Targeting transporters: promoting blood-brain barrier repair in response to oxidative stress injury

Abstract

The blood-brain barrier (BBB) is a physical and biochemical barrier that precisely regulates the ability of endogenous and exogenous substances to accumulate within brain tissue. It possesses structural and biochemical features (i.e., tight junction and adherens junction protein complexes, influx and efflux transporters) that work in concert to control solute permeation. Oxidative stress, a critical component of several diseases including cerebral hypoxia/ischemia and peripheral inflammatory pain, can cause considerable injury to the BBB and lead to significant CNS pathology. This suggests a critical need for novel therapeutic approaches that can protect the BBB in diseases with an oxidative stress component. Recent studies have identified molecular targets (i.e., putative membrane transporters, intracellular signaling systems) that can be exploited for optimization of endothelial drug delivery or for control of transport of endogenous substrates such as the antioxidant glutathione (GSH). In particular, targeting transporters offers a unique approach to protect BBB integrity by promoting repair of cell-cell interactions at the level of the brain microvascular endothelium. This review summarizes current knowledge in this area and emphasizes those targets that present considerable opportunity for providing BBB protection and/or promoting BBB repair in the setting of oxidative stress. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.

Keywords: Blood–brain barrier; Endothelial cell; Membrane transporter; Multidrug resistance proteins; Organic anion transporting polypeptides; Oxidative stress.

Figure 1

Basic molecular organization of tight junction protein complexes and adherens junctions at the blood-brain barrier. Adapted from Ronaldson and Davis (2012). Curr Pharm Des. 18: 3624–3644.

Figure 2

Endothelial localization of drug transporters known to be involved in transport of therapeutic agents at the blood-brain barrier. Adapted from Ronaldson and Davis (2012). Curr Pharm Des. 18: 3624–3644.

Figure 3

Generation of reactive oxygen species (ROS) in brain microvascular endothelial cells. During disease, mitochondrial superoxide levels increase via NO inhibition of cytochrome complexes and oxidation of reducing equivalents in the electron transport chain. Complex I as well as both sides of complex III (i.e., Qi and Qo sites) are the most common sources of mitochondrial superoxide. Superoxide generated within the intermembrane space of mitochondria can reach the cytosol through voltage-dependent mitochondrial anion channels. Superoxide levels further increase via cyclooxygenase-2, NADPH oxidase, uncoupled eNOS, and infiltrating leukocytes. The resulting high levels of superoxide coupled with the activation of NO-producing eNOS and iNOS increases the probability of peroxynitrite formation. Peroxynitrite-induced cellular damage includes protein oxidation, tyrosine nitration, DNA damage, poly(ADP-ribose) polymerase activation, lipid peroxidation, and mitochondrial dysfunction. Adapted from Thompson and Ronaldson (2014). Adv Pharmacol. 71: 165–209.