Ligustilide ameliorates cerebral ischemia-reperfusion injury by inhibiting NLRP3 inflammasome-dependent pyroptosis through enhancing Nrf2 signaling

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-08-21 DOI:10.1016/j.neuropharm.2025.110642

Yang Wang , Zhihan Wan , Ning Wang , Qian Wu , Saiwang Seto

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Abstract

Pyroptosis is a type of proinflammatory programmed cell death, that closely related to the progress of cerebral ischemia/reperfusion injury (CIRI), and NLRP3 inflammasome is the most classic pathway mediating pyroptosis. Ligustilide (LIG) is a natural compound derived from the traditional Chinese herb chuanxiong hort and angelica sinensis which can penetrate the blood-brain barrier and has a good neuroprotective effect. However, it remains unclear whether LIG could alleviate CIRI by inhibiting pyroptosis. Here, the neuroprotective effect of LIG was verified by reducing NLRP3-mediated pyroptosis, and further exploring whether the inhibition of LIG on pyroptosis was related to Nuclear factor-erythropoietin 2-related factor 2(Nrf2)activation. The results showed that LIG can reduce the injury of brain tissue after ischemia, as well as NLRP3 inflammasome-mediated pyroptosis and neuroinflammation response after MCAO/R in rats. Mechanistically, the effect of LIG on Nrf2 was detected by molecular docking, protein levels and immunofluorescence analysis. We found that LIG promoted the Nrf2 expression and reduced the production of mitochondrial ROS (mtROS), and than inhibited NLRP3 inflammasome-mediated pyroptosis. Particularly revealing was that ML385, the inhibitor of Nrf2, partly blocked the above effects of LIG. All these findings suggest that LIG may ameliorate CIRI through inhibiting NLRP3 inflammasome-mediated pyroptosis dependent on Nrf2 signaling.

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藁本内酯通过增强Nrf2信号，抑制NLRP3炎性小体依赖性焦亡，改善脑缺血再灌注损伤

焦亡是一种促炎性程序性细胞死亡，与脑缺血再灌注损伤（CIRI）的进展密切相关，NLRP3炎性小体是介导焦亡的最经典途径。liguslide （liguslide）是从中药川芎和当归中提取的天然化合物，能穿透血脑屏障，具有良好的神经保护作用。然而，LIG是否可以通过抑制焦亡来减轻CIRI尚不清楚。本研究通过降低nlrp3介导的焦亡来验证LIG的神经保护作用，并进一步探讨LIG对焦亡的抑制是否与核因子-促红细胞生成素2相关因子2（Nrf2）激活有关。结果表明，LIG可减轻大鼠缺血后脑组织损伤，以及MCAO/R后NLRP3炎症小体介导的焦亡和神经炎症反应。机制上，通过分子对接、蛋白水平和免疫荧光分析检测LIG对Nrf2的影响。我们发现，LIG促进Nrf2的表达，减少线粒体ROS （mtROS）的产生，并抑制NLRP3炎症小体介导的焦亡。特别具有启发性的是Nrf2抑制剂ML385部分阻断了LIG的上述作用。所有这些发现表明，LIG可能通过抑制NLRP3炎症小体介导的依赖于Nrf2信号的焦亡来改善CIRI。

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

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).