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.
Highlights
The mammalian blood–brain barrier (BBB) is composed of capillary endothelial cells that control the entry of nutrients and xenobiotics to the brain and preserve homeostasis of the neural microenvironment, a prerequisite for reliable neural transmission and function (Abbott et al 2006, 2010)
Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics
It has been shown that the Dm brain concentration of rhodamine 123 (Rho123) increases when the compound is coinjected with the Pgp inhibitor Cyclosporin A (CsA) (Mayer et al 2009)
Summary
The mammalian blood–brain barrier (BBB) is composed of capillary endothelial cells that control the entry of nutrients and xenobiotics to the brain and preserve homeostasis of the neural microenvironment, a prerequisite for reliable neural transmission and function (Abbott et al 2006, 2010). Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. Insect Brain Barrier Pgp Ex Vivo Screening Model a major challenge in the discovery of new drugs for central nervous system (CNS)-related diseases. The Pgp-imposed restriction of drug permeation of the BBB has been a critical issue in the drug discovery process resulting in significant efforts to establish experimental models providing information on CNS barrier efflux of test compounds. A number of cell-based in vitro models have been developed and proposed as useful tools in the drug discovery screening process and in the identification of Pgp substrates and inhibitors (Polli et al 2001; Weiss et al 2003; Mensch et al 2009)
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