Skip to main content
SpringerLink
Log in

Blood-Brain Barrier (BBB) Permeability and Transport Measurement In Vitro and In Vivo

  • Protocol
  • First Online:
Permeability Barrier

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2367))

Abstract

Quantification of the blood-brain barrier (BBB) permeability and transport in brain tissue is crucial in understanding brain disorders and developing systemic and non-systemic drug delivery strategies to the brain. This chapter summarizes BBB permeability measurement in vitro (Part I) and the in vivo non-invasive methods for quantifying the BBB permeability to solutes and brain tissue transport in rat brain by employing intravital multiphoton microscopy and a curving fitting method by using an unsteady mass transfer mathematical model (Part II).

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 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37(1):13–25. https://doi.org/10.1016/j.nbd.2009.07.030

    Article  CAS  PubMed  Google Scholar 

  2. Farkas E, Luiten PG (2001) Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog Neurobiol 64(6):575–611. https://doi.org/10.1016/s0301-0082(00)00068-x

    Article  CAS  PubMed  Google Scholar 

  3. Nicolazzo JA, Charman SA, Charman WN (2006) Methods to assess drug permeability across the blood-brain barrier. J Pharm Pharmacol 58(3):281–293. https://doi.org/10.1211/jpp.58.3.0001

    Article  CAS  PubMed  Google Scholar 

  4. Fu BM (2018) Transport across the blood-brain barrier. Adv Exp Med Biol 1097:235–259. https://doi.org/10.1007/978-3-319-96445-4_13

    Article  CAS  PubMed  Google Scholar 

  5. Cornford EM, Young D, Paxton JW, Sofia RD (1992) Blood-brain barrier penetration of felbamate. Epilepsia 33(5):944–954. https://doi.org/10.1111/j.1528-1157.1992.tb02205.x

    Article  CAS  PubMed  Google Scholar 

  6. Zlokovic BV, Begley DJ, Djuricic BM, Mitrovic DM (1986) Measurement of solute transport across the blood-brain barrier in the perfused Guinea pig brain: method and application to N-methyl-alpha-aminoisobutyric acid. J Neurochem 46(5):1444–1451. https://doi.org/10.1111/j.1471-4159.1986.tb01760.x

    Article  CAS  PubMed  Google Scholar 

  7. de Lange EC, de Boer BA, Breimer DD (1999) Microdialysis for pharmacokinetic analysis of drug transport to the brain. Adv Drug Deliv Rev 36(2–3):211–227. https://doi.org/10.1016/s0169-409x(98)00089-1

    Article  PubMed  Google Scholar 

  8. Elsinga PH, Hendrikse NH, Bart J, Vaalburg W, van Waarde A (2004) PET studies on P-glycoprotein function in the blood-brain barrier: how it affects uptake and binding of drugs within the CNS. Curr Pharm Des 10(13):1493–1503. https://doi.org/10.2174/1381612043384736

    Article  CAS  PubMed  Google Scholar 

  9. Wang R, Ashwal S, Tone B, Tian HR, Badaut J, Rasmussen A, Obenaus A (2007) Albumin reduces blood-brain barrier permeability but does not alter infarct size in a rat model of neonatal stroke. Pediatr Res 62(3):261–266. https://doi.org/10.1203/PDR.0b013e318123f757

    Article  CAS  PubMed  Google Scholar 

  10. Gaber MW, Yuan H, Killmar JT, Naimark MD, Kiani MF, Merchant TE (2004) An intravital microscopy study of radiation-induced changes in permeability and leukocyte-endothelial cell interactions in the microvessels of the rat pia mater and cremaster muscle. Brain Res Brain Res Protoc 13(1):1–10. https://doi.org/10.1016/j.brainresprot.2003.11.005

    Article  CAS  PubMed  Google Scholar 

  11. Easton AS, Fraser PA (1994) Variable restriction of albumin diffusion across inflamed cerebral microvessels of the anaesthetized rat. J Physiol 475(1):147–157. https://doi.org/10.1113/jphysiol.1994.sp020056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shi L, Palacio-Mancheno P, Badami J, Shin DW, Zeng M, Cardoso L, Tu R, Fu BM (2014) Quantification of transient increase of the blood-brain barrier permeability to macromolecules by optimized focused ultrasound combined with microbubbles. Int J Nanomedicine 9:4437–4448. https://doi.org/10.2147/IJN.S68882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shi L, Zeng M, Fu BM (2014) Temporal effects of vascular endothelial growth factor and 3,5-cyclic monophosphate on blood-brain barrier solute permeability in vivo. J Neurosci Res 92(12):1678–1689. https://doi.org/10.1002/jnr.23457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shi L, Zeng M, Sun Y, Fu BM (2014) Quantification of blood-brain barrier solute permeability and brain transport by multiphoton microscopy. J Biomech Eng 136(3):031005. https://doi.org/10.1115/1.4025892

    Article  PubMed  Google Scholar 

  15. Shin DW, Fan J, Luu E, Khalid W, Xia Y, Khadka N, Bikson M, Fu BM (2020) In vivo modulation of the blood-brain barrier permeability by transcranial direct current stimulation (tDCS). Ann Biomed Eng 48(4):1256–1270. https://doi.org/10.1007/s10439-020-02447-7

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yuan W, Lv Y, Zeng M, Fu BM (2009) Non-invasive measurement of solute permeability in cerebral microvessels of the rat. Microvasc Res 77(2):166–173. https://doi.org/10.1016/j.mvr.2008.08.004

    Article  CAS  PubMed  Google Scholar 

  17. Crone C, Olesen SP (1982) Electrical resistance of brain microvascular endothelium. Brain Res 241(1):49–55. https://doi.org/10.1016/0006-8993(82)91227-6

    Article  CAS  PubMed  Google Scholar 

  18. Pardridge WM (1998) CNS drug design based on principles of blood-brain barrier transport. J Neurochem 70(5):1781–1792. https://doi.org/10.1046/j.1471-4159.1998.70051781.x

    Article  CAS  PubMed  Google Scholar 

  19. Patlak CS, Fenstermacher JD (1975) Measurements of dog blood-brain transfer constants by ventriculocisternal perfusion. Am J Phys 229(4):877–884. https://doi.org/10.1152/ajplegacy.1975.229.4.877

    Article  CAS  Google Scholar 

  20. Nicholson C, Phillips JM (1981) Ion diffusion modified by tortuosity and volume fraction in the extracellular microenvironment of the rat cerebellum. J Physiol 321:225–257. https://doi.org/10.1113/jphysiol.1981.sp013981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Thorne RG, Nicholson C (2006) In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci U S A 103(14):5567–5572. https://doi.org/10.1073/pnas.0509425103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Stroh M, Zipfel WR, Williams RM, Webb WW, Saltzman WM (2003) Diffusion of nerve growth factor in rat striatum as determined by multiphoton microscopy. Biophys J 85(1):581–588. https://doi.org/10.1016/S0006-3495(03)74502-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ishizaki T, Chiba H, Kojima T, Fujibe M, Soma T, Miyajima H, Nagasawa K, Wada I, Sawada N (2003) Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood-brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways. Exp Cell Res 290(2):275–288. https://doi.org/10.1016/s0014-4827(03)00354-9

    Article  CAS  PubMed  Google Scholar 

  24. Lippmann ES, Al-Ahmad A, Azarin SM, Palecek SP, Shusta EV (2014) A retinoic acid-enhanced, multicellular human blood-brain barrier model derived from stem cell sources. Sci Rep 4:4160. https://doi.org/10.1038/srep04160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ma SH, Lepak LA, Hussain RJ, Shain W, Shuler ML (2005) An endothelial and astrocyte co-culture model of the blood-brain barrier utilizing an ultra-thin, nanofabricated silicon nitride membrane. Lab Chip 5(1):74–85. https://doi.org/10.1039/b405713a

    Article  CAS  PubMed  Google Scholar 

  26. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485(7399):512–516. https://doi.org/10.1038/nature11087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhao Z, Sagare AP, Ma Q, Halliday MR, Kong P, Kisler K, Winkler EA, Ramanathan A, Kanekiyo T, Bu G, Owens NC, Rege SV, Si G, Ahuja A, Zhu D, Miller CA, Schneider JA, Maeda M, Maeda T, Sugawara T, Ichida JK, Zlokovic BV (2015) Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat Neurosci 18(7):978–987. https://doi.org/10.1038/nn.4025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yuan F, Leunig M, Berk DA, Jain RK (1993) Microvascular permeability of albumin, vascular surface area, and vascular volume measured in human adenocarcinoma LS174T using dorsal chamber in SCID mice. Microvasc Res 45(3):269–289. https://doi.org/10.1006/mvre.1993.1024

    Article  CAS  PubMed  Google Scholar 

  29. Kimura M, Dietrich HH, Huxley VH, Reichner DR, Dacey RG Jr (1993) Measurement of hydraulic conductivity in isolated arterioles of rat brain cortex. Am J Phys 264(6 Pt 2):H1788–H1797. https://doi.org/10.1152/ajpheart.1993.264.6.H1788

    Article  CAS  Google Scholar 

  30. Xiang TX, Anderson BD (1994) The relationship between permeant size and permeability in lipid bilayer membranes. J Membr Biol 140(2):111–122. https://doi.org/10.1007/bf00232899

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The author would like to thank the funding support from the National Institutes of Health R01NS101362 (B. Fu) and R01AG064798 (D. Zhu).

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, The City College of the City University of New York, New York, NY, USA

    Bingmei M. Fu

  2. Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Zhen Zhao

  3. Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, USA

    Donghui Zhu

Authors
  1. Bingmei M. Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhen Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Donghui Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Bingmei M. Fu , Zhen Zhao or Donghui Zhu .

Editor information

Editors and Affiliations

  1. Ottawa, ON, Canada

    Kursad Turksen

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Science+Business Media New York

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Fu, B.M., Zhao, Z., Zhu, D. (2020). Blood-Brain Barrier (BBB) Permeability and Transport Measurement In Vitro and In Vivo. In: Turksen, K. (eds) Permeability Barrier. Methods in Molecular Biology, vol 2367. Humana, New York, NY. https://doi.org/10.1007/7651_2020_308

Download citation

  • DOI: https://doi.org/10.1007/7651_2020_308

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1672-7

  • Online ISBN: 978-1-0716-1673-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation