Several Chinese herbal medicines (CHMs) are used in the treatment of insomnia, restlessness, or anxiety. However, mechanisms underlying this effect and scientific proof for their traditional use is scarce. In the present study CHMs were screened for their ability to modulate GABA-induced chloride currents (I(GABA)), and active principles were isolated thus providing scientific evidence for their use as sedative and/or anxiolytic agents in CM. Herbal drugs were extracted successively with petroleum ether, ethyl acetate, methanol and water and further fractionated according to their bioactivity. The obtained extracts, fractions and finally pure compounds were tested for their ability to potentiate I(GABA) using the two-microelectrode voltage clamp technique on recombinant α₁β₂γ(2S) GABA(A) receptors expressed in Xenopus laevis oocytes. From all tested extracts the petroleum ether extract of Atractylodes macrocephala Koidz. rhizomes showed the strongest I(GABA) potentiation and was studied in more detail. This led to the isolation of the main components atractylenolide II and III, which seem to be responsible for the observed positive modulation of I(GABA) (166±12%, n=3 and 155±12%, n=3, respectively) in vitro. They were more active than the analogous compound atractylenolide I (96±3%, n=3) which differs in an additional double binding in position 9, 9a. Furthermore it could be shown that this effect is mediated independently of the benzodiazepine (BZ) binding site. In conclusion, A. macrocephala exerts its in vitro activity on recombinant GABA(A) receptors mainly through the two sesquiterpene lactones atractylenolide II and III (Fig. 1). This positive allosteric modulation of I(GABA) may partially be responsible for the traditional ethnopharmacological use of this herbal drug as a sedative.
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