RasGRF1 participates in the protective effect of tanshinone IIA on depressive like behaviors of a chronic unpredictable mild stress induced mouse model

• Published in: Gene 2020-09, Vol.754, p.144817-144817, Article 144817
• Main Authors: Cheng, Yuanyuan, An, Qi, Wang, Jing, Wang, Yue, Dong, Jicheng, Yin, Junbo
• Format: Article
• Language: English
• Subjects: Chronic unpredictable mild stress; Depressive-like behaviors; RasGRF1; Tanshinone IIA
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2020.144817

•Tan IIA attenuated depressive like behaviors in CUMS mice.•Tan IIA increased levels of neurotrophic factors in CUMS mice.•Tan IIA inhibited RasGRF1 expression in CUMS mice.•Tan IIA inhibited oxidative stress and pro-inflammatory cytokines in CUMS mice.•RasGRF1 knockout attenuated depressive like behaviors in CUMS mice.•RasGRF1 knockout attenuated oxidative stress in CUMS mice. Tanshinone IIA (Tan IIA) is reported to have neuroprotective effects to suppress cell apoptosis of cortical neurons induced by Aβ25-35 through inhibiting oxidative stress. Nevertheless, few studies have investigated the effects of Tan IIA on depressive disorder. Here, we aimed to measure the effects of Tan IIA on chronic unpredictable mild stress (CUMS) induced mouse model and its underlying mechanism. For 28 days, mice were subjected to CUMS while Tan IIA was administered once daily at doses of 0, 1, 2.5, 5, or 10 mg/kg. CUMS exposure increased depressive-like behaviors, as indicated by increased immobility time in the forced swim and tail suspension tests, decreased sucrose preference in the sucrose preference test, and reduced exploratory behavior in the open field test. All of these behaviors were reversed dose-dependently by Tan IIA treatment. Oxidative stress was determined by measuring malondialdehyde, glutathione peroxidase, and superoxide dismutase activity and total antioxidant capacity. Levels of pro-inflammatory factors IL-1β and IL-18, cAMP response element binding protein and brain derived neurotrophic factor were detected by ELISA and western blot assay, respectively. The results showed that CUMS increased oxidative stress and pro-inflammatory factors and decreased levels of cAMP response element binding protein and brain-derived neurotrophic factor. Tan IIA treatment again reversed these effects. Importantly, RasGRF1 expression increased in CUMS-exposed mice but decreased after Tan IIA administration. Using RasGRF1-/- mice to determine the role of RasGRF1 in mice exposed to CUMS, we found that knockdown of RasGRF1 reversed the effects of CUMS on mice, just like Tan IIA. These results indicate that Tan IIA may reverse depressive-like behaviors in CUMS-exposed mice by regulating RasGRF1.