Global and Targeted Metabolomics Reveal That Bupleurotoxin, a Toxic Type of Polyacetylene, Induces Cerebral Lesion by Inhibiting GABA Receptor in Mice

Abstract

Polyacetylenes are widely distributed in food plants and medicinal herbs, which have been shown to have highly neurotoxic effects. However, there were insufficient studies on the toxicity of these compounds. Thus, a series of experiments was designed to elucidate the toxicity mechanism of bupleurotoxin (BETX) as a representative polyacetylene. First, male BALB/c mice were intragastrically administered 2.5 mg/kg of bodyweight BETX once a day for seven consecutive days. The histopathological results showed that BETX could induce severe morphological damages in the brain hippocampus. We then used metabolomics approaches to screen serum samples from the control and BETX-treated groups. The global metabolomics results revealed 17 metabolites that were perturbed after BETX treatment. Four of these metabolites were then verified by targeted metabolomics. Bioinformatics analysis with the Ingenuity Pathway Analysis (IPA) software found a strong correlation between the GABA receptor signaling pathway and these metabolites. On the basis of these results, a validation test using a rat hippocampal neuron cell line was performed, and the results confirmed that BETX inhibited GABA-induced currents (IGABA) in a competitive manner. In summary, our study illustrated the molecular mechanism of the toxicity of polyacetylenes. In addition, our study was instructive for the study of other toxic medical herbs.