Skip to main content
SpringerLink
Log in

Blood–Brain Barrier In Vitro Models and Their Applications in Toxicology

  • Protocol
  • First Online:
In Vitro Toxicology Systems

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

  • 1769 Accesses

Abstract

Located at the level of brain capillaries, the blood–brain barrier (BBB) is a crucial component of the neurovascular unit, since its highly regulated properties are needed to maintain optimal conditions for proper neuronal and glial functions. By modelling the BBB it is possible to make predictions about whether a compound’s interaction with the BBB is likely to compromise its functionality. A dysfunctional BBB may either affect brain entry of an agent or indirectly generate unwanted effects on neurons and glial cells by disturbing the brain homeostasis.

Since the BBB controls the exchanges between the blood and brain compartments modelling the BBB in vitro can also help to investigate the ability of compounds to cross the BBB. In this chapter, the plethora of in vitro BBB models that exist today is discussed and several methods needed to set up and use of these in vitro models in the framework of in vitro toxicity study is detailed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D, Leybaert L, Molnar Z, O’Donnell ME, Povlishock JT, Saunders NR, Sharp F, Stanimirovic D, Watts RJ, Drewes LR (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12(3):169–182

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Zhang B, Chen L, Choi JJ, Hennig B, Toborek M (2012) Cerebrovascular toxicity of PCB153 is enhanced by binding to silica nanoparticles. J Neuroimmune Pharmacol 7(4):991–1001

    Article  PubMed Central  PubMed  Google Scholar 

  3. Chen L, Zhang B, Toborek M (2012) Autophagy is involved in nanoalumina-induced cerebrovascular toxicity. Nanomedicine 9(2):212–221

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Eyal S, Hsiao P, Unadkat JD (2009) Drug interactions at the blood–brain barrier: fact or fantasy? Pharmacol Ther 123(1):80–104

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Cecchelli R, Berezowski V, Lundquist S, Culot M, Renftel M, Dehouck MP, Fenart L (2007) Modelling of the blood–brain barrier in drug discovery and development. Nat Rev Drug Discov 6(8):650–661

    Article  CAS  PubMed  Google Scholar 

  6. Prieto P, Blaauboer BJ, de Boer AG, Boveri M, Cecchelli R, Clemedson C, Coecke S, Forsby A, Galla HJ, Garberg P, Greenwood J, Price A, Tahti H (2004) Blood–brain barrier in vitro models and their application in toxicology. The report and recommendations of ECVAM workshop 49. Altern Lab Anim 32(1):37–50

    CAS  PubMed  Google Scholar 

  7. Deli MA, Abraham CS, Kataoka Y, Niwa M (2005) Permeability studies on in vitro blood–brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol 25(1):59–127

    Article  PubMed  Google Scholar 

  8. Weksler BB, Subileau EA, Perriere N, Charneau P, Holloway K, Leveque M, Tricoire-Leignel H, Nicotra A, Bourdoulous S, Turowski P, Male DK, Roux F, Greenwood J, Romero IA, Couraud PO (2005) Blood–brain barrier-specific properties of a human adult brain endothelial cell line. FASEB J 19(13):1872–1874

    CAS  PubMed  Google Scholar 

  9. Urich E, Lazic SE, Molnos J, Wells I, Freskgard PO (2012) Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood–brain barrier models. PLoS One 7(5):e38149

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Meresse S, Dehouck MP, Delorme P, Bensaid M, Tauber JP, Delbart C, Fruchart JC, Cecchelli R (1989) Bovine brain endothelial cells express tight junctions and monoamine oxidase activity in long-term culture. J Neurochem 53(5):1363–1371

    Article  CAS  PubMed  Google Scholar 

  11. Abbott J, Rönnbäck L, Hansson HA (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53

    Article  CAS  PubMed  Google Scholar 

  12. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468(7323):562–566

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Lippmann ES, Azarin SM, Kay JE, Nessler RA, Wilson HK, Al-Ahmad A, Palecek SP, Shusta EV (2012) Derivation of blood–brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol 30(8):783–791

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Toth A, Veszelka S, Nakagawa S, Niwa M, Deli MA (2011) Patented in vitro blood–brain barrier models in CNS drug discovery. Recent Pat CNS Drug Discov 6(2):107–118

    Article  CAS  PubMed  Google Scholar 

  15. DeBault LE, Cancilla PA (1980) gamma-Glutamyl transpeptidase in isolated brain endothelial cells: induction by glial cells in vitro. Science 207(4431):653–655

    Article  CAS  PubMed  Google Scholar 

  16. Dehouck MP, Meresse S, Delorme P, Fruchart JC, Cecchelli R (1990) An easier, reproducible, and mass-production method to study the blood–brain barrier in vitro. J Neurochem 54(5):1798–1801

    Article  CAS  PubMed  Google Scholar 

  17. Boveri M, Berezowski V, Price A, Slupek S, Lenfant AM, Benaud C, Hartung T, Cecchelli R, Prieto P, Dehouck MP (2005) Induction of blood–brain barrier properties in cultured brain capillary endothelial cells: comparison between primary glial cells and C6 cell line. Glia 51(3):187–198

    Article  PubMed  Google Scholar 

  18. Cecchelli R, Dehouck B, Descamps L, Fenart L, Buee-Scherrer VV, Duhem C, Lundquist S, Rentfel M, Torpier G, Dehouck MP (1999) In vitro model for evaluating drug transport across the blood–brain barrier. Adv Drug Deliv Rev 36(2–3):165–178

    Article  CAS  PubMed  Google Scholar 

  19. Lundquist S, Renftel M, Brillault J, Fenart L, Cecchelli R, Dehouck MP (2002) Prediction of drug transport through the blood–brain barrier in vivo: a comparison between two in vitro cell models. Pharm Res 19(7):976–981

    Article  CAS  PubMed  Google Scholar 

  20. Culot M, Lundquist S, Vanuxeem D, Nion S, Landry C, Delplace Y, Dehouck MP, Berezowski V, Fenart L, Cecchelli R (2008) An in vitro blood–brain barrier model for high throughput (HTS) toxicological screening. Toxicol In Vitro 22(3):799–811

    Article  CAS  PubMed  Google Scholar 

  21. Vandenhaute E, Sevin E, Hallier-Vanuxeem D, Dehouck MP, Cecchelli R (2011) Case study: adapting in vitro blood–brain barrier models for use in early-stage drug discovery. Drug Discov Today 17(7–8):285–290

    PubMed  Google Scholar 

  22. Dore-Duffy P (2008) Pericytes: pluripotent cells of the blood brain barrier. Curr Pharm Des 14(16):1581–1593

    Article  CAS  PubMed  Google Scholar 

  23. Vandenhaute E, Dehouck L, Boucau MC, Sevin E, Uzbekov R, Tardivel M, Gosselet F, Fenart L, Cecchelli R, Dehouck MP (2011) Modelling the neurovascular unit and the blood–brain barrier with the unique function of pericytes. Curr Neurovasc Res 8(4):258–269

    Article  CAS  PubMed  Google Scholar 

  24. Booher J, Sensenbrenner M (1972) Growth and cultivation of dissociated neurons and glial cells from embryonic chick, rat and human brain in flask cultures. Neurobiology 2(3):97–105

    CAS  PubMed  Google Scholar 

  25. Bornstein MB (1958) Reconstituted rat tail collagen used as substrate for time tissue cultures on coverslips in Maximow slides and roller tubes. Lab Invest 7:134–139

    CAS  PubMed  Google Scholar 

  26. Hammarlund-Udenaes M, Friden M, Syvanen S, Gupta A (2008) On the rate and extent of drug delivery to the brain. Pharm Res 25(8):1737–1750

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Franke H, Galla HJ, Beuckmann CT (1999) An improved low-permeability in vitro-model of the blood–brain barrier: transport studies on retinoids, sucrose, haloperidol, caffeine and mannitol. Brain Res 818(1):65–71

    Article  CAS  PubMed  Google Scholar 

  28. Hallier-Vanuxeem D, Prieto P, Culot M, Diallo H, Landry C, Tahti H, Cecchelli R (2009) New strategy for alerting central nervous system toxicity: integration of blood–brain barrier toxicity and permeability in neurotoxicity assessment. Toxicol In Vitro 23(3):447–453

    Article  CAS  PubMed  Google Scholar 

  29. Fabulas-da Costa A, Aijjou R, Hachani J, Landry C, Cecchelli R, Culot M (2013) In vitro blood–brain barrier model adapted to repeated-dose toxicological screening. Toxicol In Vitro 27(6):1944–1953

    Article  CAS  PubMed  Google Scholar 

  30. Hammarlund-Udenaes M (2000) The use of microdialysis in CNS drug delivery studies. Pharmacokinetic perspectives and results with analgesics and antiepileptics. Adv Drug Deliv Rev 45(2–3):283–294

    Article  CAS  PubMed  Google Scholar 

  31. Kalvass JC, Maurer TS (2002) Influence of nonspecific brain and plasma binding on CNS exposure: implications for rational drug discovery. Biopharm Drug Dispos 23(8):327–338

    Article  CAS  PubMed  Google Scholar 

  32. Friden M, Gupta A, Antonsson M, Bredberg U, Hammarlund-Udenaes M (2007) In vitro methods for estimating unbound drug concentrations in the brain interstitial and intracellular fluids. Drug Metab Dispos 35(9):1711–1719

    Article  CAS  PubMed  Google Scholar 

  33. Kalvass JC, Maurer TS, Pollack GM (2007) Use of plasma and brain unbound fractions to assess the extent of brain distribution of 34 drugs: comparison of unbound concentration ratios to in vivo p-glycoprotein efflux ratios. Drug Metab Dispos 35(4):660–666

    Article  CAS  PubMed  Google Scholar 

  34. Culot M, Fabulas - da Costa A, Sevin E, Szorath E, Martinsson S et al (2013) A Simple Method for Assessing Free Brain/Free Plasma Ratios Using an In Vitro Model of the Blood Brain Barrier. PLoS ONE 8(12):e80634. doi:10.1371/journal.pone.0080634

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. BBB Laboratory, Université Lille Nord de France, UArtois EA 2465, IMPRT: IFR114, 62307, Lens Cedex, France

    Anaelle Fabulas-Da Costa, Christophe Landry, Lucie Dehouck, Emmanuel Sevin, Marie-Pierre Dehouck & Roméo Cecchelli

  2. BBB Laboratory (LBHE), Faculté des sciences Jean Perrin, University of Artois, Université Lille Nord de France, IMPRT: IFR114, Rue Jean Souvraz, SP 18, 62307, Lens Cedex, France

    Maxime Culot

Authors
  1. Anaelle Fabulas-Da Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christophe Landry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lucie Dehouck
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emmanuel Sevin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marie-Pierre Dehouck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roméo Cecchelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Maxime Culot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maxime Culot .

Editor information

Editors and Affiliations

  1. European Commission Joint Research Centre, Ispra, Varese, Italy

    Anna Bal-Price

  2. Innsbruck Medical University, Innsbruck, Austria

    Paul Jennings

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this protocol

Cite this protocol

Fabulas-Da Costa, A. et al. (2014). Blood–Brain Barrier In Vitro Models and Their Applications in Toxicology. In: Bal-Price, A., Jennings, P. (eds) In Vitro Toxicology Systems. Methods in Pharmacology and Toxicology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0521-8_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-0521-8_7

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-0520-1

  • Online ISBN: 978-1-4939-0521-8

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation