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1 Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic 1 bioRxiv preprint doi: https://doi.org/10.1101/131698; this version posted April 29, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Evolutionarily conserved roles for blood-brain barrier xenobiotic 2 transporters in endogenous steroid partitioning and behavior 3 4 Samantha J. Hindle1¶, Roeben N. Munji1,2,3,4¶, Elena Dolghih5, Garrett 5 Gaskins5,6,7, Souvinh Orng1, Hiroshi Ishimoto8, Allison Soung3,4, Michael 6 DeSalvo1, Toshihiro Kitamoto9, Michael J. Keiser5,6,7, Matthew P. Jacobson5, 7 Richard Daneman3,4* and Roland J. Bainton1* 8 9 1Department of Anesthesia and Perioperative Care, University of California San 10 Francisco, San Francisco, CA, USA 11 2Division of Clinical Pharmacology and Experimental Therapeutics, University of 12 California San Francisco, San Francisco, CA, USA 13 3Department of Anatomy, University of California San Francisco, San Francisco, 14 CA, USA 15 4Department of Pharmacology, University of California San Diego, La Jolla, CA, 16 USA 17 5Department of Pharmaceutical Chemistry, University of California San 18 Francisco, San Francisco, CA, USA 19 6Institute for Neurodegenerative Disease, University of California San Francisco, 20 San Francisco, CA, USA 21 7Department of Bioengineering and Therapeutic Sciences, University of 22 California San Francisco, San Francisco, CA, USA 1 bioRxiv preprint doi: https://doi.org/10.1101/131698; this version posted April 29, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 23 8Division of Biological Science, Graduate School of Science, Nagoya University, 24 Japan 25 9Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA 26 27 *Correspondence: 28 Dr. Roland J. Bainton, Department of Anesthesia and Perioperative Care, 29 University of California San Francisco, 600 16th Street, S312C Genentech Hall, 30 San Francisco, CA, 91518, USA. Email: [email protected] 31 Dr. Richard Daneman, Department of Pharmacology, University of California San 32 Diego, 9500 Gilman drive, Box 0636, La Jolla, CA, 92093 USA. Email: 33 [email protected] 34 35 ¶Authors contributed equally 36 37 Short title: Blood-Brain Barrier Drug Transporter Regulates Steroids and 38 Behavior 39 40 Abbreviations: 41 20-E, 20-hydroxyecdysone; ABC, ATP-binding Cassette; ADRs, Adverse Drug 42 Reactions; BBB, Blood-Brain Barrier; BVEC, brain vascular endothelial cells; 43 CNS, central nervous system; EcRLBD, ecdysone receptor ligand binding 44 domain; EF, enrichment factor; MDR, multidrug resistant; RhoB, Rhodamine B; 45 SPG, Subperineurial glia. 2 bioRxiv preprint doi: https://doi.org/10.1101/131698; this version posted April 29, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 46 47 Summary 48 Optimal brain function depends upon efficient control over the brain entry of 49 blood components; this is provided by the blood-brain barrier (BBB). Curiously, 50 some brain-impermeable drugs can still cause behavioral side effects. 51 52 To investigate this phenomenon, we asked whether the promiscuous drug efflux 53 transporter Mdr1 has dual functions in transporting drugs and endogenous 54 molecules. If this is true, brain-impermeable drugs may cause behavioral side 55 effects by affecting brain levels of endogenous molecules. 56 57 Using computational, genetic and pharmacologic approaches across diverse 58 organisms we demonstrate that BBB-localized efflux transporters are critical for 59 regulating brain levels of endogenous steroids, and steroid-regulated behaviors 60 (sleep in Drosophila and anxiety in mice). Furthermore, we show that Mdr1- 61 interacting drugs are associated with anxiety-related behaviors in humans. 62 63 We propose a general mechanism for common behavioral side effects of 64 prescription drugs: pharmacologically challenging BBB efflux transporters 65 disrupts brain levels of endogenous substrates, and implicates the BBB in 66 behavioral regulation. 67 3 bioRxiv preprint doi: https://doi.org/10.1101/131698; this version posted April 29, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 68 Introduction 69 The maintenance of central nervous system (CNS) function depends upon its 70 regulated isolation from circulating drugs and toxins (xenobiotics), as well as 71 endogenous molecules produced in the periphery. The importance of insulating 72 neural tissue is evidenced by the conserved molecular and anatomic properties 73 of blood-brain barriers (BBBs) present throughout evolutionarily diverse 74 organisms (Fig. 1A). The vertebrate BBB is composed of brain vascular 75 endothelial cells (BVECs), pericytes, basal lamina, and the endfeet of astrocytes. 76 BVECs are specialized to protect the CNS as, compared to peripheral endothelial 77 cells, they are enriched for tight junction components, chemoprotective ATP- 78 Binding Cassette (ABC) drug efflux transporters and nutrient influx transporters 79 (Daneman et al., 2010, Daneman, 2012). Similar to vertebrate BVECs, 80 Drosophila melanogaster focuses chemoprotective physiology into a single 81 functionally polarized cellular layer, the subperineurial glia (SPG). The SPG layer 82 surrounds the CNS, separating it from the blood (hemolymph) (Stork et al., 2008), 83 and similarly possesses the hallmark properties of the vertebrate BBB: tight 84 junctional physiology, potent xenobiotic efflux biology and particular metabolic 85 transport characteristics (Mayer et al., 2009, DeSalvo et al., 2014, Hindle and 86 Bainton, 2014). 87 88 Peripherally produced hydrophilic molecules, like catecholamines, are physically 89 isolated from the CNS due to the BVEC tight junctions; this crucially allows 4 bioRxiv preprint doi: https://doi.org/10.1101/131698; this version posted April 29, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 90 synaptic regulation that is independent from the peripheral nervous system 91 (Tsukita et al., 2001). Small lipophilic molecules, however, are able to freely 92 diffuse across the plasma membrane, requiring an active chemical transport 93 barrier to limit their buildup in the brain. Due to its lumenal membrane 94 localization, ABC Type B efflux transporters, like vertebrate Mdr1, can provide 95 this function, using ATP to efficiently prevent the CNS accumulation of its 96 substrates (e.g. many lipophilic drugs) (Loscher and Potschka, 2005b, van 97 Asperen et al., 1996, Loscher and Potschka, 2005a). 98 99 Mdr1 (P-glycoprotein/ABCB1) is expressed at the BBB and peripherally, in sites 100 such as gut, kidney and other endothelial cells (Thiebaut et al., 1987, Cordon- 101 Cardo et al., 1989). Unlike most transporters, it has a very broad spectrum of 102 substrates, including calcium channel blockers, calmodulin antagonists, cyclic 103 peptides, and endogenous molecules such as vitamins and steroids (Tsuruo et 104 al., 1982a, Tsuruo et al., 1982b, Tsuruo et al., 1983, Naito et al., 1989, 105 Silbermann et al., 1989, Ueda et al., 1992, Ford, 1996, Uhr et al., 2002, Muller et 106 al., 2003, Schoenfelder et al., 2012). Thus, due to its promiscuous nature and 107 physiologic localizations, Mdr1 is likely to have pharmacological interactions with 108 many endogenous molecules, some of which have direct effects on the CNS. 109 Indeed, acute, exogenous dosing of progesterone, aldosterone, cortisol or 110 corticosterone in Mdr1 loss-of-function mice (Mdr1 KO) resulted in higher CNS 111 levels (Uhr et al., 2002). Thus, the chemoprotective role of Mdr1 could have 112 consequences on steady state brain disposition of potent endobiotics. Curiously, 5 bioRxiv preprint doi: https://doi.org/10.1101/131698; this version posted April 29, 2017. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 113 previous studies on Mdr1 KO animals that showed increased emotional stress 114 behaviors, highlighted a peripheral endobiotic role for Mdr1 (Schoenfelder et al, 115 2012). However, a specific BBB role for Mdr1 that links endobiotic clearance 116 mechanisms and behavioral regulation has not yet been demonstrated. To 117 address this we took a broad look at potential endobiotic substrates and BBB- 118 enriched ABC transporters to specifically investigate their BBB role in brain 119 steroid regulation. 120 121 We first used a Drosophila model of xenobiotic efflux transporter deficiency to 122 investigate its conserved roles in CNS disposition of endogenous molecules and 123 in discrete animal behaviors. We previously identified the Drosophila Mdr1 124 homolog (Mdr65) and showed it is highly enriched at the BBB, functions
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