Vanillic Acid Protects PC12 Cells from Corticosterone-Induced Neurotoxicity via Regulating Immune and Metabolic Dysregulation Based on Computational Metabolomics

Vanillic acid is widely used in the food industry and exhibits an excellent neuroprotective effect. Nevertheless, the mechanisms underlying them are largely unexplored, especially the interactions between the neuroprotection effects of vanillic acid and inflammation-immunity-metabolism. A cell metabolomics-based mathematics algorithm was reported to interpret the potential mechanism of vanillic acid on corticosterone-induced PC12 cells by regulating immune and metabolic dysregulation. Our results showed that vanillic acid markedly inhibited the level of inflammatory factors in corticosterone-induced PC12 cells. Cell metabolomics results suggested that vanillic acid regulated the abnormality of corticosterone-induced PC12 cell metabolic profiles and markedly regulated 11 differential metabolites. Our designed scoring model base entropy weight algorithm showed that the core targets (IL2RB, IFNA13, etc.) and metabolites (lactate, ethanolamine, etc.) regulate the immunity-metabolism of vanillic acid. Furthermore, we demonstrated that vanillic acid inhibited IL2RB expression and modulated the related pathway, JAK1/STAT3 signaling. The JAK inhibitor ABT-494 was further applied to validate the effect of vanillic acid on the JAK/STAT pathway. Results indicate that vanillic acid regulates the abnormal interactions of inflammation-immunity-metabolism by repressing the IL2RB-JAK1-STAT3 pathway. Methodologically, this study contributes to the decoding of vanillic acid's antidepressive effect from the metabolism perspective combined with computer algorithms and mathematics models.