CNS Drug Delivery in Stroke: Organic Anion Transporting Polypeptide (Oatp)-Mediated Delivery of Atorvastatin is a Requirement for Neuroprotection

Abstract

Stroke is the 5th most common cause of death and the leading cause of long-term disability in the United States. Drug development for ischemic stroke is challenging as evidenced by the lack of therapeutics that have advanced beyond a phase III clinical trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical stroke studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system (CNS) drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit (NVU). Such knowledge will permit the innate biology of the BBB/NVU to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. At present, FDA-approved drug treatments for ischemic stroke are limited to recombinant-tissue plasminogen activator (r- tPA; Alteplase, Activase®), which is not available to many patients due to its short therapeutic window (i.e., 4.5 h) and clinically significant risk of bleeding complications. Although recanalization in infarcted brain tissue is critical, the adverse events associated with r-tPA treatment are not trivial and can promote neurologic and vascular injury, thus exacerbating post-stroke neurological deficits. Indeed, stroke patients still suffer from debilitating neurocognitive deficits despite the advent of reperfusion therapies. This indicates a need for discovery of stroke therapeutics and/or development of new pharmacological strategies for neuroprotection that are both safe and effective; however, the clinical utility of such compounds is highly dependent upon efficient transport from systemic circulation into ischemic brain tissue. Indeed, the BBB possess several endogenous transporters that can be targeted to promote delivery of neuroprotective agents into the CNS. It is noteworthy that most studies on BBB transporters in stroke that have been published to date have primarily focused on transport of solutes involved in stroke pathogenesis such as ions and glucose. The next frontier of transporter biology will be to discern functional properties of transport proteins at the BBB that can be targeted to optimize CNS drug delivery. Examples of such uptake transporters include organic anion transporting polypeptides (OATPs in humans; Oatps in rodents). Of note, small molecule drugs that have neuroprotective properties and are known substrates for OATPs/Oatps include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins). Data from preclinical and clinical stroke studies suggest that statins possess properties that render them effective as stroke therapeutics. Future development of neuroprotective treatment strategies for stroke with statins will depend upon an improved understanding of discrete BBB transport mechanisms that enable these drugs to achieve effective brain concentrations. Information derived from BBB transport studies can be extended to inform discovery of new drugs developed specifically for ischemic stroke treatment. An examination of the chemical properties of statins that enable these drugs to be specifically transported by OATPs/Oatps can inform structure-based drug design of such novel therapeutics. Identification of therapeutics that both confer beneficial effects in stroke and are substrates for endogenous BBB transporters presents a translational opportunity to advance stroke pharmacotherapy. Overall, endogenous transporters at the brain microvascular endothelium must be studied in detail to discern the optimal time course and the most effective routes of administration for neuroprotective drugs. Furthermore, a consideration of biological variables (i.e., age, sex, comorbid conditions such as obesity, diabetes mellitus, atrial fibrillation, hypertension, etc.) that affect stroke outcomes should be incorporated into future experimentation to develop a better understanding of BBB transport mechanisms and, ultimately, improved stroke treatment paradigms.