Pharmacology Original Paper	Planta Med 2008; 74: 1338-1344 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
Winfried Neuhaus1, Gabriele Trauner2, Daniela Gruber3, Silvester Oelzant2, Waltraud Klepal3, Brigitte Kopp2, Christian R. Noe1
1 Department of Medicinal Chemistry, University of Vienna, Pharmacy Center, Vienna, Austria 2 Department of Pharmacognosy, University of Vienna, Pharmacy Center, Vienna, Austria 3 Institution of Cell Imaging and Ultrastructure Research, University of Vienna, Vienna, Austria

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 GABA_A 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 GABA_A 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 - GABA_A receptor