Abstract
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.
Key words
blood brain-barrier - diterpenes -
Sideritis
- Lamiaceae - passive diffusion
