ABC efflux transporters at blood-central nervous system barriers and their implications for treating spinal cord disorders

Abstract

The barriers present in the interfaces between the blood and the central nervous system form a major hurdle for the pharmacological treatment of central nervous system injuries and diseases. The family of ATP-binding cassette (ABC) transporters has been widely studied regarding efflux of medications at blood-central nervous system barriers. These efflux transporters include P-glycoprotein (abcb1), 'breast cancer resistance protein' (abcg2) and the various 'multidrug resistance-associated proteins' (abccs). Understanding which efflux transporters are present at the blood-spinal cord, blood-cerebrospinal fluid and cerebrospinal fluid-spinal cord barriers is necessary to determine their involvement in limiting drug transfer from blood to the spinal cord tissue. Recent developments in the blood-brain barrier field have shown that barrier systems are dynamic and the profile of barrier defenses can alter due to conditions such as age, disease and environmental challenge. This means that a true understanding of ABC efflux transporter expression and localization should not be one static value but instead a range that represents the complex patient subpopulations that exist. In the present review, the blood-central nervous system barrier literature is discussed with a focus on the impact of ABC efflux transporters on: (i) protecting the spinal cord from adverse effects of systemically directed drugs, and (ii) limiting centrally directed drugs from accessing their active sites within the spinal cord.

Keywords: ABC transporters; ATP-binding cassette; BCRP; MRP; P-glycoprotein; PGP; blood-brain barrier; blood-spinal cord barrier; efflux; spinal cord injury.

Figure 1

Interfaces between the blood and the central nervous system (CNS). The barriers/interfaces that separate molecular transport from the systemic circulation and the CNS are summarized, in the context of the human. a) The interface in the ventricle that separates molecules in the cerebrospinal fluid (CSF) and the brain. This interface is termed the ependyma in the adult and has ventricular ependymal barrier cells (blue outline, white fill) separated by gap junctions allowing unhindered paracellular exchange. In the developing fetus the cells of this barrier, termed the neuroepithelium, are held together tightly by ‘strap junctions’ limiting paracellular transfer allowing molecules to access the brain by transcellular transport. b) The barrier between the circulation and the CSF at the choroid plexus epithelium (BCSFB). The endothelial cells of blood vessels (red outline, white fill) are largely fenestrated with epithelial cells of the choroid plexus (pink fill) held together by tight junctions preventing paracellular transfer. c). The layer of meninges that surrounds both the brain (B) and spinal cord (SC). This contains the dura (D), dural boarder cells (DB), arachnoid cells (A), pial cells (P), basement membrane (BM) and glial limitans (GL). Tight junctions exist in the arachnoid cell layer preventing paracellular transfer from molecules exiting the fenestrated blood vessels in the dural layers from accessing the arachnoid space CSF. Tight junctions also exist at the blood vessels within the pial cell layer, preventing paracellular transfer into the arachnoid CSF. d) The barriers between the blood and brain (blood brain barrier proper; BBB) and the blood and spinal cord (blood spinal cord barrier proper, BSCB). The endothelial cells of the blood vessels (red outline, white fill) are held together by tight junctions preventing paracellular transfer. Pericytes (purple fill) and astrocytes (green fill) line the outside of the barrier on the CNS side. e) The central canal of the spinal cord with ependymal cells separating CSF from spinal tissue. Arrows indicate likely routes of molecular transfer. The present figure was adapted from previous illustrations (Ranson, 1959; Saunders et al., 2016) with morphological accuracy determined from multiple studies (Brightman and Reese, 1969; Møllgård and Saunders, 1975; Nabeshima et al., 1975; Bruni and Reddy, 1987; Møllgård et al., 1987; Vandenabeele et al., 1996; Zhong et al., 2008; Daneman et al., 2010b; Garbuzova-Davis et al., 2012; Brøchner et al., 2015; Whish et al., 2015).