Tanshinone IIA Improves Depression-like Behaviors in Ovariectomized Mice

OBJECTIVE: This study aims to investigate the effect of Tanshinone IIA (Tan IIA), a major component of the root of red-rooted Salvia miltiorrhiza Bunge, on depression-like behaviors in Ovariectomized (OVX) mice and to explore the potential mechanisms. METHODS: A total of 30 female C57/BL6 mice were randomly assigned to three groups (n = 10 per group): Sham, OVX, and Tan IIA. Mice in the Sham group were subjected to a sham operation, whereas those in the OVX and Tan IIA groups were subjected to an ovariectomy to simulate menopause. OVX mice in the Tan IIA group were treated with Tan IIA (10 mg/kg) for 8 weeks. After the intervention, behavioral tests, including the Open Field Test (OFT), Forced Swimming Test (FST), and Tail Suspension Test (TST), were performed to assess the effect of Tan IIA on depression-like behaviors in OVX mice. Histopathology examination was conducted to assess the neuroprotective effect of Tan IIA on hippocampal neurons. Tissue total iron content analysis, Malondialdehyde (MDA) analysis, and Glutathione (GSH) analysis were measured to assess iron metabolism regulation and antioxidant effects, respectively. Hippocampal mitochondrial morphology was examined using a Transmission Electron Microscope (TEM) to assess the anti-ferroptotic capacity of Tan IIA. Western blot analysis was used to measure the expression of Nrf2, SLC7A11, and GPX4 to assess the effect of Tan IIA on the Nrf2 pathway. Molecular docking was conducted to verify the binding ability between Tan IIA and core protein targets of the Nrf2 pathway. RESULTS: Tan IIA treatment effectively alleviated anxiety-like and depression-like behaviors in OVX mice, reduced iron accumulation and lipid oxidative stress, and inhibited ferroptosis in the hippocampal neurons. Moreover, Tan IIA exhibits high binding affinity for Nrf2, SLC7A11, and GPX4, which contribute to increasing expression levels of the Nrf2/SLC7A11/GPX4 pathway in the hippocampus of OVX mice. DISCUSSION: Bilateral ovariectomy induced depressive and anxiety-like symptoms in female C57/BL6 mice. The presence of hippocampal ferroptosis was closely related to these symptoms. The effects of Tan IIA on hippocampal ferroptosis and the Nrf2 pathway likely contributed to the alleviation of depression- like behaviors in OVX mice. CONCLUSION: Tan IIA inhibits hippocampal ferroptosis and alleviates depression-like behaviors in OVX mice, which may be related to the up-regulation of the Nrf2/SLC7A11/GPX4 pathway.