Journal article
Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior
Cell reports (Cambridge), Vol.21(5), pp.1304-1316
10/31/2017
DOI: 10.1016/j.celrep.2017.10.026
PMCID: PMC5774027
PMID: 29091768
Abstract
Central nervous system (CNS) chemical protection depends upon discrete control of small-molecule access by the blood-brain barrier (BBB). Curiously, some drugs cause CNS side-effects despite negligible transit past the BBB. To investigate this phenomenon, we asked whether the highly BBB-enriched drug efflux transporter MDR1 has dual functions in controlling drug and endogenous molecule CNS homeostasis. If this is true, then brain-impermeable drugs could induce behavioral changes by affecting brain levels of endogenous molecules. Using computational, genetic, and pharmacologic approaches across diverse organisms, we demonstrate that BBB-localized efflux transporters are critical for regulating brain levels of endogenous steroids and steroid-regulated behaviors (sleep in Drosophila and anxiety in mice). Furthermore, we show that MDR1-interacting drugs are associated with anxiety-related behaviors in humans. We propose a general mechanism for common behavioral side effects of prescription drugs: pharmacologically challenging BBB efflux transporters disrupts brain levels of endogenous substrates and implicates the BBB in behavioral regulation.
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•Blood-brain barrier ABC drug transporters regulate CNS levels of steroids•Blood-brain barrier ABC drug transporters regulate whole animal behavior•Stress-related drug side-effects are associated with the ABC drug transporter Mdr1•Competitive Mdr1 drug/steroid interactions may shed light on adverse drug reactions
Hindle et al. shed light on the curious finding that some drugs cause behavioral side-effects despite negligible access into the brain. These authors propose a unifying hypothesis that links blood-brain barrier drug transporter function and brain access of circulating steroids to common CNS adverse drug responses.
Details
- Title: Subtitle
- Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior
- Creators
- Samantha J Hindle - Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USARoeben N Munji - Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USAElena Dolghih - Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USAGarrett Gaskins - Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USASouvinh Orng - Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USAHiroshi Ishimoto - Division of Biological Science, Graduate School of Science, Nagoya University, JapanAllison Soung - Department of Anatomy, University of California San Francisco, San Francisco, CA, USAMichael DeSalvo - Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USAToshihiro Kitamoto - Department of Anesthesia, University of Iowa, Iowa City, Iowa, USAMichael J Keiser - Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USAMatthew P Jacobson - Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USARichard Daneman - Department of Anatomy, University of California San Francisco, San Francisco, CA, USARoland J Bainton - Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.21(5), pp.1304-1316
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2017.10.026
- PMID
- 29091768
- PMCID
- PMC5774027
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- name: UCSF Department of Clinical Pharmacology and Therapeutics, award: GM007546; name: Department of Anesthesia and Perioperative Care, award: GM008440; name: NIH T32, award: GM008440; name: NIH, award: R01GM081863, R21NS082856; DOI: 10.13039/100000066, name: NIEHS, award: R21 ES021412; name: UCSF Department of Anesthesia and Perioperative Care; name: UCSF Program for Breakthrough Biomedical Research; name: NIH SBIR, award: GM093456; DOI: 10.13039/100001642, name: Glenn Foundation; name: iPQB Bioinformatics, award: Training Grant; name: NSF, award: IOS1352882; name: NIH, award: GM111126
- Language
- English
- Date published
- 10/31/2017
- Academic Unit
- Iowa Neuroscience Institute; Anesthesia; Neuroscience and Pharmacology
- Record Identifier
- 9984006345902771
Metrics
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