Di Yaqian, Xue Rui, Li Xia, Jin Zijia, Li Hanying, Wu Lanrui, Zhang Youzhi, An Lei
Key Laboratory of Geriatric Nutrition and Health, Beijing Technology and Business University, Ministry of Education, Beijing 100048, China.
Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Nutrients. 2025 Jul 11;17(14):2294. doi: 10.3390/nu17142294.
BACKGROUND/OBJECTIVES: Urolithin A (UA), a gut-derived metabolite of ellagitannins or ellagic acid, has recently gained attention for its potential benefits to brain health. The present research aimed to assess the antidepressant-like properties of UA in both in vitro and in vivo models and explored the molecular mechanisms underlying these effects.
We investigated the antidepressant effects and mechanisms of UA in a model of corticosterone-induced damage to PC12 cells and in a model of chronic socially frustrating stress.
Our results demonstrate that UA treatment (5 and 10 μM) significantly alleviated cellular damage and inflammation in corticosterone (CORT)-treated PC12 cells. Furthermore, UA administration (50 and 100 mg/kg) significantly reduced immobility time in the mouse tail suspension test (TST) and forced swim test (FST), indicating its antidepressant-like activity. Additionally, treatment with UA led to the activation of the cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling cascade and triggered the activation of adenosine monophosphate-activated protein kinase (AMPK) during these processes. Importantly, pretreatment with AMPK-specific inhibitor Compound C abolished UA's cytoprotective effects in PC12 cells, as well as its behavioral efficacy in the FST and TST, and its neurotrophic effects, highlighting the critical role of AMPK activation in mediating these effects. Furthermore, in the chronic social defeat stress (CSDS) mouse model, UA treatment (50 and 100 mg/kg) significantly alleviated depression-like behaviors, including reduced sucrose preference in the sucrose preference test, increased social avoidance behavior in the social interaction test, and anxiety-like behaviors, including diminished exploration, in the elevated plus maze test, suggesting the antidepressant-like and anxiolytic-like activities of UA. Moreover, UA treatment reversed elevated serum stress hormone levels, hippocampal inflammation, and the decreased AMPK/CREB/BDNF signaling pathway in the hippocampus of CSDS mice.
Together, these results provide compelling evidence for UA as a viable dietary supplement or therapeutic option for managing depression.
背景/目的：尿石素A（UA）是鞣花单宁或鞣花酸的肠道衍生代谢产物，最近因其对脑健康的潜在益处而受到关注。本研究旨在评估UA在体外和体内模型中的抗抑郁样特性，并探讨这些作用背后的分子机制。
我们在皮质酮诱导的PC12细胞损伤模型和慢性社会挫败应激模型中研究了UA的抗抑郁作用及其机制。
我们的结果表明，UA处理（5和10μM）显著减轻了皮质酮（CORT）处理的PC12细胞中的细胞损伤和炎症。此外，UA给药（50和100mg/kg）显著减少了小鼠悬尾试验（TST）和强迫游泳试验（FST）中的不动时间，表明其具有抗抑郁样活性。此外，在这些过程中，UA处理导致环磷酸腺苷反应元件结合蛋白（CREB）/脑源性神经营养因子（BDNF）信号级联的激活，并触发了腺苷单磷酸激活蛋白激酶（AMPK）的激活。重要的是，用AMPK特异性抑制剂化合物C预处理消除了UA在PC12细胞中的细胞保护作用，以及其在FST和TST中的行为功效及其神经营养作用，突出了AMPK激活在介导这些作用中的关键作用。此外，在慢性社会挫败应激（CSDS）小鼠模型中，UA处理（50和100mg/kg）显著减轻了抑郁样行为，包括蔗糖偏好试验中蔗糖偏好的降低、社会互动试验中社会回避行为的增加，以及高架十字迷宫试验中焦虑样行为，包括探索减少，表明UA具有抗抑郁样和抗焦虑样活性。此外，UA处理逆转了CSDS小鼠血清应激激素水平升高、海马炎症以及海马中AMPK/CREB/BDNF信号通路的降低。
总之，这些结果为UA作为一种可行的膳食补充剂或治疗抑郁症的选择提供了有力证据。
