Blood brain barrier (BBB)

The blood-brain barrier (BBB) protects central nervous system (CNS) from most compounds, including drugs, PET radiotracers, and their metabolites. In addition, CNS is protected by other two tightly regulated barriers: blood-cerebrospinal fluid barrier (BCSFB) and cerebrospinal fluid-brain barrier (CSFBB). Intact BBB is critical for normal CNS functioning, and disturbances of BBB are associated with many diseases, including MS and AD. Inflammation increases BBB permeability, promoting extravasation of leukocytes and plasma proteins, which further stimulates neuroinflammation.

BBB is composed of specialized endothelial cells, surrounded by pericytes and basal membrane. Pericytes are contractile smooth muscle -like 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 radiopharmaceuticals 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. Breast cancer resistance protein (BCRP, ABCG2) and MRPs are also important efflux transporters. ABCB1 and ABCG2 are co-localized at the BBB. P-gp function can be studied using [11C]verapamil (Lubberink, 2016) and [11C]-N-desmethyl-loperamide (Kannan et al., 2010); 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). Additionally, both of these are strong P-gp substrates with low baseline distribution volume, and therefore not suitable for assessing P-gp upregulation. [18F]MC225 is a weak P-gp substrate, providing higher baseline VT, and comparable sensitivity to P-gp function (Savolainen et al., 2017; García-Varela et al., 2021).

In drug development, drug molecules can be labelled using positron emitting isotope to assess their bio­distribution and the impact of transporters on the brain exposure of the drugs (Pottier et al., 2016; Tournier et al., 2018).

Similarly, in development of PET radiopharmaceuticals their vulnerability to pathophysiological or inadvertent changes in P-gp function should be studied by inhibiting P-gp. Partial inhibition of transporter function allows detection of physiologically relevant changes (Breuil et al., 2022).

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, glial cells, and pericytes 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 and radiopharmaceuticals across the BBB. Transferrin receptor and insulin receptor are the most studied systems in CNS drug development. Receptor for advanced glycosylation end-products (RAGE) can transport glycosylated proteins and some polypeptides from blood into the brain.

Focused ultrasound

Focused ultrasound in combination with microbubbles (FUS) can locally and temporarily enhance BBB permeability. FUS disrupts the tight junctions, opening paracellular route for drug delivery (Chen et al., 2019).


See also:



Literature

Bradbury MWB (ed.): Physiology and Pharmacology of the Blood-Brain Barrier. Springer, 1992. doi: 10.1007/978-3-642-76894-1.

Chowdhury EA, Noorani B, Alqahtani F, Bhalerao A, Raut S, Sivandzade F, Cucullo L. Understanding the brain uptake and permeability of small molecules through the BBB: A technical overview. J Cerb Blood Flow Metab. 2021; 41(8): 1797-1820. doi: 10.1177/0271678X20985946.

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. doi: 10.1146/annurev-immunol-020711-075041.

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. doi: 10.1177/0271678X16679420.

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

Harris WJ, Asselin MC, Hinz R, Parkes LM, Allan S, Schiessl I, Boutin H, Dickie BR. In vivo methods for imaging blood-brain barrier function and dysfunction. Eur J Nucl Med Mol Imaging 2023; 50(4): 1051-1083. doi: 10.1007/s00259-022-05997-1.

Iwasaki A. Immune regulation of antibody access to neuronal tissues. Trends Mol Med. 2017; 23(3): 227-245. doi: 10.1016/j.molmed.2017.01.004.

Knudsen GM, Pettigrew KD, Patlak CS, Paulson OB. Blood-brain barrier permeability measurements by double-indicator method using intravenous injection. Am J Physiol. 1994; 266: H987-H999. doi: 10.1152/ajpheart.1994.266.3.H987.

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. doi: 10.1016/j.nucmedbio.2013.09.001.

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. doi: 10.1016/j.bbadis.2015.10.004.

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. doi: 10.1038/jcbfm.2012.126.

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. doi: 10.1177/0271678X16655551.

Saunders NR, Daneman R, Dziegielewska KM, Liddelow SA. Transporters of the blood-brain and blood-CSF interfaces in development and in the adult. Mol Aspects Med. 2013; 34(2-3): 742-752. doi: 10.1016/j.mam.2012.11.006.



Tags: , , ,


Updated at: 2021-12-05
Created at: 2016-06-04
Written by: Vesa Oikonen