Membrane transporters in traumatic brain injury: Pathological, pharmacotherapeutic, and developmental implications

Abstract

Membrane transporters regulate the trafficking of endogenous and exogenous molecules across biological barriers and within the neurovascular unit. In traumatic brain injury (TBI), they moderate the dynamic movement of therapeutic drugs and injury mediators among neurons, endothelial cells and glial cells, thereby becoming important determinants of pathogenesis and effective pharmacotherapy after TBI. There are three ways transporters may impact outcomes in TBI. First, transporters likely play a key role in the clearance of injury mediators. Second, genetic association studies suggest transporters may be important in the transition of TBI from acute brain injury to a chronic neurological disease. Third, transporters dynamically control the brain penetration and efflux of many drugs and their distribution within and elimination from the brain, contributing to pharmacoresistance and possibly in some cases pharmacosensitivity. Understanding the nature of drugs or candidate drugs in development with respect to whether they are a transporter substrate or inhibitor is relevant to understand whether they distribute to their target in sufficient concentrations. Emerging data provide evidence of altered expression and function of transporters in humans after TBI. Genetic variability in expression and/or function of key transporters adds an additional dynamic, as shown in recent clinical studies. In this review, evidence supporting the role of individual membrane transporters in TBI are discussed as well as novel strategies for their modulation as possible therapeutic targets. Since data specifically targeting pediatric TBI are sparse, this review relies mainly on experimental studies using adult animals and clinical studies in adult patients.

Keywords: ATP-binding cassette transporters; Blood-brain barrier; Multidrug resistance; Neurovascular unit; Solute carriers; Traumatic brain injury.

Figure 1.. Simplified schematic highlighting select membrane transporters with suspected roles in modulating brain accumulation and efflux of endogenous and drug substrates in TBI.

Multidrug resistance associated proteins (MRP1; ABCC1), multidrug resistance protein (PGP; ABCB1), the breast cancer resistance protein (BCRP; ABCG2), and organic acid transporters (OATs; solute carriers) on the BBB and blood-CSF barrier, plasma and mitochondrial membranes of the various cells of the neurovascular unit function to pump drugs and endogenous substrates out of the brain. Inhibitors such as probenecid (green) act at MRP1 and OATs (and possibly others), reducing the efflux of organic acid and peptides including glutathione (GSH). Synergistic effects may be achieved by delivering a cysteine (Cys) donors such as N-acetylcysteine (NAC) and probenecid, to enhance both endogenous stores of GSH and provide substrate generation of GSH from cysteine (Cys), glutamate (Glu) and glycine. Genetic associations with TBI outcomes have been reported for ABCB1, ABCC1 and ABCG2.