Blood-Brain Barrier Transporters: Opportunities for Therapeutic Development in Ischemic Stroke

Abstract

Globally, stroke is a leading cause of death and long-term disability. Over the past decades, several efforts have attempted to discover new drugs or repurpose existing therapeutics to promote post-stroke neurological recovery. Preclinical stroke studies have reported successes in identifying novel neuroprotective agents; however, none of these compounds have advanced beyond a phase III clinical trial. One reason for these failures is the lack of consideration of blood-brain barrier (BBB) transport mechanisms that can enable these drugs to achieve efficacious concentrations in ischemic brain tissue. Despite the knowledge that drugs with neuroprotective properties (i.e., statins, memantine, metformin) are substrates for endogenous BBB transporters, preclinical stroke research has not extensively studied the role of transporters in central nervous system (CNS) drug delivery. Here, we review current knowledge on specific BBB uptake transporters (i.e., organic anion transporting polypeptides (OATPs in humans; Oatps in rodents); organic cation transporters (OCTs in humans; Octs in rodents) that can be targeted for improved neuroprotective drug delivery. Additionally, we provide state-of-the-art perspectives on how transporter pharmacology can be integrated into preclinical stroke research. Specifically, we discuss the utility of in vivo stroke models to transporter studies and considerations (i.e., species selection, co-morbid conditions) that will optimize the translational success of stroke pharmacotherapeutic experiments.

Keywords: blood–brain barrier; endothelial cell; ischemic stroke; neuroprotection; organic anion transporting polypeptides; organic cation transporters; statins; transporters.

Figure 1

Anatomy of the neurovascular unit.

Figure 2

Localization of ATP-Binding Cassette (ABC) transporters at the Blood-Brain Barrier (BBB). ABC efflux transporters that are known to play a critical role in central nervous system (CNS) drug disposition are shown. All of these transporters function as primary active transporters and utilize ATP as an energy source to move drug molecules against their concentration gradient. Current knowledge in the field implies that P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) function in synergy to restrict blood-to-brain transport of therapeutics [6,69].

Figure 3

Localization of drug-transporting organic anion transporting polypeptides (OATPs/Oatps) at the Blood-Brain Barrier (BBB). The rodent Oatp isoform Oatp1a4 and its human orthologue OATP1A2 are expressed at the luminal and abluminal plasma membrane of brain microvascular endothelial cells [71,76,77,78]. The driving force for these transporters is the transmembrane concentration gradient. Therefore, they will primarily facilitate blood-to-brain uptake of transport substrates when a therapeutic is administered via the systemic circulation.

Figure 4

Proposed localization of organic cation transporters (OCTs/Octs) and multidrug and toxin extruders (MATEs/Mates) at the Blood-Brain Barrier (BBB). Due to their polarized nature, OCT/Oct isoforms are believed to be localized to the luminal plasma membrane in brain microvascular endothelial cells while MATE/Mate transporters are localized to the abluminal plasma membrane. These SLC transporters function as secondary active transporters that are coupled to a proton gradient to drive substrate transport in the blood-to-brain direction.