新巴西异黄酮通过调节SIRT1改善Aβ25-35诱导小鼠的记忆缺陷和脑损伤

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2024-10-11 DOI:10.1111/cns.70068

Fengxiao Hao, Mengnan Zeng, Bing Cao, Xiwen Liang, Kaili Ye, Xinmian Jiao, Weisheng Feng, Xiaoke Zheng

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引用次数: 0

摘要

背景：阿尔茨海默病（AD）是老年人常见的慢性神经退行性疾病，目前尚无特效治疗方法可以阻止或逆转其进展。新巴西异黄酮（Neobavaisoflavone，NBIF）是一种类黄酮，已被证明具有神经保护作用，但其在阿尔茨海默病中的作用尚未被揭示。本研究探讨了NBIF对Aβ25-35诱导的脑损伤的作用和机制：本实验通过注射Aβ25-35肽（200 μM，icv）建立AD小鼠模型，口服多奈哌齐（Don，10 mg/kg/days）、NBIF-L（15 mg/kg/days）和NBIF-H（30 mg/kg/days）4周。对小鼠的学习记忆、海马病理变化、病理标志物、细胞凋亡、氧化应激、炎症、免疫细胞进行了测定。网络药理学与 GEO 数据库相结合，确定了 SIRT1（NBIF 干预 AD 的关键靶点），并测量了 SIRT1、p-STAT3 和 FOXO1 的水平。此外，还研究了SIRT1转染沉默对Aβ25-35诱导的N9细胞和N2a-APP69细胞中NBIF的拮抗活性，以评估NBIF引起的效应是否由SIRT1介导：结果表明，NBIF可改善学习记忆和海马神经元损伤，减少病理标志物、细胞凋亡、氧化应激和神经炎症，并调节免疫细胞。SIRT1是NBIF干预AD的关键靶点，NBIF可上调SIRT1，降低p-STAT3和FOXO1的表达水平。此外，沉默SIRT1可有效降低NBIF对Aβ25-35诱导的N9细胞和N2a-APP69细胞的保护作用，这表明NBIF对AD的保护作用与SIRT1有关：结论：NBIF通过抑制细胞凋亡、氧化应激和神经炎症改善了Aβ25-35诱导的脑损伤，这可能是通过SIRT1信号传导介导的。这些发现为NBIF治疗AD提供了理论依据，有助于促进AD临床治疗药物的开发。

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Neobavaisoflavone Ameliorates Memory Deficits and Brain Damage in Aβ25-35-Induced Mice by Regulating SIRT1

Background

Alzheimer's disease (AD) is a common chronic neurodegenerative disease in older people, and there is no specific treatment that can stop or reverse its progression. Neobavaisoflavone (NBIF) is a flavonoid that has been shown to have neuroprotective effects, but its role in AD has not been revealed. The present study investigated the role and mechanism of NBIF on Aβ_25-35-induced brain injury.

Methods

In this experiment, the AD mouse model was established by injection of Aβ_25-35 peptides (200 μM, icv), and Donepezil (Don, 10 mg/kg/days), NBIF-L (15 mg/kg/days), and NBIF-H (30 mg/kg/days) were administered orally for 4 weeks. Learning memory, hippocampal pathological changes, pathological markers, apoptosis, oxidative stress, inflammation, immune cells were measured in mice. Network pharmacology combined with the GEO database led to the identification of SIRT1, a key target for NBIF intervention in AD, and levels of SIRT1, p-STAT3 and FOXO1 were measured. In addition, the antagonistic activity of SIRT1 transfection silencing against NBIF in Aβ_25-35-induced in N9 cells and N2a-APP69 cells was investigated to assess whether the effects caused by NBIF were mediated by SIRT1.

Results

The results showed that NBIF ameliorated learning memory and hippocampal neuronal damage, reduced pathological markers, apoptosis, oxidative stress and neuroinflammation, and modulated immune cells. SIRT1 is a key target for NBIF intervention in AD, and NBIF upregulates SIRT1 and reduces the expression levels of p-STAT3 and FOXO1. Furthermore, silencing SIRT1 effectively reduced the protective effect of NBIF on Aβ_25-35-induced N9 cells and N2a-APP69 cells, which indicated that the protective effect of NBIF on AD is related to SIRT1.

Conclusions

NBIF ameliorated Aβ_25-35-induced brain injury by inhibiting apoptosis, oxidative stress, and neuroinflammation, which may be mediated through SIRT1 signaling. These findings provide a rationale for NBIF in the treatment of AD and help facilitate the development of clinical therapeutic agents for AD.

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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.