丹参素钠对脑缺血的治疗时间窗及其通过Nrf2途径抑制氧化应激和铁凋亡的机制

IF 3.7 3区医学 Q2 NEUROSCIENCES

Brain Research Bulletin Pub Date : 2025-05-20 DOI:10.1016/j.brainresbull.2025.111396

Chao Guo , Zhongying Ma , Xingru Tao , Kai Gao, Wei Zhang, Aidong Wen, Yi Ding, Jingwen Wang

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引用次数: 0

摘要

丹参素钠（SDSS）是丹参根的提取物，在我们之前的研究中已被证明对缺血性脑卒中（IS）具有神经保护作用。然而，其治疗时间窗和作用机制尚不清楚。铁下垂在IS的发生发展中起着至关重要的作用。核因子e2相关因子2 （Nrf2）可以正向调节铁死亡中抗脂质过氧化的重组溶质载体家族7、成员11 （SLC7A11）和谷胱甘肽过氧化物酶（GPX4）基因的转录。目的探讨SDSS的治疗时间窗及nrf2介导的氧化应激和铁下沉的药理机制。方法采用短暂性大脑中动脉闭塞（MCAO）的smice和氧糖剥夺/再氧合（OGD/R）的HT22细胞模拟IS。小鼠分别于MCAO后1、3、6、9 h给予SDSS，以确定SDSS的治疗时间窗。通过MicroRNA-seq分析MCAO组和SDSS治疗组的差异表达基因。通过分子对接、分子动力学（MD）模拟和表面等离子体共振（SPR）实验研究了SDSS与Nrf2之间的相互作用。此外，我们还研究了SDSS对Nrf2缺失小鼠的神经保护作用，以评估SDSS对Nrf2/GPX4轴的激活机制。分别用商用试剂盒、透射电镜（TEM）和Western blotting检测生物标志物（Fe2 +含量、ROS、MDA、GSH、GSH/GSSG）、线粒体结构、Nrf2、SLC7A11、GPX4、FTH1、HO-1、ACSL4和TFRC)表达。结果SDSS的治疗时间窗应在MCAO后6 h内，超过此时间SDSS不能发挥治疗作用。SDSS通过抑制ROS、MDA和Fe2+含量，提高GSH水平和GSH/GSSG比值，对小鼠和HT22细胞具有神经保护作用。在分子机制上，SDSS可结合Nrf2，提高Nrf2活性和核表达，进一步增强SLC7A11、GPX4、FTH1、HO-1表达，降低ACSL4、TFRC表达。然而，SDSS的神经保护作用及其对铁中毒相关蛋白的影响在nrf2缺陷小鼠中部分逆转。结论SDSS治疗缺血性脑卒中的时间窗较宽。SDSS可以通过抑制氧化损伤和铁下沉来潜在地减轻脑损伤，这部分是由Nrf2/GPX4轴调节的。因此，SDSS是治疗缺血性脑卒中的有希望的候选药物。

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Therapeutic time window of sodium of Danshensu on cerebral ischemia and its mechanism of inhibiting oxidative stress and ferroptosis through Nrf2 pathway

Background

Sodium of Danshensu (SDSS), extract of salvia miltiorrhiza root, has been shown to have neuroprotective effects on ischemic stroke (IS) in our previous studies. However, its therapeutic time window and mechanism of action remain unclear. Ferroptosis exerts a crucial feature in the development and progression of IS. Nuclear factor-E2-related factor 2 (Nrf2) can positively regulate the transcription of Recombinant Solute Carrier Family 7, member 11 (SLC7A11) and glutathione peroxidase (GPX4) genes that combat lipid peroxidation in ferroptosis.

Purpose

The current study aimed to assess therapeutic time window of SDSS and the pharmacological mechanism involved in Nrf2-mediated oxidative stress and ferroptosis.

Methods

Mice with transient middle cerebral artery occlusion (MCAO) and HT22 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) were induced to simulate IS. Mice were administered SDSS at 1, 3, 6 or 9 h after MCAO to determine the therapeutic time window of SDSS. MicroRNA-seq was conducted to analyze differentially expressed genes in both the MCAO and the SDSS treatment group. The interaction between SDSS and Nrf2 was also investigated using molecular docking, molecular dynamics (MD) simulations, and surface plasmon resonance (SPR) experiments. Furthermore, the neuroprotection of SDSS was investigated in Nrf2-deficient mice to assess the activation mechanism of the Nrf2/GPX4 axis by SDSS. The biomarkers (Fe^2 + content, ROS, MDA, GSH, GSH/GSSG), mitochondrial structure, these proteins (Nrf2, SLC7A11, GPX4, FTH1, HO-1, ACSL4 and TFRC) expression were detected by commercial kits, transmission electron microscope (TEM) and Western blotting, respectively.

Results

The therapeutic time window of SDSS should be within 6 hours after MCAO, beyond which SDSS cannot play a therapeutic role. SDSS played a neuroprotective affection in mice and HT22 cells by restraining ROS, MDA and Fe²⁺ content, elevating GSH level and GSH/GSSG ratio. At the molecular mechanism, SDSS can bind to Nrf2, improve Nrf2 activity and nuclear expression, further enhance SLC7A11, GPX4, FTH1, HO-1 expression and reduce ACSL4 and TFRC expression. However, the neuroprotective effects of SDSS and its effect on ferroptosis-related proteins were partially reversed in Nrf2-deficient mice.

Conclusion

The therapeutic time window of SDSS for ischemic stroke is relatively wide. The administration of SDSS can potentially mitigate brain damage through the inhibition of oxidative damage and ferroptosis, which is partly regulated by the Nrf2/GPX4 axis. Therefore, SDSS is a promising candidate for the treatment of ischemic stroke.

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来源期刊

Brain Research Bulletin 医学-神经科学

CiteScore

6.90

自引率

2.60%

发文量

253

审稿时长

67 days

期刊介绍： The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.