Role of Transporters in Central Nervous System Drug Delivery and Blood-Brain Barrier Protection: Relevance to Treatment of Stroke

Abstract

Ischemic stroke is a leading cause of morbidity and mortality in the United States. The only approved pharmacologic treatment for ischemic stroke is thrombolysis via recombinant tissue plasminogen activator (r-tPA). A short therapeutic window and serious adverse events (ie, hemorrhage, excitotoxicity) greatly limit r-tPA therapy, which indicates an essential need to develop novel stroke treatment paradigms. Transporters expressed at the blood-brain barrier (BBB) provide a significant opportunity to advance stroke therapy via central nervous system delivery of drugs that have neuroprotective properties. Examples of such transporters include organic anion-transporting polypeptides (Oatps) and organic cation transporters (Octs). In addition, multidrug resistance proteins (Mrps) are transporter targets in brain microvascular endothelial cells that can be exploited to preserve BBB integrity in the setting of stroke. Here, we review current knowledge on stroke pharmacotherapy and demonstrate how endogenous BBB transporters can be targeted for improvement of ischemic stroke treatment.

Keywords: ATP-binding cassette (ABC) transporters; Ischemic stroke; blood-brain barrier; glutathione; neuroprotection; solute carrier (SLC) transporters; vascular protection.

Figure 1.

Transporter expression in brain microvessels. Solute carrier (SLC) superfamily members (green fluorescence) (A) Oatp1a4 and (B) Oct1 and adenosine triphosphate (ATP)–binding cassette (ABC) superfamily representative (C) Mrp2 (red fluorescence) are strongly expressed in brain microvessels directly isolated from rat brain. Scale bar = 4 µm. Figure is an original and represents previously unpublished data.

Figure 2.

Structural and functional changes on the endothelial cells of the blood-brain barrier (BBB) during hypoxia/reperfusion (H/RI) injury. Hypoxia (middle) causes an increase in cell volume due to increased functional expression of the Na-K-Cl cotransporter (yellow arrow), water uptake (blue arrow), and actin upregulation (crosshatches). Increased cell volume causes the vascular lumen to shrink reducing cerebral blood flow even further. Although the expression of critical tight junction proteins—ZO-1, ZO-2, occludin, and claudin-1—remain unchanged compared with normal cells (left), there is a significant increase in paracellular permeability (arrows). When the normal blood flow is reintroduced (right), some initial changes, such as Na-K-Cl expression and activity and water permeability, revert back to normal levels, whereas others such as actin are more exacerbated. Increased tight junction protein expression (with exception of claudin-1) helps in regulating paracellular permeability. In addition to these changes, there is a significant upregulation of transporters, including luminal Abcb1 and aluminal/abluminal Oatp1a4 that can affect drug delivery across the BBB during H/RI.^– Figure is an original and previously unpublished drawing.

Figure 3.

The TGF-β signaling pathway: at the blood-brain barrier, TGF-β signaling is mediated by 2 distinct receptors designated activin receptor–like kinase 1 (ALK-1) and ALK-5. Activation of ALK-1 by binding of BMP-9 triggers phosphorylation of Smads 1, 5, and 8, whereas 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 (ie, Smad4) and form a complex that translocates into the nucleus and regulate transcription of target genes. TF indicates transcription factor; TGF-β, transforming growth factor β. Figure is an original and previously unpublished drawing.