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Review
. 2021 Apr 3;22(7):3742.
doi: 10.3390/ijms22073742.

Disease-Induced Modulation of Drug Transporters at the Blood-Brain Barrier Level

Sweilem B Al Rihani  1 , Lucy I Darakjian  1 , Malavika Deodhar  1 , Pamela Dow  1 , Jacques Turgeon  1   2 , Veronique Michaud  1   2
Affiliations
Review

Disease-Induced Modulation of Drug Transporters at the Blood-Brain Barrier Level

Sweilem B Al Rihani et al. Int J Mol Sci. .

Abstract

The blood-brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies. Pathophysiological stressors, age, and age-associated disorders may alter the expression level and functionality of transporter protein elements that modulate drug distribution and accumulation into the brain, namely, drug efficacy and toxicity. This review focuses and sheds light on the influence of inflammatory conditions and diseases such as Alzheimer's disease, epilepsy, and stroke on the expression and functionality of the BBB drug transporters, the consequential modulation of drug distribution to the brain, and their impact on drug efficacy and toxicity.

Keywords: Alzheimer’s disease; drug transporters; epilepsy; neuroinflammation; stroke; the blood–brain barrier.

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Conflict of interest statement

All authors performed this work as employees (with stock options and shares) of Tabula Rasa HealthCare (f/k/a CareKinesis). The authors have no personal conflict of interest to disclose. The funder (TRHC board of directors) had no role in the design of the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
The blood–brain barrier. (Created with BioRender, accessed on 27 January 2021).
Figure 2
Figure 2
Transport pathways across the blood–brain barrier (BBB). The passage of various molecules through the brain implies four basic mechanisms allowing specific molecules to move across the BBB membrane including: (1) the passive diffusion (spontaneous movement across a concentration gradient), (2) endocytosis (receptor-mediated, adsorptive, or bulk-phase endocytosis), (3) carrier-mediated transport (movement across a concentration gradient and energy independent), and (4) active transport (movement of molecules against a concentration gradient and energy dependent). Collectively, the four mechanism plays an essential role for maintaining brain homeostasis. (Created with BioRender, accessed on 27 January 2021).
Figure 3
Figure 3
The ABCB1 transporter at the blood–brain interfaces. In the human brain, the ABCB1 transporter is found on the luminal membrane side and restricts the penetration of compounds in the brain by limiting the uptake of several substrate drugs. (Created with BioRender, accessed on 27 January 2021).
Figure 4
Figure 4
The ABCG2 transporter at the blood–brain interfaces. ABCG2 was originally identified as the breast cancer resistance protein (BCRP). In the human brain, ABCG2 is expressed on the luminal membrane side and plays an important role in limiting exposure of drug molecules to the CNS. (Created with BioRender, accessed on 27 January 2021).
Figure 5
Figure 5
The ABCC transporters at the blood–brain interfaces. In the human brain, ABCC transporters are preferentially expressed on the luminal sides. ABCC proteins are active efflux transporters playing a role in the extrusion of several molecules. (Created with BioRender, accessed on 27 January 2021).
Figure 6
Figure 6
The blood–brain barrier (BBB) under healthy and diseased conditions. The BBB is formed by endothelial cells of the brain capillaries that are connected with tight junctions and supported by the neurovascular unit. Under neurological diseases and in aging, the BBB may undergo modulations affecting its permeability and integrity. Failure in BBB function may lead to a state of brain dyshomeostasis, neurodegeneration and brain atrophy. (Created with BioRender, accessed on 27 January 2021).
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