Skip to main content
SpringerLink
Log in

In Vitro Models of Central Nervous System Barriers for Blood-Brain Barrier Permeation Studies

  • Protocol
  • First Online:
Nanomedicines for Brain Drug Delivery

Part of the book series: Neuromethods ((NM,volume 157))

Abstract

One of the biggest challenging diseases are the neurodegenerative diseases which are not easy to target due to the presence of a complex semipermeable, dynamic, and adaptable barrier between the central nervous system (CNS) and the systemic circulation termed as the blood-brain barrier (BBB), which controls the exchange of molecules. Its semipermeable nature restricts the movement of bigger molecules, like drugs, across it and leads to minimal bioavailability of drugs in the CNS. This poses the biggest shortcoming in the development of therapeutics for CNS disorders. Although the complexity of the BBB muddles the drug delivery approaches into the CNS and can promote disease progression, understanding the composition and functions of BBB provides a platform for unraveling the way toward drug development. The BBB is comprised of brain microvascular endothelial CNS cells which communicate with other CNS cells (astrocytes, pericytes) and behave according to the state of the CNS, by retorting against pathological environments and modulating disease progression. This chapter discusses the fundamentals of BBB, permeation mechanisms, an overview of different in vitro BBB models with their advantages and disadvantages, and rationale of selecting penetration prediction methods toward the important role in the development of CNS therapeutics.

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

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 69.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 69.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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

Similar content being viewed by others

References

  1. He Y et al (2014) Cell-culture models of the blood–brain barrier. Stroke 45(8):2514–2526

    Article  PubMed  PubMed Central  Google Scholar 

  2. Stern L, Gautier R (1922) II.–Les Rapports Entre Le Liquide Céphalo-Rachidien Et Les éléments Nerveux De L’axe Cerebrospinal. Arch Int Physiol 17(4):391–448

    Google Scholar 

  3. Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol 75(3):388–397

    Article  CAS  PubMed  Google Scholar 

  4. Cecchelli R et al (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 

  5. Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood–brain barriers. Trends Immunol 33(12):579–589

    Article  CAS  PubMed  Google Scholar 

  6. Jouyban A, Soltani S (2012) Blood brain barrier permeation. In: Acree W (ed) Toxicity and drug testing. InTechOpen, London

    Google Scholar 

  7. Abbott NJ (2005) Physiology of the blood–brain barrier and its consequences for drug transport to the brain. In: International congress series. Elsevier, Amsterdam

    Book  Google Scholar 

  8. Cardoso FL, Brites D, Brito MA (2010) Looking at the blood–brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev 64(2):328–363

    Article  CAS  PubMed  Google Scholar 

  9. Prinz M, Mildner A (2011) Microglia in the CNS: immigrants from another world. Glia 59(2):177–187

    Article  PubMed  Google Scholar 

  10. Aday S et al (2016) Stem cell-based human blood–brain barrier models for drug discovery and delivery. Trends Biotechnol 34(5):382–393

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Helms HC et al (2016) In vitro models of the blood–brain barrier: an overview of commonly used brain endothelial cell culture models and guidelines for their use. J Cereb Blood Flow Metab 36(5):862–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Nair M et al (2016) Getting into the brain: potential of nanotechnology in the management of NeuroAIDS. Adv Drug Deliv Rev 103:202–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Löscher W, Potschka H (2005) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 76(1):22–76

    Article  PubMed  CAS  Google Scholar 

  15. Alavijeh MS et al (2005) Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery. NeuroRx 2(4):554–571

    Article  PubMed  PubMed Central  Google Scholar 

  16. Czupalla CJ, Liebner S, Devraj K (2014) In vitro models of the blood–brain barrier. Methods Mol Biol 1135:415–437

    Article  CAS  PubMed  Google Scholar 

  17. Garberg P et al (2005) In vitro models for the blood–brain barrier. Toxicol In Vitro 19(3):299–334

    Article  CAS  PubMed  Google Scholar 

  18. Wilhelm I, Fazakas C, Krizbai IA (2011) In vitro models of the blood-brain barrier. Acta Neurobiol Exp (Wars) 71(1):113–128

    Google Scholar 

  19. Nakagawa S et al (2009) A new blood–brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int 54(3):253–263

    Article  CAS  PubMed  Google Scholar 

  20. Lippmann ES et al (2013) Modeling the blood–brain barrier using stem cell sources. Fluids Barriers CNS 10(1):2

    Article  PubMed  PubMed Central  Google Scholar 

  21. Daniels BP et al (2013) Immortalized human cerebral microvascular endothelial cells maintain the properties of primary cells in an in vitro model of immune migration across the blood brain barrier. J Neurosci Methods 212(1):173–179

    Article  CAS  PubMed  Google Scholar 

  22. Franke H, Galla H-J, 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 

  23. Hurst R, Fritz I (1996) Properties of an immortalised vascular endothelial/glioma cell co-culture model of the blood-brain barrier. J Cell Physiol 167(1):81–88

    Article  CAS  PubMed  Google Scholar 

  24. Hori S et al (2004) A pericyte‐derived angiopoietin‐1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie‐2 activation in vitro. J Neurochem 89(2):503–513

    Article  CAS  PubMed  Google Scholar 

  25. Toimela T et al (2004) Development of an in vitro blood–brain barrier model—cytotoxicity of mercury and aluminum. Toxicol Appl Pharmacol 195(1):73–82

    Article  CAS  PubMed  Google Scholar 

  26. Armulik A et al (2010) Pericytes regulate the blood-brain barrier. Nature 468(7323):557–561

    Article  CAS  PubMed  Google Scholar 

  27. Daneman R et al (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468(7323):562–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Atluri VSR et al (2016) Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection. Int J Nanomedicine 11:4287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jayant R (2014) Layer-by-layer (LbL) assembly of anti-HIV drug for sustained release to brain using magnetic nanoparticle. J Neuroimmun Pharmacol 9(1):25–25

    Google Scholar 

  30. Jayant R, Nair M (2016) Nanotechnology for the Treatment of NeuroAIDS. J Nanomed Res 3(1):00047

    Article  Google Scholar 

  31. Jayant R, Nair M (2016) Role of biosensing technology for neuroAIDS management. J Biosensors Bioelectron 7(1):pii: e141

    Google Scholar 

  32. Jayant RD, Madhavan N (2016) Materials and methods for sustained release of active compounds. US Patent App. 15/082611

    Google Scholar 

  33. Kaushik A, Jayant RD, Nair M (2016) Advancements in nano-enabled therapeutics for neuroHIv management. Int J Nanomedicine 11:4317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tomitaka A et al (2017) Development of magneto-plasmonic nanoparticles for multimodal image-guided therapy to the brain. Nanoscale 9(2):764–773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nair M et al (2013) Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers. Nat Commun 4:1707

    Article  PubMed  CAS  Google Scholar 

  36. Pilakka-Kanthikeel S et al (2013) Targeted brain derived neurotropic factors (BDNF) delivery across the blood-brain barrier for neuro-protection using magnetic nano carriers: an in-vitro study. PLoS One 8(4):e62241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ding H et al (2014) Enhanced blood–brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation. Nanotechnology 25(5):055101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Nakagawa S et al (2007) Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol 27(6):687–694

    Article  CAS  PubMed  Google Scholar 

  39. Siddharthan V et al (2007) Human astrocytes/astrocyte-conditioned medium and shear stress enhance the barrier properties of human brain microvascular endothelial cells. Brain Res 1147:39–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tarbell JM (2010) Shear stress and the endothelial transport barrier. Cardiovasc Res 87(2):320–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bussolari SR, Dewey CF Jr, Gimbrone MA Jr (1982) Apparatus for subjecting living cells to fluid shear stress. Rev Sci Instrum 53(12):1851–1854

    Article  CAS  PubMed  Google Scholar 

  42. Naik P, Cucullo L (2012) In vitro blood–brain barrier models: current and perspective technologies. J Pharm Sci 101(4):1337–1354

    Article  CAS  PubMed  Google Scholar 

  43. Koutsiaris AG et al (2007) Volume flow and wall shear stress quantification in the human conjunctival capillaries and post-capillary venules in vivo. Biorheology 44(5-6):375–386

    PubMed  Google Scholar 

  44. Cucullo L et al (2007) Development of a humanized in vitro blood–brain barrier model to screen for brain penetration of antiepileptic drugs. Epilepsia 48(3):505–516

    Article  CAS  PubMed  Google Scholar 

  45. Cucullo L et al (2011) A dynamic in vitro BBB model for the study of immune cell trafficking into the central nervous system. J Cereb Blood Flow Metab 31(2):767–777

    Article  CAS  PubMed  Google Scholar 

  46. Booth R, Kim H (2012) Characterization of a microfluidic in vitro model of the blood-brain barrier (μBBB). Lab Chip 12(10):1784–1792

    Article  CAS  PubMed  Google Scholar 

  47. Prabhakarpandian B et al (2013) SyM-BBB: a microfluidic blood brain barrier model. Lab Chip 13(6):1093–1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Booth R, Kim H (2011) A multi-layered microfluidic device for in vitro bloodbrain barrier permeability studies. In: International conference on miniaturized systems for chemistry and life sciences

    Google Scholar 

  49. Vastag M, Keseru GM (2009) Current in vitro and in silico models of blood-brain barrier penetration: a practical view. Curr Opin Drug Discov Devel 12(1):115–124

    CAS  PubMed  Google Scholar 

  50. Abbott NJ (2004) Prediction of blood–brain barrier permeation in drug discovery from in vivo, in vitro and in silico models. Drug Discov Today Technol 1(4):407–416

    Article  CAS  PubMed  Google Scholar 

  51. Goodwin JT, Clark DE (2005) In silico predictions of blood-brain barrier penetration: considerations to “keep in mind”. J Pharmacol Exp Ther 315(2):477–483

    Article  CAS  PubMed  Google Scholar 

  52. Mensch J et al (2009) In vivo, in vitro and in silico methods for small molecule transfer across the BBB. J Pharm Sci 98(12):4429–4468

    Article  CAS  PubMed  Google Scholar 

  53. Deli MA (2011) Drug transport and the blood-brain barrier. In: Tihanyi K, Vastag M (eds) Solubility, delivery, and ADME problems of drugs and drug-candidates. Bentham Science Publication Ltd, Washington, DC, pp 144–165

    Google Scholar 

  54. Bendels S et al (2008) In silico prediction of brain and CSF permeation of small molecules using PLS regression models. Eur J Med Chem 43(8):1581–1592

    Article  CAS  PubMed  Google Scholar 

  55. Garg P, Verma J, Roy N (2008) In silico modeling for blood–brain barrier permeability predictions. In: Drug absorption studies. Springer, New York, NY, pp 510–556

    Chapter  Google Scholar 

  56. Konovalov DA et al (2007) Benchmarking of QSAR models for blood-brain barrier permeation. J Chem Inf Model 47(4):1648–1656

    Article  CAS  PubMed  Google Scholar 

  57. Liu X et al (2004) Development of a computational approach to predict blood-brain barrier permeability. Drug Metab Dispos 32(1):132–139

    Article  CAS  PubMed  Google Scholar 

  58. Abraham MH (2004) The factors that influence permeation across the blood–brain barrier. Eur J Med Chem 39(3):235–240

    Article  CAS  PubMed  Google Scholar 

  59. Lipinski CA et al (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23(1-3):3–25

    Article  CAS  Google Scholar 

  60. Lipinski CA (2004) Lead-and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol 1(4):337–341

    Article  CAS  PubMed  Google Scholar 

  61. Glave W, Hansch C (1972) Relationship between lipophilic character and anesthetic activity. J Pharm Sci 61(4):589–591

    Article  CAS  PubMed  Google Scholar 

  62. Pajouhesh H, Lenz GR (2005) Medicinal chemical properties of successful central nervous system drugs. NeuroRx 2(4):541–553

    Article  PubMed  PubMed Central  Google Scholar 

  63. Hitchcock SA (2008) Blood–brain barrier permeability considerations for CNS-targeted compound library design. Curr Opin Chem Biol 12(3):318–323

    Article  CAS  PubMed  Google Scholar 

  64. Levin VA et al (1984) Relationship of octanol/water partition coefficient and molecular weight to cellular permeability and partitioning in S49 lymphoma cells. Pharm Res 1(6):259–266

    Article  CAS  PubMed  Google Scholar 

  65. Young RC et al (1988) Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J Med Chem 31(3):656–671

    Article  CAS  PubMed  Google Scholar 

  66. Abraham MH, Takács‐Novák K, Mitchell RC (1997) On the partition of ampholytes: application to blood–brain distribution. J Pharm Sci 86(3):310–315

    Article  CAS  PubMed  Google Scholar 

  67. Liu X, Chen C, Smith BJ (2008) Progress in brain penetration evaluation in drug discovery and development. J Pharmacol Exp Ther 325(2):349–356

    Article  CAS  PubMed  Google Scholar 

  68. Sakolish CM et al (2016) Modeling barrier tissues in vitro: methods, achievements, and challenges. EBioMedicine 5:30–39

    Article  PubMed  PubMed Central  Google Scholar 

  69. Veszelka S, Kittel Á, Deli MA (2011) Tools of modelling blood–brain barrier penetrability. In: Tihanyi K, Vastag M (eds) Solubility, delivery, and ADME problems of drugs and drug-candidates. Bentham Science Publication Ltd, Washington, DC, pp 166–188

    Google Scholar 

Download references

Acknowledgments

Rahul Dev Jayant would like to acknowledge the financial support from School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC) start-up funds, and The Campbell Foundation (Florida). Abhijeet Joshi acknowledges the INSPIRE Fellowship provided by Department of Science and Technology, Government of India.

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center (TTUHSC), Amarillo, TX, USA

      Sounak Bagchi, Behnaz Lahooti, Tanya Chhibber, Sree-pooja Varahachalam & Rahul Dev Jayant

    2. Laboratory of Human Molecular Genetics, Department of Otolaryngology, Miller School of Medicine, University of Miami (UM), Miami, FL, USA

      Rahul Mittal

    3. Centre for Biosciences and Bio-medical Engineering, Indian Institute of Technology Indore (IIT-I), Indore, Madhya Pradesh, India

      Abhijeet Joshi

    Authors
    1. Sounak Bagchi
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Behnaz Lahooti
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Tanya Chhibber
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Sree-pooja Varahachalam
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Rahul Mittal
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Abhijeet Joshi
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Rahul Dev Jayant
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Sounak Bagchi or Rahul Dev Jayant .

    Editor information

    Editors and Affiliations

    1. Department of Pharmaceutical Science and Technology, University of Chile, Santiago, Chile

      Javier O. Morales

    2. 2-BBB Medicines BV, Leiden, The Netherlands

      Pieter J. Gaillard

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2021 Springer Science+Business Media, LLC, part of Springer Nature

    About this protocol

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this protocol

    Bagchi, S. et al. (2021). In Vitro Models of Central Nervous System Barriers for Blood-Brain Barrier Permeation Studies. In: Morales, J.O., Gaillard, P.J. (eds) Nanomedicines for Brain Drug Delivery. Neuromethods, vol 157. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0838-8_9

    Download citation

    • DOI: https://doi.org/10.1007/978-1-0716-0838-8_9

    • Published:

    • Publisher Name: Humana, New York, NY

    • Print ISBN: 978-1-0716-0837-1

    • Online ISBN: 978-1-0716-0838-8

    • eBook Packages: Springer Protocols

    Publish with us

    Policies and ethics

    Search

    Navigation