The grasshopper: a novel model for assessing vertebrate brain uptake

Area of Science:

• Neuroscience
• Pharmacology
• Drug Discovery

Background:

• The blood-brain barrier (BBB) is crucial for neural function but hinders drug delivery to the central nervous system.
• Existing in vitro BBB models struggle to accurately predict human BBB permeability due to its complexity.
• A universally applicable screening model for early-stage drug discovery is currently lacking.

Purpose of the Study:

• To develop a novel, ex vivo insect-based blood-brain barrier (BBB) screening model for the drug discovery phase.
• To assess the utility of this model in predicting drug brain uptake and identifying P-glycoprotein (Pgp) substrates.
• To establish a reliable and accessible method for evaluating BBB permeability in potential CNS therapeutics.

Main Methods:

• An ex vivo model utilizing intact desert locust brains exposed to compounds in an insect buffer.
• Measurement of compound concentration within the brain tissue using liquid chromatography-mass spectrometry.
• Correlation analysis with established in situ perfusion data from vertebrate models.

Main Results:

• The ex vivo insect model accurately measures drug brain uptake across the hemolymph-brain barrier.
• A linear correlation was observed between insect model data and vertebrate in situ perfusion data.
• The model successfully identified P-glycoprotein (Pgp) substrates and differentiated them from low-permeability compounds.

Conclusions:

• The developed ex vivo insect BBB model offers a viable screening tool for early drug discovery.
• This model provides a cost-effective and predictive method for assessing drug penetration into the brain.
• It aids in distinguishing between compounds with varying permeability characteristics, including Pgp-mediated transport.