Evolutionarily conserved roles for blood-brain barrier xenobiotic transporters in endogenous steroid partitioning and behavior
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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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Drosophila has an evolutionarily conserved blood-brain barrier (BBB).
“Although Drosophila has an evolutionarily conserved blood-brain barrier (BBB), treatment with both cpds suppressed mitochondrial aggregates of larval dopaminergic neurons caused by PINK1 inactivation, suggesting that these drugs go through at least the Drosophila BBB (Figures 5C–5E) (Davis et al., 2019, Hindle et al., 2017, Limmer et al., 2014, Mayer et al., 2009, Zhang et al., 2018).”
From A Cell-Based High-Throughput Screening Identified Two Compounds that Enhance PINK1-Parkin Signaling (2020) · cites this paper as Hindle et al., 2017
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References 69 · Cited by 74
- Authors
- Hindle, S. J., Munji, R. N., Dolghih, E., Gaskins, G., Orng, S., Ishimoto, H., Soung, A., DeSalvo, M., Kitamoto, T., Keiser, M. J., Jacobson, M. P., Daneman, R., & Bainton, R. J.
- Affiliations
- University of California, San Francisco (US)
- Nagoya University (JP)
- University of Iowa (US)
- Corresponding author
- Daneman, Richard
- Bainton, Roland J.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 21
- Issue
- 5
- Pages
- 1304-1316
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5774027
- OpenAlex
- W2611618612
- Cited by
- 74
- References
- 69
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 8 · 2023: 8 · 2022: 5 · 2021: 9 · 2020: 14 · 2019: 6 · 2018: 7
- FWCI
- 3.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- UCSF Department of Clinical Pharmacology and Therapeutics (GM007546)
- Department of Anesthesia and Perioperative Care (GM008440)
- NIH T32 (GM008440)
- NIH (R01GM081863, R21NS082856, GM111126)
- NIEHS (R21 ES021412)
- UCSF Department of Anesthesia and Perioperative Care
- UCSF Program for Breakthrough Biomedical Research
- NIH SBIR (GM093456)
- Glenn Foundation
- iPQB Bioinformatics (Training Grant)
- NSF (IOS1352882)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- blood-brain barrier, MDR1, P-glycoprotein, efflux pumps, endogenous steroids, sleep behavior, anxiety, drug-drug interactions, Drosophila, mice, evolutionary conservation
- MeSH terms
- Aldosterone, Animals, Behavior, Animal, Binding Sites, Blood-Brain Barrier, Brain, Central Nervous System, Drosophila, Ecdysterone, Biological Evolution, Male, Gonadal Steroid Hormones, Substrate Specificity, Xenobiotics, Cyclosporine, ATP Binding Cassette Transporter, Subfamily B, ATP Binding Cassette Transporter, Subfamily B, Member 1, Drosophila Proteins, Rats, Molecular Docking Simulation, Databases, Chemical
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