Pharmacological Survey of Medicinal Plants for Activity at Ligand-Gated Ion Channels: Selective Interaction with 5-HT3 Receptors

Abstract

The ligand-gated anion-selective ion channels are part of a superfamily of ligand-gated ion channels (LGICs) that are responsible for a majority of inhibitory signaling in the central nervous system and are the targets of numerous therapeutics. Aqueous, organic and alcoholic extracts of 47 Chinese, Bolivian and Pakistani medicinal plants were evaluated for the ability to modulate the activity of GABAA receptors. Extracts were initially screened for their ability to modulate activity of α1β2γ2 GABAA receptors expressed in HEK 293 cells. Based on the initial screen, two extracts derived from members of the Asteraceae family, Xanthium spinosum and Senecio mathewsii, were chosen for more detailed analysis. Xanthium spinosum inhibited GABAA receptor function, with an IC50 of 50 ± 10 µg/ml, while Senecio mathewsii inhibited GABAA receptor activity with an IC50 of 35 ± 3.0 µg/ml. To assess the selectivity of interaction, these extracts were also tested on two other members of the LGIC superfamily a) glycine receptors, a distinct inhibitory neurotransmitter receptor and b) 5-HT3A receptors, a cation-selective receptor. At a concentration of Xanthium spinosum that blocked 70% of GABA-activated current, only 15% of glycine-gated current, recorded from recombinant α1 glycine receptors, was blocked, suggesting a lower affinity of Xanthium spinosum for glycine receptors. Senecio mathewsii had larger inhibitory effects on glycine receptors than Xanthium spinosum, although the apparent affinity still was estimated to be three-fold lower than that seen for GABAA receptors. Xanthium spinosum and Senecio mathewsii also inhibited 5-HT3A receptor functions. Notably, the IC50 of both extracts was seven to ten-fold lower than that observed for GABAA receptors. Thus, the rank order of potency for organic extracts from both Xanthium spinosum and Senecio mathewsii was 5-HT3A receptors > GABAA receptors > glycine receptors. Therefore, these extracts may be a source of novel compounds that may serve as lead molecules for the development of novel 5-HT3 receptor antagonists.