In vitro permeability study of CNS-active diterpenes from Sideritis spp. using cellular models of blood-brain barrier

The major diterpenes andalusol, conchitriol, foliol, lagascatriol, linearol, and sidol, isolated from Sideritis spp., have been recently identified as neuroprotective agents. In this study, the blood brain-barrier permeability characteristics of these natural compounds were investigated for the first time using in silico and in vitro (RBE4 monocultures and ECV304/C6 co-cultures) methods. Computational tools revealed that these diterpenes have a favorable permeability profile to pass across the blood brain-barrier. In the RBE4 cell model, used for uptake studies, all compounds were taken up in a concentration and time-dependent manner. A bidirectional transport of diterpenes was observed across the ECV304/C6 co-culture model, with Papp values in the range of 3.7 × 10(-6) cm/sec and 9.5 × 10(-6) cm/sec for foliol and andalusol, respectively. Andalusol and lagascatriol were the most efficiently in being taken up and transported across the established blood brain-barrier in vitro model. These findings suggest that the investigated compounds from Sideritis spp. may predominantly move across the blood brain-barrier by passive diffusion. The observations have implications for understanding how CNS-active diterpenes enter the brain endothelium and traverse the blood brain-barrier, and thus exert their neuroprotective actions.