Schisandrin B ameliorates Alzheimer's disease by suppressing neuronal ferroptosis and ensuing microglia M1 polarization

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-16 DOI:10.1016/j.phymed.2025.156780

Tao Ding , Meiying Song , Yongshi Wu, Zhu Li, Shanshan Zhang, Xiang Fan

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引用次数: 0

Abstract

Background

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal damage, with poor prognosis and limited therapeutic options. Inhibition of neuronal ferroptosis has shown promise as a potential treatment for AD. Schisandrin B (Sch B), a major active component of Schisandra chinensis, exhibits potential neuroprotective effects. However, whether Sch B inhibits neuronal ferroptosis remains unclear.

Purpose

To investigate the mechanisms underlying the effects of Sch B on the GSK3β/Nrf2/GPX4 and FSP1 signaling pathways, which are the suppression of neuronal ferroptosis and the potential therapeutic intervention in AD.

Methods

We employed the 3 × Tg mouse model in vivo, and utilized the erastin-induced ferroptosis model in SH-SY5Y/APP695swe cells in vitro. Nissl staining was conducted to facilitate histopathological assessment. Assessment of neuronal ferroptosis was performed utilizing a lipid peroxidation and ferroptosis marker assay kit. Furthermore, bioinformatic analysis was executed with the application of the GEO database. Immunofluorescence and Western blot analyses were performed to quantify protein expression levels within the cellular context. ELISA was utilized to determine cytokine concentrations within the supernatant of cell cultures. RT-PCR was executed to evaluate mRNA expression levels.

Results

Sch B suppresses the activation of GSK3β, modulating the Nrf2/GPX4 signaling pathway and consequently inhibiting ferroptosis in neurons, which results in amelioration of cognitive impairment and pathological damage in 3 × Tg mice. Sch B also inhibits GSK3β activation, thereby modulating the Nrf2/GPX4 signaling pathway to prevent erastin-induced ferroptosis in SH-SY5Y695swe cells in vitro. Furthermore, Sch B modulates FSP1, enhancing its synergistic interaction with the GSK3β/Nrf2/GPX4 pathway to suppress neuronal ferroptosis. Sch B can also inhibit TNF-α release from neurons undergoing ferroptosis, thus impeding the activation of M1-type microglia, suggesting a multifaceted neuroprotective strategy against neuroinflammatory processes.

Conclusion

Sch B modulates the GSK3β/Nrf2/GPX4 pathway in conjunction with FSP1 to inhibit neuronal ferroptosis and the subsequent microglial M1 polarization mediated by neuronal ferroptosis, thereby improving cognitive impairment and pathological damage in AD.

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五味子素B通过抑制神经元铁质凋亡和随之而来的小胶质细胞M1极化来改善阿尔茨海默病

背景：阿尔茨海默病（AD）是一种以神经元损伤为特征的神经退行性疾病，预后差，治疗选择有限。抑制神经元铁下垂已显示出作为一种潜在的治疗阿尔茨海默病的希望。五味子素B （Schisandrin B, Sch B）是五味子的主要活性成分，具有潜在的神经保护作用。然而，Sch B是否抑制神经元铁下垂仍不清楚。目的探讨Sch B对GSK3β/Nrf2/GPX4和FSP1信号通路的影响，探讨其抑制AD神经元铁凋亡的机制和潜在的治疗干预作用。方法采用体内3 × Tg小鼠模型，体外SH-SY5Y/APP695swe细胞采用erastin诱导的铁下垂模型。尼氏染色便于组织病理学评估。利用脂质过氧化和铁下垂标志物测定试剂盒评估神经元铁下垂。应用GEO数据库进行生物信息学分析。免疫荧光和Western blot分析定量细胞内蛋白表达水平。ELISA法测定细胞培养上清液中细胞因子的浓度。RT-PCR检测mRNA表达水平。结果ssch B通过抑制GSK3β的激活，调节Nrf2/GPX4信号通路，抑制神经元铁凋亡，改善3 × Tg小鼠的认知功能障碍和病理损伤。Sch B还可以抑制GSK3β的激活，从而调节Nrf2/GPX4信号通路，从而在体外防止骨蛋白酶诱导的SH-SY5Y695swe细胞铁凋亡。此外，Sch B调节FSP1，增强其与GSK3β/Nrf2/GPX4通路的协同作用，抑制神经元铁凋亡。Sch B还可以抑制发生铁凋亡的神经元释放TNF-α，从而阻碍m1型小胶质细胞的激活，提示对神经炎症过程具有多方面的神经保护策略。结论sch B与FSP1共同调控GSK3β/Nrf2/GPX4通路，抑制神经元铁下沉及随后由神经元铁下沉介导的小胶质M1极化，从而改善阿尔茨海默病的认知功能障碍和病理损伤。

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

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.