Blood–Brain Barrier

Abstract

The blood–brain barrier consists of endothelial cells lining brain capillaries. It serves to restrict and control the movement of substances between the general circulation and brain extracellular fluid. It participates in regulating the volume and composition of fluid surrounding the brain through specific transport processes, and thus contributes to homoeostasis of the central nervous system. Some of these processes may be regulated hormonally, or modulated by adjacent cells including astrocytes. The barrier function of the blood–brain barrier is due to: (1) tight junctions that restrict movement of substances between the endothelial cells, (2) specific transport proteins that determine which substances can cross the barrier transcellularly and (3) enzymes that may degrade or alter substances prior to passage. Systemically administered drugs intended to treat neurological disorders must be designed to bypass the restrictive elements of the blood–brain barrier. Pathological conditions associated with the central nervous system may alter blood–brain barrier function.

Key Concepts:

  • The blood–brain barrier regulates brain extracellular fluid.

  • Brain capillaries form a tight barrier except in specialised areas.

  • Tight junctions restrict paracellular movement of substances across the blood–brain barrier.

  • Astrocytes contribute to differentiation of the blood–brain barrier.

  • Transport across the blood–brain barrier may be passive or active.

  • Enzymes contribute a metabolic barrier to the blood–brain barrier.

  • A strategy must be developed to deliver drugs to the brain.

  • Altered blood–brain barrier function in disease.

  • Structural and functional properties of the blood–brain barrier.

Keywords: brain extracellular fluid; cerebral capillary endothelial cells; tight junctions; multidrug resistance proteins

Figure 1.

The blood–brain barrier consists of endothelial cells lining brain capillaries. These cells are connected by tight junctions, which separate the plasmalemma into luminal (blood‐facing) and abluminal (brain‐facing) plasma membrane domains. The capillaries are surrounded by a basement membrane, and are closely associated with astrocytes, neurons and pericytes.

Figure 2.

Brain capillary endothelial cells forming the blood–brain barrier are polarised and possess distinct transport proteins in the luminal and abluminal plasma membranes. This illustration depicts a model describing some of these transporters. Organic nutrients like amino acids (AA) and glucose (G) move passively from blood‐to‐brain extracellular fluid, with the assistance of carrier systems in both plasma membranes. Sodium‐dependent amino acid (Na/AA) co‐transporters positioned at the abluminal membrane apparently serve to limit the influx of certain amino acids. Passive amino acid transporters in both membranes include systems L and y+. Conversely, sodium‐dependent amino acid transporters at the abluminal membrane include systems A, N, Bo,+, and a carrier system that mediates glutamate transport (Glu). Passive carriers for glutamine (Gln) and glutamate (Glu) are present in the luminal membrane, and in concert with sodium‐dependent transporters in the abluminal membrane apear to allow for removal of these amino acids from the brain. Regarding electrolytes, a sodium–hydrogen exchanger is thought to exist at the luminal membrane, as well as a nonspecific cationic channel (e.g. Na). A sodium–potassium ATPase (Na/K) is present at the abluminal membrane, and is thought to mediate active blood‐to‐brain movement of sodium.

close

References

Abbott NJ, Ronnback L and Hansson E (2006) Astrocyte‐endothelial interactions at the blood‐brain barrier. Nature Reviews Neuroscience 7: 41–53.

Betz AL and Goldstein GW (1986) Specialized properties and solute transport in brain capillaries. Annual Reviews of Physiology 48: 241–250.

Dohgu S, Takata F, Yamauchi S et al. (2005) Brain pericytes contribute to the induction and up‐regulation of blood‐brain barrier functions through transforming growth factor‐β production. Brain Research 1038: 208–215.

Drewes LR (1998) Biology of the blood–brain glucose transporter. In: Pardridge WM (ed.) Introduction to the Blood–Brain Barrier, pp. 165–174. Cambridge: Cambridge University Press.

El‐bacha R and Minn S (1999) Drug metabolizing enzymes I cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell and Molecular Biology 45: 15–25.

Frelin C and Vigne P (1998) Ion channels in endothelial cells. In: Pardridge WM (ed.) Introduction to the Blood–Brain Barrier, pp. 214–220. Cambridge: Cambridge University Press.

Ge S, Song L and Pachter J (2005) Where is the blood‐brain barrier…really? Journal of Neuroscience Research 79: 421–427.

Hawkins BT and Davis TP (2005) The blood‐brain barrier/neurovascular unit in health and disease. Pharmacological Review 57: 173–185.

Hawkins RA, Peterson DR and Vina JR (2002) The complementary membranes forming the blood–brain barrier. International Union of Biochemistry and Molecular Biology Life 54: 101–108.

Hawkins RA, Viña LR, Peterson DR et al. (2011) Amino acid transport across each side of the blood‐brain barrier. In: D'Mello JPF (ed.) Amino Acids in Nutrition and Health, pp. 191–214. Oxford: CABI.

Keep R, Ennis S and Betz A (1998) Blood‐brain barrier ion transport. In: Pardridge WM (ed.) Introduction to the Blood–Brain Barrier, pp. 207–213. Cambridge: Cambridge University Press.

Kortekaas R, Leenders KL, van Oostrom JC et al. (2005) Blood‐brain barrier dysfunction in parkinsonian midbrain in vivo. Annals of Neurology 57: 176–179.

Lee G and Bendayan R (2004) Functional expression and localization of P‐glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders. Pharmaceutical Research 21: 1313–1320.

Lo EH, Dalkara T and Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nature Reviews 4: 399–415.

Marroni M, Marchi N, Cucullo L et al. (2003) Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. Current Drug Targets 4: 297–304.

Minagar A and Alexander JS (2003) Blood‐brain barrier disruption in multiple sclerosis. Multiple Sclerosis 9: 540–549.

O'Kane R, Martinez‐Lopez I, DeJoseph M, Vina J and Hawkins R (1999) Na‐dependent glutamate transporters (EAAT 1, EAAT2, and EAAT3) of the blood‐brain barrier. Journal of Biological Chemistry 274: 31891–31895.

Papadopoulos MC, Saadoun S, Davies DC and Bell BA (2001) Emerging molecular mechanisms of brain tumour oedema. British Journal of Neurosurgery 15: 1–108.

Pardridge WM (1991) Peptide Drug Delivery to the Brain. New York: Raven Press.

Pardridge WM (1997) Drug delivery to the brain. Journal of Cerebral Blood Flow & Metabolism 17: 713–731.

Pardridge WM (2003) Blood–brain barrier drug targeting: the future of brain drug development. Molecular Interventions 3: 90–105.

Peterson DR and Hawkins RA (1998) Isolation and behavior of plasma membrane vesicles made from cerebral capillary endothelial cells. In: Pardridge WM (ed.) Introduction to the Blood–Brain Barrier, pp. 62–70. Cambridge: Cambridge University Press.

Peterson DR and Hawkins RA (2003) Transport studies using membrane vesicles. In: Nag S (ed.) Blood‐Brain Barrier: Biology and Protocols, pp. 233–248. Totowa, NJ: The Humana Press.

Prescott L and Brightman M (1998) Circumventricular organs of the brain. In: Pardridge WM (ed.) Introduction to the Blood–Brain Barrier, pp. 270–276. Cambridge: Cambridge University Press.

Ramsauer M, Krause D and Dermietzel R (2006) Angiogenesis of the blood‐brain barrier in vitro and the function of cerebral pericytes. Federation of American Societies for Experimental Biology Journal 16: 1274–1276.

Régina A, Morchoisne S, Borson N et al. (2001) Factors released by glucose‐derived astrocytes enhance glucose transporter expression and activity in rat brain endothelial cells. Biochimica et Biophysica Acta 1540: 233–242.

Reichel V, Burghard S and Huber J (2011) P‐glycoprotein and breast cancer resistance protein expression and function at the blood‐brain barrier and blood‐cerebrospinal fluid barrier (choroid plexus) in streptozotocin‐induced diabetes in rats. Brain Research 1370: 238–245.

Sanchez del Pino MM, Hawkins RA and Peterson DR (1995) Biochemical discrimination between luminal and abluminal enzyme and transport activities of the blood‐brain barrier. Journal of Biological Chemistry 270: 14907–14912.

Schiera G, Bono E, Raffa M et al. (2003) Syngergistic effects of neurons and astrocytes on the differentiation of brain capillary endothelial cells in culture. Journal of Cell and Molecular Medicine 7: 165–179.

Schinkel A (1999) P‐glycoprotein, a gatekeeper in the blood‐brain barrier. Advances in Drug Delivery Research 36: 179–194.

Smith QR and Stoll J (1998) Blood–brain barrier amino acid transport. In: Pardridge WM (ed.) Introduction to the Blood–Brain Barrier, pp. 188–197. Cambridge: Cambridge University Press.

Sobue K, Yamamoto N, Yoneda K et al. (1999) Induction of blood‐brain barrier properties in immortalized bovine brain endothelial cells by astrocyte factors. Neuroscience Research 35: 155–164.

Strange K (1992) Regulation of solute and water balance and cell volume in the central nervous system. Journal of the American Society of Nephrology 3: 12–27.

Tsuji A and Tamai I (1998) Blood–brain barrier transport of drugs. In: Pardridge WM (ed.) Introduction to the Blood–Brain Barrier, pp. 238–247. Cambridge: Cambridge University Press.

Wolburg H and Lippoldt A (2002) Tight junctions of the blood‐brain barrier: development, composition and regulation. Vascular Pharmacology 38: 323–337.

Further Reading

Begley D and Brightman M (2003) Structural and functional aspects of the blood‐brain barrier. Progress in Drug Research 61: 40–78.

Davson H, Zlokovic B, Rakic L and Segal MB (1993) An Introduction to the Blood‐Brain Barrier. Boca Raton, FL: CRC Press.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Peterson, Darryl R(Aug 2012) Blood–Brain Barrier. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000023.pub3]