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DOI: 10.1055/s-2008-1081343
© Georg Thieme Verlag KG Stuttgart · New York
Transport of a GABAA Receptor Modulator and Its Derivatives from Valeriana officinalis L. s. l. Across an in Vitro Cell Culture Model of the Blood-Brain Barrier
Publikationsverlauf
Received: March 19, 2008
Revised: May 29, 2008
Accepted: June 15, 2008
Publikationsdatum:
14. August 2008 (online)
![](https://www.thieme-connect.de/media/plantamedica/200811/lookinside/thumbnails/10.1055-s-2008-1081343-1.jpg)
Abstract
The roots and rhizome of Valeriana officinalis L. s. l. are therapeutically used for their sedative and sleep-enhancing effects. Some of the active compounds found in commonly used extracts are the sesquiterpenic acids, especially valerenic acid, which was recently identified as a GABAA receptor modulator. To interact with this receptor in the brain, substances such as valerenic acid and its derivatives acetoxyvalerenic acid and hydroxyvalerenic acid have to cross the blood-brain barrier (BBB). The aim of our study was to obtain BBB permeability data of these compounds for the first time and to elucidate possible transport pathways across our BBB in vitro model. Transport of valerenic acid, acetoxyvalerenic acid and hydroxyvalerenic acid was compared with the permeability of the GABAA modulator diazepam, which is known to penetrate into the central nervous system transcellularly by passive diffusion. Experiments were carried out with an established Transwell in vitro model based on the human cell line ECV304. Results indicated clearly that all three acids permeated significantly slower than diazepam. The ranking was confirmed in group studies as well as in single-substance studies after normalization to diazepam. Valerenic acid (1.06 ± 0.29 μm/min, factor 0.03 related to diazepam) was the slowest to permeate in the group study, followed by hydroxyvalerenic acid (2.72 ± 0.63 μm/min, factor 0.07 related to diazepam) and acetoxyvalerenic acid (3.54 ± 0.58 μm/min, factor 0.09 related to diazepam). To elucidate the contribution of the paracellular transport, studies were performed at different tightness status of the cell layers reflected by different transendothelial electrical resistance (TEER) values. Results showed an exponential correlation between transport and TEER for all three acids, whereas diazepam permeated TEER independently. In summary, it is hypothesized that the investigated compounds from Valeriana officinalis L. s. l. can probably only pass through the BBB by a still unknown transport system and not transcellularly by passive diffusion.
Abbreviations
ACM: astrocyte-conditioned medium
BBB: blood-brain barrier
BMEC: brain microvascular endothelial cells
DMP: 2,2-dimethoxypropane
ESEM: environmental scanning electron microscopy
GABA: γ-aminobutyric acid
SEM: scanning electron microscopy
TEER: transendothelial electrical resistance
TEM: transmission electron microscopy
Key words
Valeriana officinalis L. s. l. - Valerianaceae - blood-brain barrier - valerenic acid - ECV304 - GABAA receptor
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Christian R. Noe
Department of Medicinal Chemistry
University of Vienna
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Austria
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