Evidence map›Paper›PMID 18560012›Full record

ReviewPharmacological reviews2008

Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy.

David S Miller, Björn Bauer, Anika M S Hartz

Open access · greenAbstract readReview
PubMed Full text at PMC Publisher
In one paragraph

Review in Pharmacological reviews, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 172 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
172citing papers in PubMed, 1 pooled it
13.3field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

172 citing papers in PubMed, 1 synthesis or guideline pooled it, 384 citations in OpenAlex.

  1. Role ofAmerican journal of men's health
    Pooled it
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  14. Comparative analysis of the uptake of the HFluids and barriers of the CNS · 2025
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112 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

3 authors at 3 institutions in 1 country.

David S MillerLaboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. miller@niehs.nih.gov
Björn Bauer
Anika M S Hartz
National Institute of Environmental Health Sciences · USNational Institutes of Health · USUniversity of Minnesota, Duluth · US

Funding

CELLULAR MECHANISMS OF XENOBIOTIC TRANSPORTZ01ES080048 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI MILLER, DAVID · 1991 to 2008
$2.0M
Membrane Transporters For AiIDS Antiviral DrugsZ01ES080060 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI MILLER, DAVID · 2000 to 2008
$1.1M
Intramural NIH HHS Z01 ES080048Intramural NIH HHS Z01 ES080060Intramural NIH HHS Z99 ES999999
6 · The paper itself

Abstract

Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.

Indexed as

AnimalsATP Binding Cassette Transporter, Subfamily B, Member 1Biological TransportBlood-Brain BarrierBrainBrain IschemiaBrain NeoplasmsCentral Nervous System AgentsEncephalitisHIV InfectionsHumansImmunity, InnateMicrocirculationNeurodegenerative DiseasesSeizuresSignal TransductionATP Binding Cassette Transporter, Subfamily B, Member 1Central Nervous System Agents

Identifiers

PMID18560012
PMCPMC2634288
OpenAlexW2163967054

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.