Abstract
The blood-brain barrier (BBB) limits the pharmacotherapy of several brain disorders. In addition to the structural and metabolic characteristics of the BBB, the ATP-driven, drug efflux transporter P-glycoprotein (Pgp) is a selective gatekeeper of the BBB; thus, it is a primary hindrance to drug delivery into the brain. Here, we review the complex regulation of Pgp expression and functional activity at the BBB with an emphasis on recent studies from our laboratory. In addition to traditional processes such as transcriptional regulation and posttranscriptional or posttranslational modification of Pgp expression and functionality, novel mechanisms such as intra- and intercellular Pgp trafficking and intracellular Pgp-mediated lysosomal sequestration in BBB endothelial cells with subsequent disposal by blood neutrophils are discussed. These intrinsic mechanisms of active drug extrusion at the BBB are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the treatment of brain diseases and enhance drug delivery to the brain.
Highlights
The blood-brain barrier (BBB) provides a natural defense against toxic or infective agents circulating in the blood and restricts the brain penetration of most drugs, forming a bottleneck in drug development for brain diseases [1,2]
Many of such compounds are subject to active efflux by promiscuous ATP-binding cassette (ABC) transporters such as P-glycoprotein (Pgp; MDR1; ABCB1), breast cancer resistance protein (BCRP; ABCG2) or multidrug resistance proteins (MRPs; ABCCs) that are located at the apical, blood-facing membrane of brain capillary endothelial cells (BCECs) and pump drugs back into the blood before they reach the brain parenchyma [1]
Several therapeutically important drug categories, including antiepileptic drugs (AEDs; typically termed anti-seizure drugs [ASDs]), antidepressant drugs, anticancer drugs, or certain anti-infectious agents are restricted in their brain penetration by efflux transporters such as Pgp, which may result in the drug resistance of brain diseases [1,5,6,7]
Summary
The blood-brain barrier (BBB) provides a natural defense against toxic or infective agents circulating in the blood and restricts the brain penetration of most drugs, forming a bottleneck in drug development for brain diseases [1,2]. Lipophilic, and uncharged compounds, such as anesthetic agents, can penetrate relatively freely through the BBB by passive diffusion to reach their targets in the brain Many of such compounds are subject to active efflux by promiscuous ATP-binding cassette (ABC) transporters such as P-glycoprotein (Pgp; MDR1; ABCB1), breast cancer resistance protein (BCRP; ABCG2) or multidrug resistance proteins (MRPs; ABCCs) that are located at the apical, blood-facing membrane of BCECs and pump drugs back into the blood before they reach the brain parenchyma [1]. Several therapeutically important drug categories, including antiepileptic drugs (AEDs; typically termed anti-seizure drugs [ASDs]), antidepressant drugs, anticancer drugs, or certain anti-infectious agents are restricted in their brain penetration by efflux transporters such as Pgp, which may result in the drug resistance of brain diseases [1,5,6,7] In theory, this problem may be resolved by the coadministration of Pgp inhibitors. This hypothesis was examined in a series of studies, which will be described in Section 3 of this review, after shortly discussing more conventional mechanisms of Pgp regulation at the BBB
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