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

TitleTransport Mechanisms at the Blood-Brain Barrier and in Cellular Compartments of the Neurovascular Unit: Focus on CNS Delivery of Small Molecule Drugs.
Publication TypeJournal Article
Year of Publication2022
AuthorsRonaldson PT, Davis TP
JournalPharmaceutics
Volume14
Issue7
Date Published2022 Jul 20
ISSN1999-4923
Abstract

Ischemic stroke is a primary origin of morbidity and mortality in the United States and around the world. Indeed, several research projects have attempted to discover new drugs or repurpose existing therapeutics to advance stroke pharmacotherapy. Many of these preclinical stroke studies have reported positive results for neuroprotective agents; however, only one compound (3K3A-activated protein C (3K3A-APC)) has advanced to Phase III clinical trial evaluation. One reason for these many failures is the lack of consideration of transport mechanisms at the blood-brain barrier (BBB) and neurovascular unit (NVU). These endogenous transport processes function as a "gateway" that is a primary determinant of efficacious brain concentrations for centrally acting drugs. Despite the knowledge that some neuroprotective agents (i.e., statins and memantine) are substrates for these endogenous BBB transporters, preclinical stroke studies have largely ignored the role of transporters in CNS drug disposition. Here, we review the current knowledge on specific BBB transporters that either limit drug uptake into the brain (i.e., ATP-binding cassette (ABC) transporters) or can be targeted for optimized drug delivery (i.e., solute carrier (SLC) transporters). Additionally, we highlight the current knowledge on transporter expression in astrocytes, microglia, pericytes, and neurons with an emphasis on transport mechanisms in these cell types that can influence drug distribution within the brain.

DOI10.3390/pharmaceutics14071501
Alternate JournalPharmaceutics
PubMed ID35890396
PubMed Central IDPMC9324459
Grant ListR01 DA051812 / DA / NIDA NIH HHS / United States
R01 NS084941 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Thomas P Davis, PhD
Patrick T Ronaldson, PhD, FAAPS