Alliance for Research on the Mediterranean and North Africa (ARENA), University of Tsukuba, Tsukuba, Japan.
Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
Geroscience. 2024 Apr;46(2):1671-1691. doi: 10.1007/s11357-023-00919-x. Epub 2023 Sep 18.
In recent years, exploring natural compounds with functional properties to ameliorate aging-associated cognitive decline has become a research priority to ensure healthy aging. In the present study, we investigated the effects of Trigonelline (TG), a plant alkaloid, on memory and spatial learning in 16-week-old senescence-accelerated mouse model SAMP8 using an integrated approach for cognitive and molecular biology aspects. After 30 days of oral administration of TG at the dose of 5 mg/kg/day, the mice were trained in Morris Water Maze task. TG-treated SAMP8 mice exhibited significant improvement in the parameters of escape latency, distance moved, and annulus crossing index. Next, we performed a whole-genome transcriptome profiling of the mouse hippocampus using microarrays. Gene ontology analyses showed that a wide range of biological processes, including nervous system development, mitochondrial function, ATP synthesis, and several signaling pathways related to inflammation, autophagy, and neurotransmitter release, were significantly enriched in TG-treated SAMP8 compared to nontreated. Further, a nonlinear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP), was applied to identify clusters of functions that revealed TG primarily regulated pathways related to inflammation, followed by those involved in neurotransmitter release. In addition, a protein-protein interaction network analysis indicated that TG may exert its biological effects through negatively modulating Traf6-mediated NF-κB activation. Finally, ELISA test showed that TG treatment significantly decreased proinflammatory cytokines- TNFα and IL6 and increased neurotransmitters- dopamine, noradrenaline, and serotonin in mouse hippocampus. Altogether, our integrated bio-cognitive approach highlights the potential of TG in alleviating age-related memory and spatial impairment.
近年来，探索具有功能特性的天然化合物以改善与衰老相关的认知能力下降已成为研究重点，以确保健康衰老。在本研究中，我们采用认知和分子生物学综合方法，研究了植物生物碱三甲基六氢吡啶（TG）对 16 周龄快速老化模型小鼠 SAMP8 记忆和空间学习的影响。在每天 5mg/kg 的剂量下口服 TG30 天后，对小鼠进行 Morris 水迷宫任务训练。TG 处理的 SAMP8 小鼠在逃避潜伏期、移动距离和环穿越指数等参数上均有显著改善。接下来，我们使用微阵列对小鼠海马体进行全基因组转录组谱分析。GO 分析表明，在 TG 处理的 SAMP8 中，包括神经系统发育、线粒体功能、ATP 合成以及与炎症、自噬和神经递质释放相关的几种信号通路在内的广泛生物学过程显著富集。此外，非线性降维技术 Uniform Manifold Approximation and Projection (UMAP) 被应用于识别功能聚类，结果显示 TG 主要调节与炎症相关的途径，其次是与神经递质释放相关的途径。此外，蛋白质-蛋白质相互作用网络分析表明，TG 可能通过负向调节 Traf6 介导的 NF-κB 激活来发挥其生物学作用。最后，ELISA 测试表明，TG 处理可显著降低小鼠海马体中的促炎细胞因子 TNFα 和 IL6，增加神经递质多巴胺、去甲肾上腺素和 5-羟色胺。综上所述，我们的综合生物认知方法强调了 TG 缓解与年龄相关的记忆和空间损伤的潜力。
