The ABC of the Blood-Brain Barrier - Regulation of Drug Efflux Pumps

Abstract

According to the World Health Organization Central nervous system disorders are the major medical challenge of the 21st Century, yet treatments for many CNS disorders are either inadequate or absent. One reason is the existence of the blood-brain barrier, which strictly limits the access of substances to the brain. A key element of the barrier function is the expression of ABC export proteins in the luminal membrane of brain microvessel endothelial cells. Understanding the signaling cascades and the response to endogenous and exogenous stimuli, which lead to altered expression or function of the transporters as well as subsequent modulation of the transporters, may offer novel strategies to overcome the barrier and to improve drug delivery to the brain. This review gives a short overview about structure of the key elements of the blood-brain barrier with emphasis on ABC transporters. An insight into regulation of function and expression of these transport proteins is given and the involvement of these transporters in CNS diseases is discussed.

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“…In addition, both TPV and BOC are substrates and inhibitors of the drug transporter P-glycoprotein (ABCB1), which is required to limit the permeability of the BBB and protect the brain from drug-related toxicity. BOC acts also as an inhibitor of the efflux transporter breast cancer resistance protein (ABCG2) [7,8]. It could be argued that the inhibitory effect of protease inhibitors on ABCB1 and ABCG2 contributes to interferon-α accumulation in the brain through a defective clearance across the BBB.…”

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“…BCSF mainly regulates the exchange of molecules between the blood and CSF, controlling the penetration within the interstitial fluid of the brain parenchyma (Bhaskar et al, 2010;Gilmore et al, 2008;Mahringer et al, 2011). Moreover, another interface, the avascular arachnoid epithelium, has a relatively small surface that is the main reason why it is not a significant surface for exchange between blood and CNS (Abbott et al, 2010).…”

“…This type of transport causes the active efflux of drugs from brain back to blood (Bhaskar et al, 2010). Therefore, one strategy to improve the efficacy of CNS drugs would be the modulation of transport proteins mainly responsible for the drug efflux, being responsible for their passage across the BBB (Mahringer et al, 2011).…”

“…These proteins collectively hamper brain uptake of a huge variety of lipophilic xenobiotics, potentially toxic metabolites and also drugs. Several other transport proteins and receptors are expressed at the BBB, such as the non-ABC transporters Oat3 (organic anion transporter) and Oatp2 (organic anion transporting polypeptide that handles steroid and drug conjugates, certain opioid peptides, and the cardiac glycoside, digoxin) that, when coupled to the appropriate ion gradients, are capable of driving organic anions into the endothelial cells (Agarwal et al, 2011;Bauer et al, 2005;Hermann and Patak, 2011;Mahringer et al, 2011).…”

“…Its highest activities seem to be in the luminal plasma membrane of the capillary endothelium (Mahringer et al, 2011). Mdr1 is often overexpressed in tumour cells which contributes to the multi-drug resistant phenotype commonly seen in cancer (Fisher et al, 2007).…”