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Characterization of a novel brain barrier ex vivo insect-based P-glycoprotein screening model.

Andersson, Olga; Badisco, Liesbeth; Hansen, Ane Håkansson; Hansen, Steen Honoré; Hellman, Karin LU ; Nielsen, Peter Aadal; Olsen, Line Rørbæk; Verdonck, Rik; Abbott, N Joan and Vanden Broeck, Jozef, et al. (2014) In Pharmacology research & perspectives 2(4). p.00050-00050
Abstract
In earlier studies insects were proposed as suitable models for vertebrate blood-brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain barrier of the desert locust (Schistocerca gregaria). In an in vivo study on the locust, we found an increased uptake of the two well-known Pgp substrates, rhodamine 123 and loperamide after co-administration with the Pgp inhibitors cyclosporine A or verapamil. Furthermore, ex vivo studies on isolated locust brains demonstrated differences in permeation of high and low permeability compounds. The vertebrate Pgp inhibitor verapamil did not affect the... (More)
In earlier studies insects were proposed as suitable models for vertebrate blood-brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain barrier of the desert locust (Schistocerca gregaria). In an in vivo study on the locust, we found an increased uptake of the two well-known Pgp substrates, rhodamine 123 and loperamide after co-administration with the Pgp inhibitors cyclosporine A or verapamil. Furthermore, ex vivo studies on isolated locust brains demonstrated differences in permeation of high and low permeability compounds. The vertebrate Pgp inhibitor verapamil did not affect the uptake of passively diffusing compounds but significantly increased the brain uptake of Pgp substrates in the ex vivo model. In addition, studies at 2°C and 30°C showed differences in brain uptake between Pgp-effluxed and passively diffusing compounds. The transcriptome data show a high degree of sequence identity of the locust Pgp transporter protein sequences to the human Pgp sequence (37%), as well as the presence of conserved domains. As in vertebrates, the locust brain-barrier function is morphologically confined to one specific cell layer and by using a whole-brain ex vivo drug exposure technique our locust model may retain the major cues that maintain and modulate the physiological function of the brain barrier. We show that the locust model has the potential to act as a robust and convenient model for assessing BBB permeability in early drug discovery. (Less)
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Pharmacology research & perspectives
volume
2
issue
4
pages
00050 - 00050
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John Wiley & Sons
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  • pmid:25505597
ISSN
2052-1707
DOI
10.1002/prp2.50
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English
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730c1631-f350-4ad6-9fa7-c7813271b6c4 (old id 4908275)
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http://www.ncbi.nlm.nih.gov/pubmed/25505597?dopt=Abstract
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@article{730c1631-f350-4ad6-9fa7-c7813271b6c4,
  abstract     = {In earlier studies insects were proposed as suitable models for vertebrate blood-brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain barrier of the desert locust (Schistocerca gregaria). In an in vivo study on the locust, we found an increased uptake of the two well-known Pgp substrates, rhodamine 123 and loperamide after co-administration with the Pgp inhibitors cyclosporine A or verapamil. Furthermore, ex vivo studies on isolated locust brains demonstrated differences in permeation of high and low permeability compounds. The vertebrate Pgp inhibitor verapamil did not affect the uptake of passively diffusing compounds but significantly increased the brain uptake of Pgp substrates in the ex vivo model. In addition, studies at 2°C and 30°C showed differences in brain uptake between Pgp-effluxed and passively diffusing compounds. The transcriptome data show a high degree of sequence identity of the locust Pgp transporter protein sequences to the human Pgp sequence (37%), as well as the presence of conserved domains. As in vertebrates, the locust brain-barrier function is morphologically confined to one specific cell layer and by using a whole-brain ex vivo drug exposure technique our locust model may retain the major cues that maintain and modulate the physiological function of the brain barrier. We show that the locust model has the potential to act as a robust and convenient model for assessing BBB permeability in early drug discovery.},
  author       = {Andersson, Olga and Badisco, Liesbeth and Hansen, Ane Håkansson and Hansen, Steen Honoré and Hellman, Karin and Nielsen, Peter Aadal and Olsen, Line Rørbæk and Verdonck, Rik and Abbott, N Joan and Vanden Broeck, Jozef and Andersson, Gunnar},
  issn         = {2052-1707},
  language     = {eng},
  number       = {4},
  pages        = {00050--00050},
  publisher    = {John Wiley & Sons},
  series       = {Pharmacology research & perspectives},
  title        = {Characterization of a novel brain barrier ex vivo insect-based P-glycoprotein screening model.},
  url          = {http://dx.doi.org/10.1002/prp2.50},
  volume       = {2},
  year         = {2014},
}