Evolutionarily conserved roles for blood-brain barrier xenobiotic transporters in endogenous steroid partitioning and behavior
Evolutionarily conserved roles for blood-brain barrier xenobiotic transporters in endogenous steroid partitioning and behavior
Summary Optimal brain function depends upon efficient control over the brain entry of blood components; this is provided by the blood-brain barrier (BBB). Curiously, some brain-impermeable drugs can still cause behavioral side effects. To investigate this phenomenon, we asked whether the promiscuous drug efflux transporter Mdr1 has dual functions in transporting drugs and endogenous molecules. If this is true, brain-impermeable drugs may cause behavioral side effects 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. Abbreviations20-E20-hydroxyecdysoneABCATP-binding CassetteADRsAdverse Drug ReactionsBBBBlood-Brain BarrierBVECbrain vascular endothelial cellsCNScentral nervous systemEcRLBDecdysone receptor ligand binding domainEFenrichment factorMDRmultidrug resistantRhoBRhodamine BSPGSubperineurial glia
Bainton Roland J.、Munji Roeben N.、Dolghih Elena、Ishimoto Hiroshi、Daneman Richard、DeSalvo Michael、Soung Allison、Hindle Samantha J.、Jacobson Matthew P.、Orng Souvinh、Kitamoto Toshihiro、Gaskins Garrett、Keiser Michael J.
Department of Anesthesia and Perioperative Care, University of California San FranciscoDepartment of Anesthesia and Perioperative Care, University of California San Francisco||Division of Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco||Department of Anatomy, University of California San Francisco||Department of Pharmacology, University of California San DiegoDepartment of Pharmaceutical Chemistry, University of California San FranciscoDivision of Biological Science, Graduate School of Science, Nagoya UniversityDepartment of Anatomy, University of California San Francisco||Department of Pharmacology, University of California San DiegoDepartment of Anesthesia and Perioperative Care, University of California San FranciscoDepartment of Anatomy, University of California San Francisco||Department of Pharmacology, University of California San DiegoDepartment of Anesthesia and Perioperative Care, University of California San FranciscoDepartment of Pharmaceutical Chemistry, University of California San FranciscoDepartment of Anesthesia and Perioperative Care, University of California San FranciscoDepartment of Anesthesia, University of IowaDepartment of Pharmaceutical Chemistry, University of California San Francisco||Institute for Neurodegenerative Disease, University of California San Francisco||Department of Bioengineering and Therapeutic Sciences, University of California San FranciscoDepartment of Pharmaceutical Chemistry, University of California San Francisco||Institute for Neurodegenerative Disease, University of California San Francisco||Department of Bioengineering and Therapeutic Sciences, University of California San Francisco
基础医学生理学
Bainton Roland J.,Munji Roeben N.,Dolghih Elena,Ishimoto Hiroshi,Daneman Richard,DeSalvo Michael,Soung Allison,Hindle Samantha J.,Jacobson Matthew P.,Orng Souvinh,Kitamoto Toshihiro,Gaskins Garrett,Keiser Michael J..Evolutionarily conserved roles for blood-brain barrier xenobiotic transporters in endogenous steroid partitioning and behavior[EB/OL].(2025-03-28)[2025-05-18].https://www.biorxiv.org/content/10.1101/131698.点此复制
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