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Aim: We investigated the effects and target of gastrodin (GAS) for treating depression through network pharmacology combined with experimentation., Methods: 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., Results: 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., Conclusion: 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., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

To explore the antidepressant effects and targets of atractylenolide I (ATR) through a network pharmacological approach. Relevant targets of ATR and depression analyzed by network pharmacology were scored (identifying 5-HT2A targets). Through elevated plus maze, open field, tail suspension, and forced swimming tests, the behavioral changes of mice with depression (chronic unpredictable mild stress [CUMS]) were examined, and the levels of neurotransmitters including serotonin, dopamine, and norepinephrine (5-HT, DA, and NE) were determined. The binding of ATR to 5-HT2A was verified by small molecular-protein docking. ATR improved the behaviors of CUMS mice, elevated their levels of neurotransmitters 5-HT, DA, and NE, and exerted a protective effect on their nerve cell injury. After 5-HT2A knockout, ATR failed to further improve the CUMS behaviors. According to the results of small molecular-protein docking and network pharmacological analysis, ATR acted as an inhibitor by binding to 5-HT2A. ATR can improve the behaviors and modulate the neurotransmitters of CUMS mice by targeting 5-HT2A., (© 2023 John Wiley & Sons Ltd.)

Aim: We aimed to explored the role of Antcin K in resisting depression and its targets., Methods: LPS/IFN-γwas used to induce the activation of microglial BV2 cells. Following Antcin K pretreatment, the proportion of M1 cells was determined using flow cytometry (FCM), the expression of cytokines was measured through ELISA, and that of CDb and NLRP3 was analyzed by cell fluorescence staining. The protein levels were detected by Western-blot assay. After NLRP3 was knocked down in BV2 cells (BV2-nlrp3 -/- ), the M1 polarization level was detected with Antcin K treatment. The targeted binding relation of Antcin K with NLRP3 was confirmed through small molecule-protein docking and co-immunoprecipitation assay. The chronic unpredictable stress model (CUMS) was constructed to mimic the depression mice. After the administration of Antcin K, the neurological behavior of CUMS mice were detected by open-field test (OFT), elevated plus maze, forced swimming test (FST), and tail suspension test (TST). In addition, the expression of CD11b and IBA-1 was detected through histochemical staining, and the tissue pathological changes were detected by H&E staining., Results: Antcin K suppressed the M1 polarization of BV2 cells and reduced the expression of inflammatory factors. Meanwhile, NLRP3 exhibited targeted binding relation with Antcin K, and Antcin K lost its effect after NLRP3 knockdown. In the CUMS mouse model, Antcin K improved the depression status and neurological behaviors in mice, and decreased central neuroinflammation and microglial cell polarization., Conclusion: Antcin K targets NLRP3 to suppress microglial cell polarization, alleviate central inflammation in mice and improve their neurological behaviors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)