Department of Geriatrics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong District, Shanghai, 201203, China.
Sci Rep. 2022 Nov 19;12(1):19959. doi: 10.1038/s41598-022-24378-0.
Cinnamon aqueous extract's active substance base remains unclear and its mechanisms, mainly the therapeutic target of anti-Alzheimer's disease (AD)-related GABAergic synaptic dysfunction, remain unclear. Here, 30 chemical components were identified in the aqueous extract of cinnamon using LC/MS; secondly, we explored the brain-targeting components of the aqueous extract of cinnamon, and 17 components had a good absorption due to the blood-brain barrier (BBB) limitation; thirdly, further clustering analysis of active ingredient targets by network pharmacology showed that the GABA pathway with GABRG2 as the core target was significantly enriched; then, we used prominent protein-protein interactions (PPI), relying on a protein-metabolite network, and identified the GABRA1, GABRB2 and GABRA5 as the closest targets to GABRG2; finally, the affinity between the target and its cognate active compound was predicted by molecular docking. In general, we screened five components, methyl cinnamate, propyl cinnamate, ( +)-procyanidin B2, procyanidin B1, and myristicin as the brain synapse-targeting active substances of cinnamon using a systematic strategy, and identified GABRA1, GABRB2, GABRA5 and GABRG2 as core therapeutic targets of cinnamon against Alzheimer's disease-related GABAergic synaptic dysfunction. Exploring the mechanism of cinnamon' activities through multi-components and multiple targets strategies promise to reduce the threat of single- target and symptom-based drug discovery failure.
肉桂水提物的活性物质基础尚不清楚，其作用机制，主要是抗阿尔茨海默病（AD）相关 GABA 能突触功能障碍的治疗靶点，也不清楚。本研究采用 LC/MS 鉴定肉桂水提物中的 30 种化学成分；其次，我们探索了肉桂水提物的脑靶向成分，有 17 种成分由于血脑屏障（BBB）的限制而具有良好的吸收性；然后，通过网络药理学对活性成分靶点进行进一步聚类分析，表明以 GABRG2 为核心靶点的 GABA 通路显著富集；接着，我们利用突出的蛋白质-蛋白质相互作用（PPI），基于蛋白质-代谢物网络，鉴定出 GABRA1、GABRB2 和 GABRA5 是与 GABRG2 最接近的靶点；最后，通过分子对接预测了靶点与其同源活性化合物的亲和力。总之，我们采用系统策略筛选出肉桂水提物中的 5 种成分，肉桂酸甲酯、肉桂酸丙酯、（ +）-原花青素 B2、原花青素 B1 和肉豆蔻醚作为肉桂水提物针对阿尔茨海默病相关 GABA 能突触功能障碍的脑突触靶向活性物质，并鉴定出 GABRA1、GABRB2、GABRA5 和 GABRG2 为肉桂治疗阿尔茨海默病相关 GABA 能突触功能障碍的核心治疗靶点。通过多成分、多靶点策略探索肉桂的作用机制有望降低单靶点和基于症状的药物发现失败的威胁。
