Document Type

Journal Article

Department/Unit

School of Chinese Medicine

Title

Global and targeted metabolomics reveal that bupleurotoxin, a toxic type of polyacetylene, induces cerebral lesion by inhibiting GABA receptor in mice

Language

English

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.

Keywords

bupleurotoxin, GABA receptor, metabolic profiles, neurotoxicity, polyacetylenes

Publication Date

2-2014

Source Publication Title

Journal of Proteome Research

Volume

13

Issue

2

Start Page

925

End Page

933

Publisher

American Chemical Society

Peer Reviewed

1

Copyright

© 2013 American Chemical Society

Funder

The work was supported by program NCET Foundation, NSFC(81230090), partially supported by Global Research Network for Medicinal Plants (GRNMP) and King Saud University, Shanghai Leading Academic Discipline Project (B906), Key laboratory of drug research for special environments, PLA, Shanghai Engineering Research Center for the Preparation of Bioactive Natural Products (10DZ2251300) and the Scientific Foundation of Shanghai China (12401900801, 09DZ1975700, 09DZ1971500, 10DZ1971700). National Major Project of China (2011ZX09307-002-03). National Key Technology R&D Program of China (2012BAI29B06).

DOI

10.1021/pr400968c

Link to Publisher's Edition

http://dx.doi.org/10.1021/pr400968c

ISSN (print)

15353893

ISSN (electronic)

15353907

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