title: In vitro permeability study of CNS-active diterpenes from Sideritis spp. using cellular models of blood-brain barrier.
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.
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, University Complutense, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: González-Burgos
authors.forename: M Emilia
authors.initials: ME
authors.lastname: Carretero
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Gómez-Serranillos
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques; D004058:Diffusion; D004224:Diterpenes / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism*; D010539:Permeability; D051381:Rats; D031365:Sideritis / Q000737:chemistry*
chemical_list: D004224:Diterpenes; D018696:Neuroprotective Agents