Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

Abstract

Drug delivery to the central nervous system (CNS) is greatly limited by the blood-brain barrier (BBB). Physical and biochemical properties of the BBB have rendered treatment of CNS diseases, including those with a hypoxia/reoxygenation (H/R) component, extremely difficult. Targeting endogenous BBB transporters from the ATP-binding cassette (ABC) superfamily (i.e., P-glycoprotein (P-gp)) or from the solute carrier (SLC) family (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents)) has been suggested as a strategy that can improve delivery of drugs to the brain. With respect to P-gp, direct pharmacological inhibition using small molecules or selective regulation by targeting intracellular signaling pathways has been explored. These approaches have been largely unsuccessful due to toxicity issues and unpredictable pharmacokinetics. Therefore, our laboratory has proposed that optimization of CNS drug delivery, particularly for treatment of diseases with an H/R component, can be achieved by targeting Oatp isoforms at the BBB. As the major drug transporting Oatp isoform, Oatp1a4 has demonstrated blood-to-brain transport of substrate drugs with neuroprotective properties. Furthermore, our laboratory has shown that targeting Oatp1a4 regulation (i.e., TGF-β signaling mediated via the ALK-1 and ALK-5 transmembrane receptors) represents an opportunity to control Oatp1a4 functional expression for the purpose of delivering therapeutics to the CNS. In this review, we will discuss limitations of targeting P-gp-mediated transport activity and the advantages of targeting Oatp-mediated transport. Through this discussion, we will also provide critical information on novel approaches to improve CNS drug delivery by targeting endogenous uptake transporters expressed at the BBB.

Keywords: P-glycoprotein; blood-brain barrier; drug delivery; organic anion transporting polypeptides; transporters.

Fig. 1

Proposed localization of ABC and SLC transporters at the blood-brain barrier. The blood-brain barrier consists of endothelial cells linked together by tight junction complexes, limiting paracellular diffusion of solutes. Efflux transporters (i.e., P-gp, MRPs/Mrps, BCRP/Bcrp) limit transcellular transport of xenobiotics while SLC uptake transporters (i.e., Oatp1a4) permit selective uptake of solutes into the brain

Fig. 2

Structure of Smad Proteins, critical molecules involved in TGF-β Signaling. R-Smad consists of two highly conserved globular regions known as MH1 located on the N-terminus and MH2 located on the C-terminus, which are joined together by a variable linker region. Phosphorylation of R-Smads occurs on the SSXS motif located on the C-terminus. The MH1 region contains nuclear localization signal and plays a role in DNA binding, while the MH2 region is involved in protein-protein interaction, which includes dimerization with other Smad proteins and transcription factors

Fig. 3

The TGF-β signaling pathway. At the BBB, TGF-β signaling is mediated by two distinct receptors designated ALK-1 and ALK-5. Activation of ALK-1 by binding of BMP-9 triggers phosphorylation of Smads 1, 5, and 8, while activation of ALK-5 via TGF-β, triggers phosphorylation of Smads 2 and 3. Once phosphorylated, these Smad signal-transducing proteins bind to the common Smad (i.e., Smad4) and form a complex that translocate into the nucleus and regulate transcription of target genes