Pharmacology of the Blood Brain Barrier: Targeting CNS Disorders

1. Auflage 2014
ISBN: 978-0-12-800338-1
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 71, 512 Seiten

Reihe: Advances in Pharmacology

This new volume of Advances in Pharmacology presents pharmacology of the blood brain barrier, focusing on targeting CNS disorders. With a variety of chapters and the best authors in the field, the volume is an essential resource for pharmacologists, immunologists and biochemists alike. - Contributions from the best authors in the field - An essential resource for pharmacologists, immunologists, and biochemists

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Chapter One ABC Transporter Regulation by Signaling at the Blood–Brain Barrier
Relevance to Pharmacology
David S. Miller1    Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA
1 Corresponding author: email address: [e-mail] Abstract
Brain capillary endothelial cells express multiple ATP-binding cassette transport proteins on the luminal, blood-facing, plasma membrane. There these transporters function as ATP-driven efflux pumps for xenobiotics and endogenous metabolites, providing an important element of the barrier. When the transporters limit neurotoxicant entry into the central nervous system (CNS), they are neuroprotective; when they limit therapeutic drug entry, they are obstacles to drug delivery to treat CNS diseases. Certainly, changes in the transporter expression and transport activity can have a profound effect on CNS pharmacotherapy, with increased transport activity reducing drug access to the brain and vice versa. Here, I review the signals that alter transporter expression and transport function with an emphasis on P-glycoprotein, MRP2, and breast cancer resistance protein (ABCG2) (BCRP), the efflux transporters for which we have the most detailed picture of regulation. Recent work shows that transporter protein expression can be upregulated in response to inflammatory and oxidative stress, therapeutic drugs, diet, and persistent environmental pollutants; as a consequence, drug delivery to the brain is reduced. For many of these stimuli, the transcription factor, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B), appears to be involved. However, NF-?B activation and nuclear translocation is often initiated by upstream signaling. In contrast, basal transport activity of P-glycoprotein and BCRP can be reduced through complex signaling pathways. Targeting such signals provides opportunities to rapidly and reversibly increase brain accumulation of drugs that are transporter substrates. The extent to which such signaling-based strategies can be utilized in the clinic remains to be seen. Keywords P-glycoprotein Multidrug resistance-associated proteins Breast-cancer-related protein Altered expression Reduced transport activity Signaling Abbreviations ABC ATP-binding cassette AEDs antiepileptic drugs AhR arylhydrocarbon receptor Akt protein kinase B BCRP breast cancer resistance protein (ABCG2) CAR constitutive androstane receptor CNS central nervous system COX-2 cyclooxygenase-2 E2 17-ß-estradiol EP-1 prostaglandin E2 receptor ER estrogen receptor ET-1 endothelin-1 GR glucocorticoid receptor GSK-3ß glycogen synthase kinase 3 beta iNOS inducible nitric oxide synthase MRP multidrug resistance-associated protein (ABCC subfamily) NF-?B nuclear factor kappa-light-chain-enhancer of activated B cells NMDA N-methyl-d-aspartate Nrf2 nuclear factor (erythroid-derived 2)-like 2 PI3-K phosphatidylinositide 3-kinase PKCß1 protein kinase C isoform ß1 PTEN phosphatase and tensin homolog PXR pregnane X receptor S1P sphingosine-1-phosphate S1PR1 sphingosine-1-phosphate receptor 1 TNF-a tumor necrosis factor-a VDR vitamin D receptor VEGF vascular endothelial growth factor 1 Introduction
Biological signaling refers to the transfer of information within organisms, tissues, and cells and over the dimensions of space and time. In essence, this flow of information allows the various parts of multicellular organisms and cells to communicate with each other and be aware of alterations in their extracellular and intracellular microenvironment so that they can respond appropriately and preserve homeostasis. In general, cells sense changes in their external environment as altered levels of nutrients, toxicants, stressors, and signaling molecules that might be receptor ligands or hormones. Cells then change the form of the message and respond by altered cellular function, e.g., altered pattern of gene expression, activation or inhibition of metabolism, release of additional signals. On the one hand, cell signaling is a part of a complex system of communication that governs basic cell, tissue, and organismal activities and coordinates actions and responses. On the other hand, aberrant signaling is the mechanistic basis for many diseases, including cancer and diabetes. The traditional concept of biological signaling has invoked discrete pathways. However, we have long known that these pathways intersect, that the intersections are numerous and that the connected pathways can form complex signaling networks. It has become clear that a full understanding of cell function and regulation requires knowledge of the major signaling pathways, the underlying structure of signaling networks, the emergent features of the networks, and the ways by which changes in network structure affect the transmission and flow of information over space and time. Whether we are considering genetic or metabolic networks, the existence of complex network structures within cells has important implications. First, network structure indicates that multiple paths are available for signals to flow from point A to point B (Janes & Lauffenberger, 2013). This implies that the path taken and the integrated response can be context-dependent, i.e., determined by what else may be happening within the cell or tissue. For example, such complexity has been shown to be the basis for interaction between growth factor and proinflammatory signaling (Janes & Lauffenberger, 2013). Second, complex multicomponent signaling pathways provide opportunities for feedback, signal amplification, and interactions involving multiple signals and signaling pathways. Third, added complexity comes from the fact that signaling networks have an intrinsic spatial component, since signals often must cross multiple cellular domains, e.g., plasma membrane, cytoplasm, and nucleus. Cellular signaling networks come in two flavors: genetic and metabolic. Genetic networks are characterized by a structure that is focused on gene expression and thus leads to alterations in the mRNA and/or protein expression of key components; these in turn affect cell function (Boucher & Jenna, 2013). Because of the time required for transcription/translation, responses mediated through genetic networks occur over timescales of tens of minutes to hours. Metabolic networks consist of proteins that function as switches turning off or on other key enzymes, channels, and transporters. They provide the capability to rapidly alter cell function, often within seconds or minutes. They also may be key elements of genetic networks, providing intermediate connections among, e.g., spatially removed elements (Janes & Lauffenberger, 2013). As shown below, it is clear that ATP-binding cassette (ABC) transporters at the blood–brain barrier respond to both genomic and nongenomic signals, resulting in changes in protein expression and activity (genomic) and in transport activity but not in protein expression (nongenomic or metabolic). 2 ABC Transporters at the Blood–Brain Barrier
This review is focused on the regulation of blood–brain barrier transporters that are members of the ABC family and that handle foreign chemicals (xenobiotics). The human genome contains 49 genes encoding ABC transporters, divided into seven different subfamilies, A–G, based on their evolutionary divergence (Moitra & Dean, 2011). The defining molecular signature of ABC family members is the presence of several consensus sequences including two ATP-binding motifs (Walker A and Walker B), as well as the ABC signature C motif (ALSGGQ) (Kuhnline Sloan et al., 2012). ABC family members include proteins that function as ATP-driven transporters on both surface and intracellular membranes, ion channels, and receptors. Mutations in some of the ABC genes result in genetic disorders such as cystic fibrosis (ABCC7, CFTR, the Cystic Fibrosis Transmembrane Regulator, a chloride channel), Dubin Johnson's syndrome (ABCC2, MRP2, a metabolite and drug transporter), progressive familial intrahepatic cholestasis (ABCB11, BSEP, a bile salt efflux pump), and retinal degeneration (ABCA4, a lipid flippase) (Moitra & Dean, 2011). For vertebrates, three ABC subfamilies, B, C, and G, contain...