Alleviation of Microglia Mediating Hippocampal Neuron Impairments and Depression-Related Behaviors by Urolithin B via the SIRT1-FOXO1 Pathway

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-04-16 DOI:10.1111/cns.70379

Cuilan Liu, Di Zhao, Guoxing Yu, HengWei Du, Lihong Xu, Yifan Cao, Minghu Cui, Wentao Wang, Dan Wang, Jing Liu, Fantao Meng, Fengai Hu, Wei Li, Jing Du, Chen Li

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Abstract

Aims

Conventional antidepressants exhibit limited efficacy and delayed onset. This study aimed to elucidate the antidepressant effects of urolithin B (UB) and its regulatory role in microglia-mediated hippocampal neuronal dysfunction.

Methods

The mouse model of depression was established using both chronic unpredicted stress (CUS) and lipopolysaccharide (LPS) injection. The therapeutic efficacy of UB was assessed through behavioral paradigms. The microglia activation, cellular cytotoxicity and apoptosis levels, and underlying molecular mechanisms were delineated utilizing proteomics analysis, immunofluorescence staining, real-time PCR and Western blotting.

Results

UB efficiently alleviated depression-related behaviors, accompanied by suppressed microglia activation, neuroinflammation, changes of classic activation (M1)/alternative activation (M2) polarization and recovered sirtuin-1 (SIRT1) and forkhead box protein O1 (FOXO1) expression in the hippocampus. Additionally, UB reduced the cytotoxicity and apoptosis of HT22 cells and depression-related phenotypes treated by the cellular supernatant from LPS-incubated BV2 cells, which was mediated by the SIRT1-FOXO1 pathway. The proteomics analysis of the cellular supernatant content revealed abundant secreting proteins among the LPS/UB application.

Conclusion

This study confirmed that microglial SIRT1 mediates UB's antidepressant effects, positioning UB as a promising therapeutic candidate for depression by targeting neuroinflammatory pathways.

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尿素B通过SIRT1-FOXO1通路减轻小胶质细胞介导的海马神经元损伤和抑郁相关行为

目的：传统抗抑郁药物疗效有限，起效延迟。本研究旨在阐明尿素B （UB）的抗抑郁作用及其在小胶质细胞介导的海马神经元功能障碍中的调节作用。方法采用慢性不可预测应激（CUS）和脂多糖（LPS）注射建立小鼠抑郁模型。通过行为范式评估UB的治疗效果。利用蛋白质组学分析、免疫荧光染色、实时荧光定量PCR和Western blotting分析小胶质细胞的活化、细胞毒性和凋亡水平以及潜在的分子机制。结果UB有效缓解抑郁相关行为，同时抑制小胶质细胞活化、神经炎症、经典活化(M1)/替代活化（M2）极化改变，恢复海马sirtuin-1 （SIRT1）和叉头盒蛋白O1 （FOXO1）表达。此外，UB降低了lps培养的BV2细胞上清处理的HT22细胞的细胞毒性和凋亡，以及抑郁相关表型，这是由SIRT1-FOXO1途径介导的。细胞上清含量的蛋白质组学分析显示LPS/UB应用中有丰富的分泌蛋白。结论本研究证实了小胶质细胞SIRT1介导UB的抗抑郁作用，将UB定位为一种有希望的治疗抑郁症的候选药物，通过靶向神经炎症途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.