Hu Yudie, Xiao Ran, Wang Cong, Meng Huihui, Yao Benxing, Xu Qian, Xu Xi, Wang Junsong
Center of Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, 210094, China.
Metabolomics. 2025 Jul 11;21(4):100. doi: 10.1007/s11306-025-02306-3.
Post-stroke depression (PSD) pathophysiology involves glutamate excitotoxicity mediated through 'postsynaptic density protein95-neuronal nitric oxide synthase' (PSD95-nNOS) coupling. However, the therapeutic mechanisms of targeting this complex remain incompletely understood.
To elucidate the antidepressant mechanisms of the PSD95-nNOS decoupler ZL006 using an innovative integrated metabolomics approach.
We developed an innovative integrated metabolomics approach to investigate the antidepressant mechanisms of ZL006, a selective PSD95-nNOS decoupler. Using a rat model of PSD, we employed untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics combined with a novel analytical framework that distinguished treatment efficacy-associated metabolites from drug bias-associated ones. This classification enabled identification of primary drug mechanisms versus secondary responses. Pathway analyses focused on proteins interacting with drug-specific metabolites, with key findings validated through quantitative polymerase chain reaction (qPCR).
ZL006 demonstrated dose-dependent antidepressant effects while modulating multiple neurotransmitter pathways, including tryptophan, tyrosine, and arginine metabolism, along with steroid hormone synthesis. Our integrated metabolomics approach revealed vascular endothelial growth factor (VEGF) signaling, hypoxia-inducible factor (HIF) pathway, and tight junction regulation as primary mechanisms of action.
This novel metabolomics strategy, by discriminating between treatment-associated and compound-intrinsic pathways, provided unprecedented mechanistic insights into ZL006's therapeutic effects. The findings suggest that ZL006 alleviates PSD through coordinated modulation of neuroplasticity, angiogenesis, and stress responses via PSD95-nNOS targeting. This integrated analytical approach presents a valuable framework for mechanistic investigation of therapeutic compounds.
中风后抑郁症（PSD）的病理生理学涉及通过“突触后致密蛋白95-神经元型一氧化氮合酶”（PSD95-nNOS）偶联介导的谷氨酸兴奋性毒性。然而，针对这一复合体的治疗机制仍未完全明确。
采用创新的综合代谢组学方法阐明PSD95-nNOS解偶联剂ZL006的抗抑郁机制。
我们开发了一种创新的综合代谢组学方法来研究选择性PSD95-nNOS解偶联剂ZL006的抗抑郁机制。利用PSD大鼠模型，我们采用非靶向液相色谱-质谱（LC-MS）代谢组学，并结合一种新颖的分析框架，将与治疗效果相关的代谢物与药物偏差相关的代谢物区分开来。这种分类有助于识别主要药物机制与次要反应。通路分析聚焦于与药物特异性代谢物相互作用的蛋白质，并通过定量聚合酶链反应（qPCR）验证关键发现。
ZL006表现出剂量依赖性抗抑郁作用，同时调节多种神经递质途径，包括色氨酸、酪氨酸和精氨酸代谢以及类固醇激素合成。我们的综合代谢组学方法揭示血管内皮生长因子（VEGF）信号通路、缺氧诱导因子（HIF）途径和紧密连接调节是主要作用机制。
这种新颖的代谢组学策略通过区分与治疗相关的途径和化合物固有途径，为ZL006的治疗效果提供了前所未有的机制见解。研究结果表明，ZL006通过靶向PSD95-nNOS协同调节神经可塑性、血管生成和应激反应来减轻PSD。这种综合分析方法为治疗化合物的机制研究提供了一个有价值的框架。
