Senkyunolide A protects neural cells against corticosterone-induced apoptosis by modulating protein phosphatase 2A and α-synuclein signaling

Background: Depression is characterized by a pathological injury to the hippocampal neurons. Senkyunolide A (Sen A) is one of the major active components of Dan-zhi-xiao-yao-san, which is widely used in the treatment of depression-related disorders. Materials and methods: In the present study, it was hypothesized that the antidepressant effect of Dan-zhi-xiao-yao-san depended on the function of Sen A and the authors attempted to reveal the molecular mechanism associated with the treatment. An in vitro depression model was induced using corticosterone (Cort), and the effect of Sen A on the cell viability, apoptosis, and protein phosphatase 2A/alpha-synuclein (PP2A/alpha-syn) signaling was detected. To validate the mechanism driving the therapeutic effect of Sen A, activity of PP2A and alpha-syn was modulated and the effect on neural cells was evaluated. Results: The results showed that SenA protects Cort-induced cell apoptosis in PC12 cells. In addition, SenA increased Cort-induced reduction of PP2A activity, while it decreased the expression of p-PP2A, alpha-syn, andp-alpha-syn (Serl29). Further, modulation of PP2A activity with specific inhibitor okadaic acid (OA) increased Cort-induced cell apoptosis. while PP2A activator D-erythro-sphingosine (SPH) exhibited an opposite effect. The neuroprotective effects of SenA on neural cells also depended on inhibition of alpha-syn function, the regulation of which would influence the activity of PP2A in a negative loop. Conclusion: Collectively, the results suggested that the neuroprotective effects of SenA were exerted by modulating activities of PP2A activities and alpha-syn. The findings partially explained the mechanism associated with the neuroprotective effect of SenA.