Abstract:
:The blood-brain barrier (BBB) serves as a protective mechanism for the brain by preventing entry of potentially harmful substances from free access to the central nervous system (CNS). Tight junctions present between the brain microvessel endothelial cells form a diffusion barrier, which selectively excludes most blood-borne substances from entering the brain. Astrocytic end-feet tightly ensheath the vessel wall and appear to be critical for the induction and maintenance of the barrier properties of the brain capillary endothelial cells. Because of these properties, the BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are substrates for drug efflux transporters such as P-glycoprotein (Pgp), multidrug resistance proteins (MRPs) or organic anion transporting polypeptides (OATPs) that are expressed at brain capillary endothelial cells and/or astrocytic end-feet and are key elements of the molecular machinery that confers the special permeability properties to the BBB. The combined action of these carrier systems results in rapid efflux of xenobiotics from the CNS. The objective of this review is to summarize transporter characteristics (cellular localization, specificity, regulation, and potential inhibition) for drug efflux transport systems identified in the BBB and blood-cerebrospinal fluid (CSF) barrier. A variety of experimental approaches available to ascertain or predict the impact of efflux transport on brain access of therapeutic drugs also are described and critically discussed. The potential impact of efflux transport on the pharmacodynamics of agents acting in the CNS is illustrated. Furthermore, the current knowledge about drug efflux transporters as a major determinant of multidrug resistance of brain diseases such as epilepsy is reviewed. Finally, we summarize strategies for modulating or by-passing drug efflux transporters at the BBB as novel therapeutic approaches to drug-resistant brain diseases.
journal_name
Prog Neurobioljournal_title
Progress in neurobiologyauthors
Löscher W,Potschka Hdoi
10.1016/j.pneurobio.2005.04.006keywords:
subject
Has Abstractpub_date
2005-05-01 00:00:00pages
22-76issue
1eissn
0301-0082issn
1873-5118pii
S0301-0082(05)00044-4journal_volume
76pub_type
杂志文章,评审abstract::Microglia, macrophages that reside in the brain, can express at least 12 different ion channels, including voltage-gated proton channels. The properties of H+ currents in microglia are similar to those in other phagocytes. Proton currents are elicited by depolarizing the membrane potential, but activation also depends...
journal_title:Progress in neurobiology
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journal_title:Progress in neurobiology
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journal_title:Progress in neurobiology
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journal_title:Progress in neurobiology
pub_type: 杂志文章,评审
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journal_title:Progress in neurobiology
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journal_title:Progress in neurobiology
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journal_title:Progress in neurobiology
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更新日期:2014-02-01 00:00:00
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journal_title:Progress in neurobiology
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journal_title:Progress in neurobiology
pub_type: 杂志文章,评审
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journal_title:Progress in neurobiology
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doi:10.1016/j.pneurobio.2018.09.002
更新日期:2019-05-01 00:00:00
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journal_title:Progress in neurobiology
pub_type: 杂志文章,评审
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journal_title:Progress in neurobiology
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更新日期:2017-01-01 00:00:00
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journal_title:Progress in neurobiology
pub_type: 杂志文章,评审
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journal_title:Progress in neurobiology
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journal_title:Progress in neurobiology
pub_type: 杂志文章,评审
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更新日期:1996-02-01 00:00:00
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journal_title:Progress in neurobiology
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