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

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.

The Role of Immune Dysfunction in Parkinson’s Disease Development

“…Utilizing endogenous transport systems to ferry therapeutic agents across the BBB is an active area of research. This involves designing drugs or drug carriers that can hijack existing transport mechanisms, aiming to enhance the specificity and efficiency of drug delivery while minimizing potential side effects [59]. Peptides that can target specific receptors on the BBB have been investigated for their potential to facilitate drug transport across the barrier.…”

CNSMolGen: A Bidirectional Recurrent Neural Network-Based Generative Model for De Novo Central Nervous System Drug Design

“…1 However, the number of approved drugs targeting these diseases remains limited, partially attributed to the blood−brain barrier (BBB) that prevents the access of drug molecules into the CNS. 2,3 Consequently, the discovery and development of novel and effective drugs for the treatment of human CNS disorders remains a crucial responsibility in the field of pharmaceutical sciences. 4,5 To address this problem, several innovative approaches have been developed and used in CNS drug discovery, including the identification of molecular drug targets 6,7 and drug design aided by either physics-based modeling or deep learning-based artificial intelligence (AI).…”

“…Along with the social construction of population aging, the incidence of CNS disorders, including Alzheimer disease (AD), Parkinson’s disease (PD), and depression, is continuously increasing . However, the number of approved drugs targeting these diseases remains limited, partially attributed to the blood–brain barrier (BBB) that prevents the access of drug molecules into the CNS. , Consequently, the discovery and development of novel and effective drugs for the treatment of human CNS disorders remains a crucial responsibility in the field of pharmaceutical sciences. , …”

Advanced Blood–Brain Barrier Drug Delivery

“…Certain BBB transporters mediate the transport of endogenous ligands or drugs in the brain-to-blood direction, and they are active efflux transporters (AET). In this Special Issue, Ronaldson and Davis [ 13 ] review the major AETs at the BBB—which are transporters derived from both the SLC and ATP-binding cassette (ABC) gene families—and emphasize the differential expression of transporters in the multiple cells that comprise the neuro-vascular unit, including the capillary endothelium, capillary pericyte, the astrocyte endfeet or neuronal endings that contact the capillary basement membrane, and peri-vascular cells such as microglia [ 13 ]. There are seven ABC gene families, ABCA through ABCG, which encompass ~50 transporters.…”

“…There are seven ABC gene families, ABCA through ABCG, which encompass ~50 transporters. The most widely studied ABC transporters at the BBB are p-glycoprotein (ABCB1), breast cancer resistance protein, BCRP (ABCG2), and multidrug resistance protein MRP1-6 (ABCC1-C6) [ 13 ]. SLC transporters also contribute to the active efflux from the brain to blood of ligands and drugs, including members of the SLC21 family (now named the SLCO family), and include OATP1A2, and the mouse homologue, Oatp1a4 [ 13 ].…”