Neuhaus Winfried, Trauner Gabriele, Gruber Daniela, Oelzant Silvester, Klepal Waltraud, Kopp Brigitte, Noe Christian R
Department of Medicinal Chemistry, University of Vienna, Pharmacy Center, Vienna, Austria.
Planta Med. 2008 Sep;74(11):1338-44. doi: 10.1055/s-2008-1081343. Epub 2008 Aug 14.
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 microm/min, factor 0.03 related to diazepam) was the slowest to permeate in the group study, followed by hydroxyvalerenic acid (2.72 +/- 0.63 microm/min, factor 0.07 related to diazepam) and acetoxyvalerenic acid (3.54 +/- 0.58 microm/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.
缬草（Valeriana officinalis L. s. l.）的根及根茎因其镇静和助眠作用而用于治疗。常用提取物中发现的一些活性化合物是倍半萜酸，尤其是缬草烯酸，其最近被鉴定为一种γ-氨基丁酸（A）受体调节剂。为了在大脑中与该受体相互作用，诸如缬草烯酸及其衍生物乙酰氧基缬草烯酸和羟基缬草烯酸之类的物质必须穿过血脑屏障（BBB）。我们研究的目的是首次获得这些化合物的血脑屏障通透性数据，并阐明在我们的体外血脑屏障模型中可能的转运途径。将缬草烯酸、乙酰氧基缬草烯酸和羟基缬草烯酸的转运与γ-氨基丁酸（A）调节剂地西泮的通透性进行比较，已知地西泮通过被动扩散经细胞跨膜进入中枢神经系统。实验是使用基于人细胞系ECV304建立的Transwell体外模型进行的。结果清楚地表明，所有三种酸的渗透速度均明显慢于地西泮。在成组研究以及单物质研究中，经与地西泮标准化后，该排序得到了证实。在成组研究中，缬草烯酸（1.06±0.29μm/min，相对于地西泮的系数为0.03）渗透最慢，其次是羟基缬草烯酸（2.72±0.63μm/min，相对于地西泮的系数为0.07）和乙酰氧基缬草烯酸（3.54±0.58μm/min，相对于地西泮的系数为0.09）。为了阐明细胞旁转运的作用，在由不同跨内皮电阻（TEER）值反映的细胞层不同紧密状态下进行了研究。结果表明，所有三种酸的转运与TEER之间呈指数相关，而地西泮的渗透与TEER无关。总之，据推测，缬草中研究的这些化合物可能只能通过一种尚不清楚的转运系统穿过血脑屏障，而不能通过被动扩散经细胞跨膜。
