Neuroprotective effect of Saikogenin F on corticosterone-induced cytotoxicity in PC12 cells involves P2X7R-NLRP3 and cAMP-PKA pathways.

Saikogenin F (SGF) is a metabolite of Saikosaponin A (SSA) in vivo. However, in comparison to SSA, the neuroprotective efficacy and mechanisms of SGF remain uncertain in depression. The objective of this study was to explore the neuroprotective effects and mechanisms of SGF in corticosterone (CORT)-induced PC12 cells. Initially, analyses using MTT assays and flow cytometry demonstrated that SGF enhanced cell viability, inhibited cell death, and reduced levels of reactive oxygen species, lactate dehydrogenase and mitochondrial membrane potential. Furthermore, metabolomic analysis revealed that metabolic disorders were occurring in CORT-induced PC12 cells. SGF significantly reversed alterations in 13 metabolites and influenced 5 metabolic pathways. Of the five metabolic pathways, the regulation of purine metabolism is the most significantly affected by SGF. This study subsequently examined the regulatory impact of SGF on the P2X7R-NLRP3 and cAMP-PKA signaling pathways associated with purine metabolism, aiming to elucidate its neuroprotective mechanism. Enzyme-linked immunoassays and western blot analyses indicated that SGF significantly modulated the expression of proteins involved in these two pathways. These results show for the first time that SGF protected PC12 cells from damage caused by CORT through the regulation of the P2X7R-NLRP3 and cAMP-PKA signaling pathways in this study.