Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior

Abstract

Summary 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.

Endocytosis at the Drosophila blood–brain barrier as a function for sleep

“…The hemolymph-brain barrier, like its mammalian counterpart, contains numerous transporters and receptors ( DeSalvo et al, 2014 ) serving to selectively move nutrients and metabolites in, and deleterious compounds such as xenobiotics out. Mutants for the xenobiotic transporter, Mdr65 , show greater total sleep, but effects have not been directly mapped to the barrier ( Hindle et al, 2017 ). We demonstrated recently that efflux transporters in the Drosophila BBB are under circadian regulation such that they preferentially pump out xenobiotics during the day.…”

Bridging barriers: a comparative look at the blood–brain barrier across organisms

“…These glial cells undergo polyploidization during larval stages, greatly increasing their cell area to seal the brain as it develops (Unhavaithaya and Orr-Weaver 2012). SPGs express nutrient transporters and have specialized septate junctions, similar to the expression pattern of nutrient transporters and specialized tight junction complexes in vertebrate BBB endothelial cells (Limmer et al 2014;Hindle et al 2017). Interaction with other glial cell types, including perineurial glial cells, has also been shown to be important in regulating size selectivity of the hemolymphbrain barrier through fenestrations (cellular pores) (Stork et al 2008).…”

Drosophila glia: Few cell types and many conserved functions

“…Third, xenobiotic exporters found in the mammalian blood-brain barrier are also found at the Drosophila blood-brain barrier (Hindle et al, 2017;Mayer et al, 2009).…”