Blood brain barrier (BBB)

The blood-brain barrier (BBB) protects central nervous system (CNS) from most compounds, including drugs, PET tracers, and their metabolites. Intact BBB is critical for normal CNS functioning, and disturbances of BBB are associated with many diseases, including MS. BBB is composed of specialized endothelial cells, surrounded by pericytes and basal membrane. Pericytes are contractile smooth muscle cells, but also exhibit macrophage-like activities. The microvasculature in the CNS is lined and supported by endothelial basement membrane and extracellular matrix, produced by astrocytes. Astrocytes produce also a parenchymal basement membrane, which, if intact, prevents the extravasated leukocytes from entering the CNS. Endothelial cells of CNS capillaries are closely connected to each other with tight junctions, and contain 5-10 times more mitochondria than endothelial cells elsewhere. Endothelial cells express different transporters and enzymes on the luminal (apical) and basolateral sides.

Active transport or facilitated diffusion is required for most molecules to pass the BBB; organic anion transporting polypeptides (OATPs), organic anion transporters (OATs), organic cation transporters (OCTs), monocarboxylate transporters (MCTs), nucleoside transporters, GLUT1, and any many others, facilitate the entry of many drugs and PET tracers into the brain. Large neutral amino acid transporter (LNAA) is needed in brain uptake of L-DOPA and [18F]FDOPA.

ATP-dependent export proteins, mainly P-glycoprotein (P-gp, ABCB1) transports diverse substrates from CNS to the capillaries. P-gp also contributes to the clearance of β-amyloid from the brain, and its function may be impaired in neuroinflammation. P-gp function is markedly decreased in Alzheimer’s disease, and increased in epilepsy. BCRP (ABCG2) and MRPs are also important efflux transporters. P-gp function can be studied using [11C]verapamil (Lubberink, 2016); increased tracer uptake in the brain implied decreased P-gp function. [11C]verapamil however is not an optimal tracer: its radiolabelled metabolite [11C]D617 is also a P-gp substrate (Raaphorst et al., 2017).

Astrocytes in BBB

Astrocytes are the most abundant cell type in the brain, and they surround the brain capillaries, maintaining the homeostasis of the brain and BBB components. Astrocytes and glial cells can regulate the permeability of the BBB. Astrocytes are important in keeping the extracellular glutamate concentration under excitotoxic level.

Antibodies

BBB and blood-nerve barrier (BNB) prevent the entry of antibodies into healthy central and peripheral nervous system. Proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, and some other signalling molecules can bind to endothelial cells, leading to weakening of the barrier. Secretion of IFN-γ and other cytokines by T cells can also open the barrier, and activated T cells themselves can enter the nervous tissue via different routes. Stimulated T cells can open tissue access to the antibodies.

Carriers

BBB blocks the entry of most substances into the CNS, but the capillary endothelial cells express a wide array of transporters and receptors, which can be targeted to carry therapeutic drugs across the BBB. Transferrin receptor and insulin receptor are the most studied systems for this use.


See also:



References

Di L, Kerns EH (eds.): Blood-Brain Barrier in Drug Discovery. Wiley, 2015.

Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. Brain-reactive antibodies and disease. Annu Rev Immunol. 2013; 31: 345-385.

Dorovini-Zis K (ed.): The Blood-Brain Barrier in Health and Disease. Volume 1: Morphology, Biology and Immune Function. CRC Press, 2016.

Dorovini-Zis K (ed.): The Blood-Brain Barrier in Health and Disease. Volume 2: Pathophysiology and Pathology. CRC Press, 2016.

Erdö F, Denes L, de Lange E. Age-associated physiological and pathological changes at the blood-brain barrier: a review. J Cereb Blood Flow Metab. 2017; 37(1): 4-24.

Fricker G, Ott M, Mahringer A (eds.): The Blood Brain Barrier (BBB). Springer, 2014. DOI 10.1007/978-3-662-43787-2.

Iwasaki A. Immune regulation of antibody access to neuronal tissues. Trends Mol Med. 2017; 23(3): 227-245.

Kroll T, Elmenhorst D, Matusch A, Celik AA, Wedekind F, Weisshaupt A, Beer S, Bauer A. [18F]Altanserin and small animal PET: impact of multidrug efflux transporters on ligand brain uptake and subsequent quantification of 5-HT2A receptor densities in the rat brain. Nucl Med Biol. 2014; 41: 1-9.

Lécuyer M-A, Kebir H, Prat A. Glial influences on BBB functions and molecular players in immune cell trafficking. Biochim Biophys Acta 2016; 1862: 472-482.

Lyck R, Enzmann G (eds.): The Blood Brain Barrier and Inflammation. Springer, 2017. doi: 10.1007/978-3-319-45514-3.

Nag S. Blood-Brain Barrier. In: Aminoff MJ, Daroff RB (eds.): Encyclopedia of the Neurological Sciences, 2nd ed, Academic Press, 2014. p 434-440.

Pardridge WM. Drug transport across the blood-brain barrier. J Cerebr Blood Flow Metab. 2012; 32: 1959-1972.

Rempe RG, Hartz AMS, Bauer B. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J Cerebr Blood Flow Metab. 2016; 36(9): 1481-1507.



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Created at: 2016-06-04
Updated at: 2017-10-23
Written by: Vesa Oikonen