Identification of the Active Ingredient Accounting for the Biological Effects of Ligusticum chuanxiong

Abstract

Ligusticum chuanxiong Hort. (Umbelliferae) is a common Chinese medicinal herb for cardiovascular diseases. Although a number of components have been identified from the herb, the correlation between herbal pharmacological effects and its constituents at comparable quantities is yet to be established; and hence, the active constituents accounting for therapeutic effects of the herb remain unclear. In the current study, using butylidenephthalide, a minor ingredient with a low content in the herb as an example, an integrative approach of chemical analysis, intestinal permeability screening, pharmacokinetics and functional response evaluation to identify the active constituents accounting for the pharmacological effects of Ligusticum chuanxiong is presented. About seventeen constituents were determined in the herbal extract, however, using a Caco-2 cell intestinal absorption model as a first-round screening strategy, including butylidenephthalide, five of the seventeen constituents were observed to have medium to high intestinal permeability. Although it has a low content (~ 0.01–0.05%) in the herb, further pharmacokinetic study demonstrated adequate plasma concentrations of butylidenephthalide in rats. Pharmacological activity studies also revealed its vasorelaxation, anti-platelet aggregation and anti-thrombotic effects. The results demonstrated that butylidenephthalide is one of the main active ingredients accounting for bioactivities of Ligusticum chuanxiong mainly due to, after administration of the herbal extract, 1) significant biotransformation of butylidenephthalide from a co-existing ingredient in the herb and 2) synergistic effects produced by butylidenephthalide with co-existing constituents. Furthermore, our findings suggested that a minor component in the herb may be account for herbal activities and use of the integrated pharmacokinetic and pharmacodynamic approach should be more appropriate for the identification of true bioactive ingredients of herbs.