Scholar 

  29. Pardridge, W. M. Drug and gene targeting to the brain with molecular Trojan horses. Nature Rev. Drug Discov. 1, 131–139 (2002).

    CAS  Google Scholar 

  30. Scherrmann, J. M. Drug delivery to brain via the blood–brain barrier. Vascul Pharmacol. 38, 349–354 (2002).

    CAS  PubMed  Google Scholar 

  31. Demeule, M. et al. High transcytosis of melanotransferrin (P97) across the blood–brain barrier. J. Neurochem. 83, 924–933 (2002).

    CAS  PubMed  Google Scholar 

  32. Abulrob, A., Sprong, H., Van Bergen en Henegouwen, P. & Stanimirovic, D. The blood–brain barrier transmigrating single domain antibody: mechanisms of transport and antigenic epitopes in human brain endothelial cells. J. Neurochem. 95, 1201–1214 (2005).

    CAS  PubMed  Google Scholar 

  33. Benchenane, K. et al. Tissue-type plasminogen activator crosses the intact blood–brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis. Circulation 111, 2241–2249 (2005).

    CAS  PubMed  Google Scholar 

  34. Benchenane, K. et al. Oxygen glucose deprivation switches the transport of tPA across the blood–brain barrier from an LRP-dependent to an increased LRP-independent process. Stroke 36, 1065–1070 (2005).

    PubMed  Google Scholar 

  35. Lopez-Atalaya, J. P. et al. Recombinant Desmodus rotundus salivary plasminogen activator crosses the blood–brain barrier through a low-density lipoprotein receptor-related protein-dependent mechanism without exerting neurotoxic effects. Stroke 38, 1036–1043 (2007).

    CAS  PubMed  Google Scholar 

  36. Brillault, J., Berezowski, V., Cecchelli, R. & Dehouck, M. P. Intercommunications between brain capillary endothelial cells and glial cells increase the transcellular permeability of the blood–brain barrier during ischaemia. J. Neurochem. 83, 807–817 (2002).

    CAS  PubMed  Google Scholar 

  37. Hirano, A., Kawanami, T. & Llena J. F. Electron microscopy of the blood–brain barrier in disease. Microsc. Res. Tech. 27, 543–556 (1994).

    CAS  PubMed  Google Scholar 

  38. Joó, F. Increased production of coated vesicles in the brain capillaries during enhanced permeability of the blood–brain barrier. Br. J. Exp. Pathol. 52, 646–649 (1971).

    PubMed  PubMed Central  Google Scholar 

  39. Povlishock, J. T., Becker, D. P., Sullivan, H. G. & Miller, J. D. Vascular permeability alterations to horseradish peroxidase in experimental brain injury. Brain Res. 153, 223–239 (1978).

    CAS  PubMed  Google Scholar 

  40. Ford, J. M. Modulators of multidrug resistance. Preclinical studies. Hematol. Oncol. Clin. North Am. 9, 337–361 (1995).

    CAS  PubMed  Google Scholar 

  41. Schinkel, A. H. et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77, 491–502 (1994).

    CAS  PubMed  Google Scholar 

  42. Schinkel, A. H. The physiological function of drug transporting P-glycoproteins. Semin. Cancer Biol. 8, 161–170 (1997).

    CAS  PubMed  Google Scholar 

  43. Schinkel, A. H. & Jonker, J. W. Mammalian drug efflux transporters of the ATP-binding cassette (ABC) family: an overview. Adv. Drug Deliv. Rev. 55, 3–29 (2003).

    CAS  PubMed  Google Scholar 

  44. Kruh, G. D., Guo, Y., Hopper-Borge, E., Belinsky, M. G. & Chen, Z. S. ABCC10, ABCC11 and ABCC12. Pflugers Arch. 26 Jul 2006 [Epub ahead of print].

    Google Scholar 

  45. Zhang, Y. Schuetz, J. D., Elmquist, W. F. & Miller, D. W. Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells. JPET 311, 449–455 (2004).

    CAS  Google Scholar 

  46. Soontornmalai, A., Vlaming, M. L. & Fritschy, J. M. Differential, strain-specific cellular and subcellular distribution of multidrug transporters in murine choroid plexus and blood–brain barrier. Neurosci. 138, 159–169 (2006).

    CAS  Google Scholar 

  47. Sugarawa, I., Hamada, H., Tsuruo, T. & Mori, S. Specialized localization of P-glycoprotein recognized by MRK16 monoclonal antibody in endothelial cells of the brain and the spinal cord. Jpn. J. Cancer Res. 81, 727–730 (1990).

    Google Scholar 

  48. Tsuji, A. et al. P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci. 51, 1427–1437 (1992).

    CAS  PubMed  Google Scholar 

  49. Stewart, P. A., Beliveau, R. & Rogers, K. A. Cellular localization of P-glycoprotein in brain versus gonadal capillaries. J. Histochem. Cytochem. 44, 679–685 (1996).

    CAS  PubMed  Google Scholar 

  50. Beaulieu, E., Demeule, M., Ghitescu, L. & Béliveau, R. P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochem. J. 326, 539–544 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Scherrmann, J. M. Expression and function of multidrug resistance transporters at the blood–brain barriers. Expert Opin Drug Metab. Toxicol. 1, 233–246 (2005).

    CAS  PubMed  Google Scholar 

  52. Dallas, S., Miller, D. S. & Bendayan, R. Multidrug resistance-associated proteins: expression and function in the central nervous system. Pharmacol Rev. 58, 140–161 (2006).

    CAS  PubMed  Google Scholar 

  53. Seetharaman, S., Barrand, M. A., Maskell, L. & Scheper, R. J. Multidrug resistance-related transport proteins in isolated human brain microvessels and in cells cultured from these isolates. J. Neurochem. 70, 1151–1159 (1998).

    CAS  PubMed  Google Scholar 

  54. Gutmann, H., Fricker, G., Drewe, J., Toeroek, M. & Miller, D. S. Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol. Pharmacol. 56, 383–389 (1999).

    CAS  PubMed  Google Scholar 

  55. Sugiyama, Y., Kusuhara, H. & Suzuki, H. Kinetic and biochemical analysis of carrier-mediated efflux of drugs through the blood-brain and blood-cerebrospinal fluid barriers: importance in the drug delivery to the brain. J. Control Release 62, 179–186 (1999).

    CAS  PubMed  Google Scholar 

  56. Fenart, L. et al. Inhibition of P-glycoprotein: rapid assessment of its implication in blood–brain barrier integrity and drug transport to the brain by an in vitro model of the blood–brain barrier. Pharm. Res. 15, 993–1000 (1998).

    CAS  PubMed  Google Scholar 

  57. Berezowski, V., Landry, C., Dehouck, M. P., Cecchelli, R. & Fenart, L. Contribution of glial cells and pericytes to the mRNA profiles of P-glycoprotein and multidrug resistance-associated proteins in an in vitro model of the blood–brain barrier. Brain Res. 1018, 1–9 (2004).

    CAS  PubMed  Google Scholar 

  58. Borst, P., Evers, R., Kool, M. & Wijnholds, J. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl Cancer Inst. 92, 1295–1302 (2000).

    CAS  PubMed  Google Scholar 

  59. Loscher, W. & Potschka, H. Blood–brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2, 86–98 (2005).

    PubMed  PubMed Central  Google Scholar 

  60. Evers, R. et al. Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells. J. Clin. Invest. 97, 1211–1218 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kusuhara, H. & Sugiyama, Y. Active efflux across the blood–brain barrier:carrier family. NeuroRx. 2, 73–85 (2005).

    PubMed  PubMed Central  Google Scholar 

  62. Eisenblatter, T., Huwel, S. & Galla, H. J. Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood–brain barrier. Brain Res. 971, 221–231 (2003).

    CAS  PubMed  Google Scholar 

  63. Abbott, N. J. Prediction of blood–brain barrier permeation in drug discovery from in vivo, in vitro and in silico models. Drug Discov. Today: Technol. 1, 407–416 (2004).

    CAS  Google Scholar 

  64. Reichel, A. The role of blood–brain barrier studies in the pharmaceutical industry. Curr. Drug Metab. 7, 183–203 (2006).

    CAS  PubMed  Google Scholar 

  65. Joó, F. The blood–brain barrier in vitro: ten years of research on microvessels isolated from the brain. Neurochem. Int. 7, 1–25 (1985).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  67. Weksler, B. B. et al. Blood–brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J. 19, 1872–1874 (2005).

    CAS  PubMed  Google Scholar 

  68. Kannan, R., Chakrabarti, R., Tang, D., Kim, K. J. & Kaplowitz, N. GSH transport in human cerebrovascular endothelial cells and human astrocytes: Evidence for luminal localization of Na+-dependent GSH transport in HCEC. Brain Res. 852, 374–382 (2000).

    CAS  PubMed  Google Scholar 

  69. Demeuse, P. et al. Compartmentalized coculture of rat brain endothelial cells and astrocytes: a syngenic model to study the blood–brain barrier. J. Neurosci. Methods 121, 21–31 (2002).

    PubMed  Google Scholar 

  70. Perrière, N. et al. A functional in vitro model of rat blood–brain barrier for molecular analysis of efflux transporters. Brain Res. 1150, 1–13 (2007).

    PubMed  Google Scholar 

  71. Coisne, C., et al. Development and characterization of a mouse syngenic in vitro blood–brain barrier model: A new tool to examine inflammatory events on cerebral endothelium. Lab Invest. 85, 735–746 (2005).

    Google Scholar 

  72. Méresse, S. et al. Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. J. Neurochem. 53, 1363–1371 (1989).

    PubMed  Google Scholar 

  73. Dehouck, M. P., Méresse, S., Delorme, P., Fruchard, J. C. & Cecchelli, R. An easier, reproducible and mass production method to study the blood–brain barrier in vitro. J. Neurochem. 54, 1798–1801 (1990). One of the earliest papers describing a reproducible method for developing a BBB co-culture model with brain endothelial and glial cells that could be used in the pharmaceutical industry. Besides its use as BBB permeability and transport screen, the model has also been used in mechanistic studies in physiological and pathological conditions.

    CAS  PubMed  Google Scholar 

  74. Cecchelli, R. et al. In vitro model for evaluating drug transport across the blood–brain barrier. Adv. Drug Deliv. Rev. 36, 165–178 (1999).

    CAS  PubMed  Google Scholar 

  75. Rubin, L. L. et al. A cell culture model of the blood–brain barrier. J. Cell Biol. 115, 1725–1735 (1991).

    CAS  PubMed  Google Scholar 

  76. O´Donnell, M. E., Martinez, A. & Sun, D. Cerebral microvascular endothelial cell NA-K-Cl co-transport: Regulation by astrocyte-conditioned medium. Am. J. Physiol. 268, C747–C754 (1995).

    Google Scholar 

  77. Hurst, R. D. & Fritz, I. B Properties of an immortalised vascular endothelial/glioma cell co-culture model of the blood–brain barrier, J. Cell Physiol. 167, 81–88 (1996).

    CAS  PubMed  Google Scholar 

  78. Boveri, M. et al. Induction of blood–brain barrier properties in cultured brain capillary endothelial cells: comparison between primary glial cells and C6 cell line. Glia 51, 187–198 (2005).

    PubMed  Google Scholar 

  79. Hoheisel, D. et al. Hydrocortisone reinforces the blood–brain barrier properties in a serum free cell culture system. Biochem. Biophys. Res. Commun. 247, 312–315 (1998).

    CAS  PubMed  Google Scholar 

  80. Franke, H., Galla, H. J. & Beuckmann, C. T. An improved low-permeability in vitro-model of the blood–brain barrier: transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol. Brain Res. 818, 65–71, (1999).

    CAS  PubMed  Google Scholar 

  81. Zhang, Y. et al. Porcine brain microvessel endothelial cells as an in vitro model to predict in vivo blood–brain barrier permeability. Drug Metab. Dispos. 34, 1935–1943 (2006).

    CAS  PubMed  Google Scholar 

  82. Arthur, F. E., Shivers, R. R. & Bowman, P. D. Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro model. Dev. Brain Res. 36, 155–159 (1987).

    Google Scholar 

  83. Descamps, L., Coisne, C., Dehouck, B., Cecchelli, R. & Torpier, G. Protective effect of glial cells against lipopolysaccharide-mediated blood–brain barrier injury. Glia 42, 46–58 (2003).

    PubMed  Google Scholar 

  84. Roux, F. & Couraud, P. O. Rat brain endothelial cell lines for the study of blood–brain barrier permeability and transport functions. Cell Mol. Neurobiol. 25, 41–58 (2005).

    PubMed  Google Scholar 

  85. Förster, C. et al. Occludin as direct target for glucocorticoid-induced improvement of blood–brain barrier properties in a murine in vitro system. J. Physiol. 565, 475–486 (2005).

    PubMed  PubMed Central  Google Scholar 

  86. Scism, J. L. et al. Evaluation of an in vitro coculture model for the blood–brain barrier: Comparison of human umbilical vein endothelial cells (ECV304) and rat glioma cells (C6) from two commercial sources. In Vitro Cell Dev. Biol. Anim. 35, 580–592 (1999).

    CAS  PubMed  Google Scholar 

  87. Dejana, E. Endothelial cell–cell junctions: happy together. Nature Rev. Mol. Cell Biol. 5, 261–270, (2004).

    CAS  Google Scholar 

  88. Vorbrodt, A. W. & Dobrogowska, D. H. Molecular anatomy of intercellular junctions in brain endothelial and epithelial barriers: electron microscopist's view. Brain Res. Brain Res. Rev. 42, 221–242 (2003).

    CAS  PubMed  Google Scholar 

  89. Lundquist, S. et al. Prediction of drug transport through the blood–brain barrier in vivo: a comparison between two in vitro cell models. Pharm. Res. 19, 976–981 (2002).

    CAS  PubMed  Google Scholar 

  90. Franzén, B. et al. Gene and protein expression profiling of human cerebral endothelial cells activated with tumor necrosis factor-α. Mol. Brain Res. 115, 130–146 (2003). References 90–96 demonstrate efforts in identifying genes and proteins at the brain endothelium that could be potential therapeutic targets and highlight differences between peripheral and brain endothelium.

    PubMed  Google Scholar 

  91. Shusta, E. V., Boado, R. J., Mathern, G. W. & Pardridge, W. M. Vascular genomics of the human brain. J. Cereb. Blood Flow Metab. 22, 245–252 (2002).

    CAS  PubMed  Google Scholar 

  92. Li, J. Y., Boado, R. J. & Pardridge, W. M. Blood–brain barrier genomics. J. Cereb. Blood Flow Metab. 21, 61–68 (2001).

    CAS  PubMed  Google Scholar 

  93. Li, J. Y., Boado, R. J. & Pardridge, W. M. Rat blood–brain barrier genomics. II. J. Cereb. Blood Flow Metab. 22, 1319–1326 (2002).

    CAS  PubMed  Google Scholar 

  94. Shusta, E. V., Boado, R. J. & Pardridge, W. M. Vascular proteomics and subtractive antibody expression cloning. Mol. Cell. Proteomics 1, 75–82 (2002).

    CAS  PubMed  Google Scholar 

  95. Shusta, E. V., Zhu, C., Boado, R. J. & Pardridge, W. M. Subtractive expression cloning reveals high expression of CD46 at the blood–brain barrier. J. Neuropathol. Exp. Neurol. 61, 597–604 (2002).

    CAS  PubMed  Google Scholar 

  96. Shusta, E. V., Li J. Y., Boado, R. J. & Pardridge, W. M. The Ro52/SS-A autoantigen has elevated expression at the brain microvasculature. Neuroreport 14, 1861–1865 (2003).

    CAS  PubMed  Google Scholar 

  97. Stanness, K. A. et al. Morphological and functional characterisation of an in vitro blood–brain barrier model. Brain Res. 771, 329–342 (1997).

    CAS  PubMed  Google Scholar 

  98. Cucullo, L., et al. Development of a humanized in vitro blood–brain barrier model to screen for brain penetration of antiepileptic drugs. Epilepsia 48, 505–516 (2007).

    CAS  PubMed  Google Scholar 

  99. Leybaert, L. Neurobarrier coupling in the brain: a partner of neurovascular and neurometabolic coupling? J. Cereb. Blood Flow Metab. 25, 2–16 (2005).

    CAS  PubMed  Google Scholar 

  100. Berezowski, V. et al. Transport screening of drug cocktails through an in vitro blood–brain barrier: is it a good strategy for increasing the throughput of the discovery pipeline? Pharm Res. 21, 756–760 (2004).

    CAS  PubMed  Google Scholar 

  101. Dehouck, B. et al. A new function for the LDL receptor: transcytosis of LDL across the blood–brain barrier. J. Cell Biol. 138, 877–889 (1997). One of the first papers describing trancytosis of LDL across the BBB in vitro.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Cipolla, M. J., Crete, R., Vitullo, L. & Rix, R. D. Transcellular transport as a mechanism of blood–brain barrier disruption during stroke. Front. Biosci. 9, 777–785 (2004).

    CAS  PubMed  Google Scholar 

  103. Kaur, C., Sivakumar, V., Zhang, Y. & Ling, E. A. Hypoxia-induced astrocytic reaction and increased vascular permeability in the rat cerebellum. Glia 54, 826–839 (2006).

    CAS  PubMed  Google Scholar 

  104. Spencer, B. J. & Verma, I. M. Targeted delivery of proteins across the blood–brain barrier. Proc. Natl Acad. Sci. USA 104, 7594–7599 (2007).

    CAS  PubMed  Google Scholar 

  105. Enerson, B. E. & Drewes, L. R. The rat blood–brain barrier transcriptome. J. Cereb. Blood Flow Metab. 26, 959–973 (2006).

    CAS  PubMed  Google Scholar 

  106. Fiala, M. et al. Amyloid-β induces chemokine secretion and monocyte migration across a human blood–brain barrier. Mol. Med. 4, 480–489 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Giri, R. et al. β-amyloid-induced migration of monocytes across human brain endothelial cells involves RAGE and PECAM-1. Am. J. Physiol. Cell Physiol. 279, C1772–C1781 (2000).

    CAS  PubMed  Google Scholar 

  108. Poduslo, J. F., Curran, G. L., Wengenack, T. M., Malester, B. & Duff, K. Permeability of proteins at the blood–brain barrier in the normal adult mouse and the double transgenic mouse model of Alzheimer´s disease. Neurobiol. Dis. 8, 555–567 (2001).

    CAS  PubMed  Google Scholar 

  109. Ujiie, M., Dickstein, D. L., Carlow, D. A. & Jefferies, W. A. Blood–brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10, 463–470 (2003).

    CAS  PubMed  Google Scholar 

  110. Iadecola, C. Atherosclerosis and neurodegeneration: unexpected conspirators in Alzheimer's dementia. Arterioscler. Thromb. Vasc. Biol. 23, 1951–1953 (2003).

    CAS  PubMed  Google Scholar 

  111. Thomas, T., Thomas, G., McLendon, C., Sutton, T. & Mullan, M. β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature 380, 168–171 (1996). An important paper linking Aβ to vascular reactivity by free radicals.

    CAS  PubMed  Google Scholar 

  112. Paris, D. et al. Vasoactive effects of Aβ in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: role of inflammation. Neurol. Res. 25, 642–651 (2003).

    CAS  PubMed  Google Scholar 

  113. Iadecola, C. et al. SOD1 rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein. Nature Neurosci. 2, 157–161 (1999). An interesting paper showing that vascular oxidative stress alters endothelium-dependent cerebral blood-flow responses in mice overexpressing amyloid precursor protein.

    CAS  PubMed  Google Scholar 

  114. DeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M. & Holtzman, D. M. Brain to plasma amyloid-β efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science 295, 2264–2267 (2002). References 111–114 demonstrate transport of Aβ across the blood–brain barrier from blood-to-brain and from brain-to-blood indicating the importance of kinetic and dynamic considerations in the study of Aβ accumulation in brain.

    CAS  PubMed  Google Scholar 

  115. Minagar, A. & Alexander, J. S. Blood–brain barrier disruption in multiple sclerosis. Mult. Scler. 9, 540–549 (2003).

    CAS  PubMed  Google Scholar 

  116. Veldhuis, W. B. et al. Interferon-β prevents cytokine-induced neutrophil infiltration and attenuates blood–brain barrier disruption. J. Cereb. Blood Flow Metab. 23, 1060–1069 (2003).

    CAS  PubMed  Google Scholar 

  117. Dallasta, L. M. et al. Blood–brain barrier tight junction disruption in human immunodeficiency virus-1 encephalitis. Am. J. Pathol. 155, 1915–1927 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Davies, D. C. Blood–brain barrier breakdown in septic encephalopathy and brain tumors. J. Anat. 200, 639–646 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Lo, E. H., Dalkara, T. & Moskowitz, M. A. Mechanisms, challenges and opportunities in stroke. Nature Rev. Neurosci. 4, 399–415 (2003).

    CAS  Google Scholar 

  120. Gasche, Y. et al. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischaemia in mice: a possible role in blood–brain barrier dysfuntion. J. Cereb. Blood Flow Metab. 19, 1020–1028 (1999).

    CAS  PubMed  Google Scholar 

  121. Huber, J. D. et al. Inflammatory pain alters blood–brain barrier permeability and tight junctional protein expression. Am. J. Physiol. Heart Circ. Physiol. 280, H1241–H1248 (2001).

    CAS  PubMed  Google Scholar 

  122. Weidenfeller, C., Svendsen, C. N., Shusta, E. V. Differentiating embryonic neural progenitor cells induce blood–brain barrier properties. J. Neurochem. 101, 555–565 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Zhang, Z. G., Zhang, L., Jiang, Q. & Chopp, M. Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischaemia in the adult mouse. Circ. Res. 90, 284–288 (2002).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Ministry of Research of France (fellowship to M. Culot).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Romeo Cecchelli.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Alzheimer´s disease

multiple sclerosis

Glossary

Choroid plexus

Site of cerebrospinal fluid production in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.

Circumventricular organs

Small structures bordering the ventricular spaces in the midline of the brain that have common morphologic and endocrine-like characteristics. They make cellular contacts with both blood and cerebrospinal fluid.

Arachnoid membrane

A fibrous membrane that covers the brain and spinal cord. It is separated from the pia mater by the subarachnoid space in which the cerebrospinal fluid flows.

Astrocytic end-feet

Part of the astrocyte which envelopes the capillary endothelium in the brain.

Pericyte

A cell of mesodermal origin and contractile-phagocytic phenotype that is associated with the outer surface of brain capillaries. It is embedded in the basal lamina between astrocyte end-feet and endothelium.

Transcytosis

An energy-requiring mode of transport across cells that involves vesicles endocytosing from one membrane (for example, blood side) and releasing contents at the opposite side (for example, brain side).

Transendothelial electrical resistance

In this Review, this refers to the electrical resistance across the BBB. The high electrical resistance of the mature BBB is considered to be due to its complex tight junctions.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cecchelli, R., Berezowski, V., Lundquist, S. et al. Modelling of the blood–brain barrier in drug discovery and development. Nat Rev Drug Discov 6, 650–661 (2007). https://doi.org/10.1038/nrd2368

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2368

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing