Organic Cation Transporter (OCT/OCTN) Expression at Brain Barrier Sites: Focus on CNS Drug Delivery

Abstract

Therapeutic delivery to the central nervous system (CNS) continues to be a considerable challenge in the pharmacological treatment and management of neurological disorders. This is primarily due to the physiological and biochemical characteristics of brain barrier sites (i.e., blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB)). Drug uptake into brain tissue is highly restricted by expression of tight junction protein complexes and adherens junctions between brain microvascular endothelial cells and choroid plexus epithelial cells. Additionally, efflux transport proteins expressed at the plasma membrane of these same endothelial and epithelial cells act to limit CNS concentrations of centrally acting drugs. In contrast, facilitated diffusion via transporter proteins allows for substrate-specific flux of molecules across the plasma membrane, directing drug uptake into the CNS. Organic Cation Transporters (OCTs) and Novel Organic Cation Transporters (OCTNs) are two subfamilies of the solute carrier 22 (SLC22) family of proteins that have significant potential to mediate delivery of positively charged, zwitterionic, and uncharged therapeutics. While expression of these transporters has been well characterized in peripheral tissues, the functional expression of OCT and OCTN transporters at CNS barrier sites and their role in delivery of therapeutic drugs to molecular targets in the brain require more detailed analysis. In this chapter, we will review current knowledge on localization, function, and regulation of OCT and OCTN isoforms at the BBB and BCSFB with a particular emphasis on how these transporters can be utilized for CNS delivery of therapeutic agents.

Keywords: Blood–Brain Barrier (BBB); Blood–Cerebrospinal Fluid Barrier (BCSFB); Brain parenchymal transporters; CNS drug delivery; Organic cation transport.

Fig. 1

Structure of CNS barriers. (a) Blood–brain barrier composed of endothelial cells lining the systemic circulation expressing numerous tight junction protein complexes and adherens junctions (green) regulated by other cells within the neurovascular unit including the astrocytes (purple), neurons (yellow), microglia (blue), and pericytes (orange). (b) Blood–cerebrospinal fluid barrier composed of choroid plexus epithelial cells (blue) expressing tight junction protein complexes to regulated molecular passage from the fenestrated capillaries into the cerebrospinal fluid (Created with biorender.com)

Fig. 2

Proposed localization of OCT and OCTN transporters at the BBB. (a) Based on previous studies, various OCT and OCTN isoforms have been detected in brain microvessel endothelial cells (Created with biorender.com). (b) Fluorescence confocal microscopy data from our laboratory has shown that Oct1 is expressed in isolated microvessels from the brain of Sprague-Dawley rats. Green = Oct1; Blue = DAPI. Scale bar = 4 μm (Adapted from Brzica et al. J Cent Nerv Syst Dis. 9:1179573517693802, 2017)

Fig. 3

Proposed localization of OCT and OCTN transporters at the BCSFB (Created with biorender.com)

Fig. 4

Proposed localization of OCT and OCTN transporters in neurons and in glial cells within brain parenchyma (Created with biorender.com)