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.

Metformin Preserves VE–Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF/VEGFR2/p-Src in an Intraventricular Hemorrhage Rat Model

“…Rats were euthanized at day 7, the brains were used for ventricular volume calculation (n = 6 per group), western blot (n = 6 per group) and brain histology (n = 4 per group). Second, rats were treated with metformin [ 65 , 66 ] (Abcam, 50 mg/kg, i.p.) or saline (equal volume, i.p.)…”

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

“…The BBB (blood-brain barrier) blocks entry of the majority of drugs into the brain, and represents a challenge for the therapy of neurodegenerative conditions, as reviewed ( Partridge, 2012 ; Nilles et al, 2022 ). Some small lipid-soluble drugs cross by lipid-mediated diffusion.…”

Transport Mechanisms at the Blood–Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs

“…While OATP2B1 localization in cerebral microvasculature has not been confirmed, it is likely that this transporter is expressed at the abluminal membrane and contributes to the movement of solutes out of the endothelial cell and into the brain parenchyma [ 81 ]. Relevant Oatp transport substrates that exert pharmacological/physiological effects in the brain include statins (i.e., atorvastatin, pravastatin, and rosuvastatin), prostaglandin E 2 , dehydroepiandrosterone sulfate (DHEAS), and estradiol-17β-glucuronide [ 17 , 25 , 82 , 83 ].…”

“…Overall, the Oct/Mate system provides an excellent opportunity to deliver cationic therapeutics to the brain. Examples of such drugs include memantine, amantadine, metformin, pramipexole, selegiline, varenicline, and amisulpride [ 17 , 86 , 88 , 91 , 92 ].…”