Contribution of Carrier-Mediated Transport Systems to the Blood–Brain Barrier as a Supporting and Protecting Interface for the Brain; Importance for CNS Drug Discovery and Development

Abstract

The blood-brain barrier (BBB) forms an interface between the circulating blood and the brain and possesses various carrier-mediated transport systems for small molecules to support and protect CNS function. For example, the blood-to-brain influx transport systems supply nutrients, such as glucose and amino acids. Consequently, xenobiotic drugs recognized by influx transporters are expected to have high permeability across the BBB. On the other hand, efflux transporters, including ATP-binding cassette transporters such as P-glycoprotein located at the luminal membrane of endothelial cells, function as clearance systems for metabolites and neurotoxic compounds produced in the brain. Drugs recognized by these transporters are expected to show low BBB permeability and low distribution to the brain. Despite recent progress, the transport mechanisms at the BBB have not been fully clarified yet, especially in humans. However, an understanding of the human BBB transport system is critical, because species differences mean that it can be difficult to extrapolate data obtained in experimental animals during drug development to humans. Recent progress in methodologies is allowing us to address this issue. Positron emission tomography can be used to evaluate the activity of human BBB transport systems in vivo. Proteomic studies may also provide important insights into human BBB function. Construction of a human BBB transporter atlas would be a most important advance from the viewpoint of CNS drug discovery and drug delivery to the brain.

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“…Tight junctions between adjacent endothelial cells of the BBB restrict the nonspecific paracellular diffusion of compounds. Additional BBB features allow the control of the transcellular diffusion of compounds like drug transporters involved in influx and/or efflux (Ohtsuki and Terasaki, 2007). It is essential, therefore, to identify the transporters and properties that govern their functions at the BBB and to understand how some drugs can reach the brain parenchyma and why others do not.…”

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“…They impede free exchange of solutes (Ohtsuki and Terasaki 2007 ) with the exception of lipidsoluble molecules smaller than 400 Da with less than nine hydrogen bonds, which are able to cross BBB via lipid mediated diffusion (Pardridge 2007 ). Structurally, the cells are connected to each other via tight junctions (TJs), adherens junctions (AJs) (Hawkins and Davis 2005 ), and gap junctions (Boulay et al 2015 ), which are required for the compact characteristics of the barrier.…”