Lai Huaqing, Fan Pinglong, Zhang Pengxiang, Zhang Meng, Li Xinmu, Kuang Boyu, Zhou Run, Wang Wenfei, Jiang Hong, Wang Zhenzhen, Chen Naihong
School of Pharmaceutical Sciences, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Theranostics. 2025 Jul 24;15(16):8150-8175. doi: 10.7150/thno.115587. eCollection 2025.
The limitations of current depression treatments highlight the importance of developing new therapeutic strategies. Tanshinone I (Tan I), a naturally occurring lipophilic diterpene compound, has promising activities including inflammation inhibition, cellular autophagy or apoptosis modulation, and anti-oxidative stress. However, the potential antidepressant effects of Tan I and the mechanism behind its action have yet to be established. The antidepressant effect of Tan I was evaluated using animal behavior tests. The chronic unpredictable stress (CUS) mice and C3 overexpressing mice were used to investigate the mechanism of Tan I in microglia-mediated synaptic engulfment, and to explore the effect of Tan I on the improvement of functional magnetic resonance imaging (fMRI)-based network changes in depression-like mice. Here, it is found that Tan I efficiently improved the CUS-induced depressive-like behaviors, attenuated synaptic loss, and inhibited microglial activation. The drug affinity responsive target stability assay and microscale thermophoresis revealed that the specific target of Tan I is complement C3. Furthermore, Tan I decreased the CUS-induced synaptic loss by inhibiting the deposition of C3 deposition onto synapses and subsequent microglia-mediated synaptic engulfment. Importantly, Tan I also improved fMRI-based network changes in CUS mice. Overexpression of C3 in the medial prefrontal cortex (mPFC) of normal mice leads to depressive-like behavior, accompanied by synaptic loss and reduced fMRI-based network changes. In contrast, administration of Tan I inhibits microglia-mediated synaptic phagocytosis and improves fMRI-based network changes, which in turn ameliorate the depressive-like behaviors in C3-overexpressing mice. Collectively, the study demonstrated that Tan I acts as a potent natural C3 modulator that binds directly to C3, blocks the C3-CR3 axis and downstream signal transducer and activator of transcription 3 (STAT3) signaling pathway, inhibits microglia-mediated synaptic engulfment, and improves fMRI-based network changes, which in turn exert antidepressant effects.
当前抑郁症治疗方法的局限性凸显了开发新治疗策略的重要性。丹参酮I（Tan I）是一种天然存在的亲脂性二萜化合物，具有包括抑制炎症、调节细胞自噬或凋亡以及抗氧化应激等有前景的活性。然而，Tan I的潜在抗抑郁作用及其作用机制尚未明确。使用动物行为测试评估了Tan I的抗抑郁作用。利用慢性不可预测应激（CUS）小鼠和C3过表达小鼠来研究Tan I在小胶质细胞介导的突触吞噬中的作用机制，并探索Tan I对改善基于功能磁共振成像（fMRI）的抑郁症样小鼠网络变化的影响。在此发现，Tan I有效改善了CUS诱导的抑郁样行为，减轻了突触损失，并抑制了小胶质细胞的激活。药物亲和力响应靶点稳定性测定和微量热泳分析表明Tan I的特异性靶点是补体C3。此外，Tan I通过抑制C3在突触上的沉积以及随后小胶质细胞介导的突触吞噬，减少了CUS诱导的突触损失。重要的是，Tan I还改善了CUS小鼠基于fMRI的网络变化。正常小鼠内侧前额叶皮质（mPFC）中C3的过表达导致抑郁样行为，伴有突触损失和基于fMRI的网络变化减少。相反，给予Tan I可抑制小胶质细胞介导的突触吞噬并改善基于fMRI的网络变化，进而改善C3过表达小鼠的抑郁样行为。总体而言，该研究表明Tan I作为一种有效的天然C3调节剂，直接与C3结合，阻断C3-CR3轴和下游信号转导子和转录激活子3（STAT3）信号通路，抑制小胶质细胞介导的突触吞噬，并改善基于fMRI的网络变化，进而发挥抗抑郁作用。
