The grasshopper: a novel model for assessing vertebrate brain uptake

The aim with the present study is to develop a blood-brain barrier (BBB) permeability model, which is applicable in the drug discovery phase. The BBB ensures proper neural function but it restricts many drugs from entering the brain and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability but the permeability characteristics of the human BBB are notoriously complex and hard to predict. Consequently, one single suitable BBB permeability screening model, which is generally applicable in the early drug discovery phase, does not yet exist. A new refined ex vivo insect based BBB screening model that uses an intact, viable whole brain under controlled 'in vitro' like exposure conditions is presented. This model uses intact brains from dessert locusts, which are placed in a well containing the compound solubilized in an insect buffer. After a limited period of time the brain is removed and the compound concentration in the brain is measured by conventional LC-MS. The data presented here includes 25 known drugs and the data shows that the ex vivo insect model can be used to measure the brain uptake over the hemolymph barrier of drugs and that the brain uptake shows linear correlation with in situ perfusion data obtained in vertebrates. Moreover, this study shows that the insect ex vivo model is able to identify Pgp substrates and the model allows differentiation between low permeability compounds and compounds that are Pgp substrates.