Modulation of GABA_A Receptors by Valerian Extracts is Related to the Content of Valerenic Acid

Abstract

Valeriana officinalis L. is a traditionally used sleep remedy, however, the mechanism of action and the substances responsible for its sedative and sleep-enhancing properties are not fully understood. As we previously identified valerenic acid as a subunit-specific allosteric modulator of GABA_A receptors, we now investigated the relation between modulation of GABA_A receptors by Valerian extracts of different polarity and the content of sesquiterpenic acids (valerenic acid, acetoxyvalerenic acid). All extracts were analysed by HPLC concerning the content of sesquiterpenic acids. GABA_A receptors composed of α₁, β₂ and γ_2S subunits were expressed in Xenopus laevis oocytes and the modulation of chloride currents through GABA_A receptors (I_GABA) by Valerian extracts was investigated using the two-microelectrode voltage clamp technique. Apolar extracts induced a significant enhancement of I_GABA, whereas polar extracts showed no effect. These results were confirmed by fractionating a highly active ethyl acetate extract: again fractions with high contents of valerenic acid exhibited strong receptor activation. In addition, removal of sesquiterpenic acids from the ethyl acetate extract led to a loss of I_GABA enhancement. In conclusion, our data show that the extent of GABA_A receptor modulation by Valerian extracts is related to the content of valerenic acid.

Abbreviations

AVA:acetoxyvalerenic acid

CNS:central nervous system

EA:crude ethyl acetate extract

EtOAc:ethyl acetate extract

GABA:γ-amino butyric acid

GABA_A receptor:GABA activated type A receptor

H₂O:distilled water extract

HVA:hydroxyvalerenic acid

I_GABA:GABA-induced chloride current through GABA_A receptors

MeOH:methanol extract

PE:petroleum ether extract

RV:reservoir volumina

TLC:thin layer chroamtography

VA:valerenic acid

VLC:vacuum liquid chromatography

Key words

Valeriana officinalis - Valerianaceae - GABA_A-modulation - valerenic acid

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