College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China.
Department of Neurology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
CNS Neurosci Ther. 2024 Mar;30(3):e14444. doi: 10.1111/cns.14444. Epub 2023 Aug 31.
We investigated the effects and target of gastrodin (GAS) for treating depression through network pharmacology combined with experimentation.
The therapeutic target and signal of GAS for depression were analyzed by network pharmacology. Depression in mice was mimicked with a chronic unpredictable mouse stress (CUMS) model. Through open field, elevated plus maze, forced swimming, and tail suspension tests, the effects of GAS on the CUMS mice behaviors were examined, and the levels of neurotransmitters were detected. The histopathological changes were assayed by H&E and IHC staining, and the protein expressions were detected by Western blotting. Small molecule-protein docking and molecular dynamics experiments were conducted to simulate the binding mode between GAS and Caspase-3.
Network pharmacological analysis revealed that Caspase-3 was the action target of GAS. GAS could improve depression-like behaviors in CUMS mice, elevate their neurotransmitter levels, ameliorate their nerve cell injury, and inhibit their Caspase-3 expression. After knocking out Caspase-3, the effects of GAS were inhibited. Molecular dynamics simulation and small molecule-protein docking found that GAS bound to Caspase-3 at SER25, inhibiting the maturation and activation of Caspase-3.
We find that GAS can act as a Caspase-3 inhibitor, which improves depression-like behaviors and nerve cell injury in CUMS mice by inhibiting Caspase-3-mediated apoptosis.
通过网络药理学结合实验研究天麻素（GAS）治疗抑郁症的作用和靶点。
采用网络药理学分析 GAS 治疗抑郁症的治疗靶点和信号。采用慢性不可预测性应激（CUMS）小鼠模型模拟抑郁症。通过旷场实验、高架十字迷宫实验、强迫游泳实验和悬尾实验，观察 GAS 对 CUMS 小鼠行为的影响，并检测神经递质水平。通过 H&E 和 IHC 染色检测组织病理学变化，通过 Western blot 检测蛋白表达。进行小分子-蛋白对接和分子动力学实验，模拟 GAS 与 Caspase-3 的结合模式。
网络药理学分析表明 Caspase-3 是 GAS 的作用靶点。GAS 可改善 CUMS 小鼠的抑郁样行为，提高其神经递质水平，改善神经细胞损伤，抑制其 Caspase-3 表达。敲除 Caspase-3 后，GAS 的作用被抑制。分子动力学模拟和小分子-蛋白对接发现，GAS 与 Caspase-3 结合于 SER25，抑制 Caspase-3 的成熟和激活。
我们发现 GAS 可以作为 Caspase-3 抑制剂，通过抑制 Caspase-3 介导的细胞凋亡，改善 CUMS 小鼠的抑郁样行为和神经细胞损伤。
