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.
Highlights
According to 2019 epidemiological data, there were 12.2 million cases of stroke globally, which resulted in 6.55 million deaths [1]
FDA-approved drug treatments for ischemic stroke are limited to fibrinolytic therapy with recombinant tissue plasminogen activator (rt-PA)
The vast majority of transport studies in the setting of stroke have been limited to those membrane transport mechanisms that contribute to pathophysiological injury such as ion transporters and glucose transporters
Summary
According to 2019 epidemiological data, there were 12.2 million cases of stroke globally, which resulted in 6.55 million deaths [1]. An additional consideration is that studies examining neuroprotection and/or neural repair in experimental stroke have not evaluated specific biological mechanisms (i.e., transporters) that can be targeted to enable drugs to efficiently permeate the BBB This critical consideration is highlighted by the clinical failure of the antioxidant drug disufenton sodium (i.e., NXY-059, Cerovive®) that was developed as a stroke therapeutic. Several preclinical stroke studies have explored other technologies for CNS delivery of drugs including nanoparticles [32,33,34], liposomes [35,36], dendrimers [37], or therapeutic antibodies targeting the transferrin receptor for receptor-mediated transcytosis [38] While these approaches have shown varying degrees of potential for clinical translation, they do not utilize putative membrane transporters that are functionally expressed at the BBB and, will not be discussed in this review
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