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Evolutionary Conservation of Vertebrate Blood-Brain Barrier Chemoprotective Mechanisms in Drosophila

Department of Anesthesia and Perioperative Care, San Francisco General Hospital, and Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 04/2009; 29(11):3538-50. DOI: 10.1523/JNEUROSCI.5564-08.2009
Source: PubMed

ABSTRACT Pharmacologic remedy of many brain diseases is difficult because of the powerful drug exclusion properties of the blood-brain barrier (BBB). Chemical isolation of the vertebrate brain is achieved through the highly integrated, anatomically compact and functionally overlapping chemical isolation processes of the BBB. These include functions that need to be coordinated between tight diffusion junctions and unidirectionally acting xenobiotic transporters. Understanding of many of these processes has been hampered, because they are not well mimicked by ex vivo models of the BBB and have been experimentally difficult and expensive to disentangle in intact rodent models. Here we show that the Drosophila melanogaster (Dm) humoral/CNS barrier conserves the xenobiotic exclusion properties found in the vertebrate vascular endothelium. We characterize a fly ATP binding cassette (ABC) transporter, Mdr65, that functions similarly to mammalian xenobiotic BBB transporters and show that varying its levels solely in the Dm BBB changes the inherent sensitivity of the barrier to cytotoxic pharmaceuticals. Furthermore, we demonstrate orthologous function between Mdr65 and vertebrate ABC transporters by rescuing chemical protection of the Dm brain with human MDR1/Pgp. These data indicate that the ancient origins of CNS chemoprotection extend to both conserved molecular means and functionally analogous anatomic spaces that together promote CNS selective drug partition. Thus, Dm presents an experimentally tractable system for analyzing physiological properties of the BBB in an intact organism.

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    • "mdr50 and the least effect was by mdr65, suggesting that mdr49 and mdr50 could be having a more direct role in polyQ-mediated pathogenesis. This can also be related to the functional differences between these genes (Mayer et al. 2009; Ricardo and Lehmann 2009). On comparing the observations , it was found that mdr65-RNAi background showed a significant decrease in mild phenotype just like mdr49-RNAi and mdr50-RNAi. "
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    • "In addition to the cell types shown above are the filopodia bearing perineurial glial cells at the edge of the carpet cell (4) and the glial cells found at the margin of the eye imaginal disc (5). et al., 2005; Stork et al., 2008; Mayer et al., 2009 "
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    • "Genetic studies in Drosophila have greatly added to our understanding of the essential components of chemical barriers (Bellen et al. 1998; Schwabe et al. 2005; Stork et al. 2008; Tepass et al. 2001; Wu and Beitel 2004), but thus far most of these studies primarily have identified structurally essential genes for the development of polarized epithelia. Subtle modulators of the chemical barrier were discovered in adult organisms using behavior screens as in the case of the Moody GPCR (Bainton et al. 2005; Mayer et al. 2009). The above physiologic screen suggests that chemical, metabolic, and immune functions of surface glia are woven together in a remarkably diminutive interface and hints at analogous functions to vertebrate BBB cellular layers. "
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