Tanshinone ⅡA Ameliorates Chronic Unpredictable Mild Stress Induced Depression-Like Behaviors: Integrating Network Pharmacology and Molecular Mechanism Evaluation

Background: Depression is a commonly occurring mental disease and many active ingredients of herbs have been proven to effectively alleviate depression. Objectives: To investigate the effects of Tanshinone IIA (Tan IIA) on depression and determine potential mechanisms. Materials and Methods: The antidepressant mechanism of Tan IIA was predicted by network pharmacology. Then, we established Chronic Unpredictable Mild Stress (CUMS)-induced depression in a mouse model for validation and the mice were administered with Tan IIA during the 15th day-the 28th day (20 and 40 mg/kg). And related proteins were determined by western blotting or immunofluorescence. The levels of cytokines and neurotransmitters were detected by ELISA. Synaptic changes were visualized by Golgi staining and western blotting. Results: Network pharmacology predicted PI3K/Akt pathway and TNF-α/TNFR1 pathway played significant roles in the treatment of depression by Tan IIA. And CUMS mice was used to verify. Tan IIA reduced the immobility time of CUMS mice in Forced Swim Test (FST) and Tail Suspension Test (TST). Meanwhile, CUMS mice consumed more sucrose after Tan IIA treatment and it improved the body weight. Importantly, Tan IIA alleviated CUMS-stimulated release of IL-1β and TNF-α, activation of astrocytes and microglia, reduction of synaptic proteins (PSD95, Arc, BDNF). Moreover, Tan IIA promotes the phosphorylation of PI3K/Akt and inhibits the expression of TNFR1 in the hippocampal. Conclusion: Tan IIA improves depression-like behaviors possibly through inhibiting neuroinflammation, increasing synaptic plasticity and improving neurotransmitter levels in the hippocampus.