Liquiritin protects PC12 cells from corticosterone-induced neurotoxicity via regulation of metabolic disorders, attenuation ERK1/2-NF-κB pathway, activation Nrf2-Keap1 pathway, and inhibition mitochondrial apoptosis pathway.

Liquiritin, a flavone derived from the medicine food homology plant liquorice, possesses neuroprotective. However, the neuroprotective mechanism is not clear. In this study, metabolomics based LC-MS was performed to discover the metabolite changes in PC12 cells treated with corticosterone-induced neurotoxicity after liquiritin treatment. A total of 30 metabolites were identified as differential metabolites. Among them, 11 metabolites were regulated by liquiritin, and involved in the D-glutamine and D-glutamate metabolism, and glutathione metabolism, etc. Based on the results of metabolomics, three cell signaling pathways related to these metabolic pathways were verified. The results showed that the ERK1/2-NF-κB pathway related to the D-glutamine and D-glutamate metabolism was attenuated by liquiritin via down-regulation phospho-ERK1/2, phospho-IκBα, phospho-NF-κB protein expression levels. Furthermore, the Nrf2-Keap1 pathway related to glutathione metabolism was activated by liquiritin via up-regulation Nrf2, Keap1, HO-1, NQO1 protein expression levels, and increased SOD, CAT, GSH-PX enzyme activity, thus exerting antioxidant activity. Additionally, liquiritin inhibited the mitochondrial apoptosis by decreasing the Ca2+ concentration, improving MMP, up-regulating Bcl-2, and down-regulating Bax, cytochrome C, cleaved-Caspase-3 expression levels. These results suggest that the neuroprotective mechanisms of liquiritin are connected to the regulation of metabolic disorders, activation Nrf2/Keap1 pathway, attenuation ERK1/2/NF-κB pathway, and inhibition mitochondrial apoptosis pathway.