Speers Alex B, García-Jaramillo Manuel, Feryn Alicia, Matthews Donald G, Lichtenberg Talia, Caruso Maya, Wright Kirsten M, Quinn Joseph F, Stevens Jan F, Maier Claudia S, Soumyanath Amala, Gray Nora E
Department of Neurology, Oregon Health & Science University, Portland, OR, United States.
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States.
Front Pharmacol. 2021 Dec 16;12:788312. doi: 10.3389/fphar.2021.788312. eCollection 2021.
is an herb used in Ayurvedic and traditional Chinese medicine for its beneficial effects on brain health and cognition. Our group has previously shown that a water extract of (CAW) elicits cognitive-enhancing effects in animal models of aging and Alzheimer's disease, including a dose-related effect of CAW on memory in the 5xFAD mouse model of -amyloid accumulation. Here, we endeavor to elucidate the mechanisms underlying the effects of CAW in the brain by conducting a metabolomic analysis of cortical tissue from 5xFAD mice treated with increasing concentrations of CAW. Tissue was collected from 8-month-old male and female 5xFAD mice and their wild-type littermates treated with CAW (0, 200, 500, or 1,000 mg/kg/d) dissolved in their drinking water for 5 weeks. High-performance liquid chromatography coupled to high-resolution mass spectrometry analysis was performed and relative levels of 120 annotated metabolites were assessed in the treatment groups. Metabolomic analysis revealed sex differences in the effect of the 5xFAD genotype on metabolite levels compared to wild-type mice, and variations in the metabolomic response to CAW depending on sex, genotype, and CAW dose. In at least three of the four treated groups (5xFAD or wild-type, male or female), CAW (500 mg/kg/d) significantly altered metabolic pathways related to purine metabolism, nicotinate and nicotinamide metabolism, and glycerophospholipid metabolism. The results are in line with some of our previous findings regarding specific mechanisms of action of CAW (e.g., improving mitochondrial function, reducing oxidative stress, and increasing synaptic density). Furthermore, these findings provide new information about additional, potential mechanisms for the cognitive-enhancing effect of CAW, including upregulation of nicotinamide adenine dinucleotide in the brain and modulation of brain-derived neurotrophic factor. These metabolic pathways have been implicated in the pathophysiology of Alzheimer's disease, highlighting the therapeutic potential of CAW in this neurodegenerative disease.
是一种在阿育吠陀医学和传统中医中使用的草药，因其对大脑健康和认知有有益影响。我们的团队之前已经表明，（某种草药名称未给出，假设为CAW）的水提取物在衰老和阿尔茨海默病的动物模型中具有认知增强作用，包括CAW对淀粉样蛋白积累的5xFAD小鼠模型中记忆的剂量相关效应。在这里，我们通过对用不同浓度CAW处理的5xFAD小鼠的皮质组织进行代谢组学分析，来阐明CAW在大脑中作用的潜在机制。从8个月大的雄性和雌性5xFAD小鼠及其野生型同窝小鼠中收集组织，这些小鼠饮用溶解有CAW（0、200、500或1000mg/kg/d）的水5周。进行了高效液相色谱与高分辨率质谱联用分析，并评估了各治疗组中120种注释代谢物的相对水平。代谢组学分析揭示了与野生型小鼠相比，5xFAD基因型对代谢物水平影响的性别差异，以及根据性别、基因型和CAW剂量对CAW的代谢组学反应的变化。在四个处理组中的至少三个组（5xFAD或野生型，雄性或雌性）中，CAW（500mg/kg/d）显著改变了与嘌呤代谢、烟酸和烟酰胺代谢以及甘油磷脂代谢相关的代谢途径。这些结果与我们之前关于CAW特定作用机制的一些发现一致（例如，改善线粒体功能、减少氧化应激和增加突触密度）。此外，这些发现提供了关于CAW认知增强作用的其他潜在机制的新信息，包括大脑中烟酰胺腺嘌呤二核苷酸的上调和脑源性神经营养因子的调节。这些代谢途径与阿尔茨海默病的病理生理学有关，突出了CAW在这种神经退行性疾病中的治疗潜力。
