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

• Published in: International journal of molecular sciences Vol. 23; no. 3; p. 1898
• Main Authors: Nilles, Kelsy L., Williams, Erica I., Betterton, Robert D., Davis, Thomas P., Ronaldson, Patrick T.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.02.2022; MDPI
• Subjects: Animals; Blood-Brain Barrier - metabolism; Comorbidity; Disease Models, Animal; Drug therapy; Edema; Endothelium; Extracellular matrix; Gene Expression Regulation - drug effects; Glucose; Human subjects; Humans; Ischemic Stroke - drug therapy; Ischemic Stroke - metabolism; Molecular Targeted Therapy; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - therapeutic use; Organic Anion Transporters - metabolism; Organic Cation Transport Proteins - metabolism; Permeability; Proteins; Review; Sodium; Solute movement; Stroke; blood–brain barrier; transporters; organic anion transporting polypeptides; endothelial cell; neuroprotection; statins; organic cation transporters; ischemic stroke
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031898

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.