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Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior.
Hindle, Samantha J; Munji, Roeben N; Dolghih, Elena; Gaskins, Garrett; Orng, Souvinh; Ishimoto, Hiroshi; Soung, Allison; DeSalvo, Michael; Kitamoto, Toshihiro; Keiser, Michael J; Jacobson, Matthew P; Daneman, Richard; Bainton, Roland J.
Afiliación
  • Hindle SJ; Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.
  • Munji RN; Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA; Division of Clinical Pharmacology and Experimental Therapeutics, University of California San Francisco, San Francisco, CA, USA; Department of Anatomy, University of California San Franci
  • Dolghih E; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
  • Gaskins G; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francis
  • Orng S; Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.
  • Ishimoto H; Division of Biological Science, Graduate School of Science, Nagoya University, Japan.
  • Soung A; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
  • DeSalvo M; Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA.
  • Kitamoto T; Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.
  • Keiser MJ; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA; Institute for Neurodegenerative Disease, University of California San Francisco, San Francisco, CA, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francis
  • Jacobson MP; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
  • Daneman R; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA; Department of Pharmacology, University of California San Diego, La Jolla, CA, USA. Electronic address: rdaneman@ucsd.edu.
  • Bainton RJ; Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, CA, USA. Electronic address: roland.bainton@ucsf.edu.
Cell Rep ; 21(5): 1304-1316, 2017 Oct 31.
Article en En | MEDLINE | ID: mdl-29091768
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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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Hormonas Esteroides Gonadales / Barrera Hematoencefálica / Xenobióticos / Sistema Nervioso Central Límite: Animals Idioma: En Revista: Cell Rep Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Hormonas Esteroides Gonadales / Barrera Hematoencefálica / Xenobióticos / Sistema Nervioso Central Límite: Animals Idioma: En Revista: Cell Rep Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos