Transporters at CNS Barrier Sites: Obstacles or Opportunities for Drug Delivery?

Abstract

The blood-brain barrier (BBB) and blood-cerebrospinal fluid (BCSF) barriers are critical determinants of CNS homeostasis. Additionally, the BBB and BCSF barriers are formidable obstacles to effective CNS drug delivery. These brain barrier sites express putative influx and efflux transporters that precisely control permeation of circulating solutes including drugs. The study of transporters has enabled a shift away from “brute force” approaches to delivering drugs by physically circumventing brain barriers towards chemical approaches that can target specific compounds of the BBB and/or BCSF barrier. However, our understanding of transporters at the BBB and BCSF barriers has primarily focused on understanding efflux transporters that efficiently prevent drugs from attaining therapeutic concentrations in the CNS. Recently, through the characterization of multiple endogenously expressed uptake transporters, this paradigm has shifted to the study of brain transporter targets that can facilitate drug delivery (i.e., influx transporters). Additionally, signaling pathways and trafficking mechanisms have been identified for several endogenous BBB/BCSF transporters, thereby offering even more opportunities to understand how transporters can be exploited for optimization of CNS drug delivery. This review presents an overview of the BBB and BCSF barrier as well as the many families of transporters functionally expressed at these barrier sites. Furthermore, we present an overview of various strategies that have been designed and utilized to deliver therapeutic agents to the brain with a particular emphasis on those approaches that directly target endogenous BBB/BCSF barrier transporters.

Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells

“…1). The following efflux transporters are expressed in neurons 1,[10][11][12] : the ATP-binding cassette transporter A1 (ABCA1), which eliminates cholesterol; P-glycoprotein (P-gp), which eliminates various anticancer drugs, hydrophobic cations, and neutral compounds; and multidrug resistanceassociated protein 1, which eliminates conjugates of glutathione, sulfate, and glucuronic acid. These efflux transporters are expressed at lower levels under normal conditions because neurons are nonproliferative cells, show low metabolic capacity, and minimally produce unnecessary compounds in the intracellular space.…”

“…Thus, such membrane transporters are recognized as "physiological" transporters that play a key role as the regulatory system of neurotransmission. On the other hand, efflux transporters are also expressed in neurons 1) and involved in pumping out intracellularly invasive xenobiotics and intracellularly produced metabolites to the extracellular space (Fig. 1).…”

Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury

“…Considerable research has focused on studying mechanisms that limit endothelial membrane transport by describing the role of P-gp in restricting drug uptake from the systemic circulation (Hartz and Bauer, 2010; Tournier et al 2011; Slosky et al 2013; Sanchez-Covarrubias et al 2014); however, clinical trials targeting P-gp with small molecule inhibitors have been unsuccessful in improving pharmacotherapy due to inhibitor toxicity and/or enhanced global tissue penetration of drugs (Potschka, 2010; Kalvass et al 2011; Palmeira et al 2012). An alternative approach for optimizing delivery of drugs across the endothelial plasma membrane is to focus on BBB transporters that are involved in cellular uptake of drugs.…”

P-glycoprotein Trafficking as a Therapeutic Target to Optimize CNS Drug Delivery

“…Arrows indicate the proposed direction of substrate transport. (Adapted from (Sanchez-Covarrubias et al, 2014)…”