Poliumoside alleviates microglia-mediated inflammation and blood-brain barrier disruption via modulating the polarization of microglia after ischemic stroke in mice

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-23 DOI:10.1016/j.phymed.2025.156881

Yuxiao Gao , Jingjing Wang , Cong Zhang , Huan Wang , Bin Wang , Xiangjian Zhang

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引用次数: 0

Abstract

Background

Ischemic stroke remains a life-threatening condition with limited therapeutic options. Microglia-mediated neuroinflammation critically exacerbates acute ischemic injury. The active compound poliumoside (Pol) in Callicarpa kwangtungensis Chun exhibits significant anti-inflammatory effects. The therapeutic potential of Pol for ischemic stroke remains unknown and promising.

Purpose

The current study aimed to investigate the effect of Pol on acute ischemic stroke in mice, and to elucidate the underlying mechanisms.

Study design and methods

Ischemic stroke mice model was induced by transient middle cerebral artery occlusion model (tMCAO). Pol was administered by intraperitoneal injection after stroke. Neurological deficits were monitored up to 3 days after stroke. Microglial polarization, and microglia-associated inflammatory cytokines and blood-brain barrier (BBB) integrity were detected in the peri‑infarct cortex at day 1 after stroke. RNA-seq analysis was performed to identify potential pathways recruited by Pol. Primary cortical neuron, BV2 microglia cell lines and mouse brain microvascular endothelial cell lines(bEnd.3) were employed to explore the underlying mechanism in vitro.

Results

Compared with the tMCAO group, Pol significantly alleviated neurological deficits and reduced infarct size in mice. In vitro and in vivo experiments demonstrated that Pol regulates microglial polarization, down-regulates inflammatory factor levels (IL-6 and TNF-α), and attenuates inflammation-mediated BBB damage while maintaining tight junction proteins expression (ZO-1, claudin-5, occludin). Through investigation of the underlying mechanism combined with RNA-seq analysis and experimental results, we established that Pol down-regulated the JAK/STAT3 pathway both in vitro and in vivo, which was corroborated by the use of the JAK inhibitor tofacitinib.

Conclusion

Pol regulates microglial polarization in ischemic stroke by down-regulating JAK/STAT3 signaling pathway, alleviating the microglia-mediated inflammatory response and the destruction of blood-brain barrier.

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脊髓灰质炎皂苷通过调节小鼠缺血性脑卒中后小胶质细胞的极化减轻小胶质细胞介导的炎症和血脑屏障破坏

背景：非化学性中风仍然是一种危及生命的疾病，治疗选择有限。小胶质细胞介导的神经炎症可严重加重急性缺血性损伤。黄柏中有效成分poliumoside （Pol）具有明显的抗炎作用。Pol对缺血性脑卒中的治疗潜力仍然未知，但前景广阔。目的探讨Pol对小鼠急性缺血性脑卒中的影响，并探讨其作用机制。研究设计与方法采用短暂性大脑中动脉闭塞模型（tMCAO）建立小鼠化学性脑卒中模型。脑卒中后通过腹腔注射给予Pol。中风后监测神经功能缺损至3天。卒中后第1天，在梗死周围皮层检测到小胶质细胞极化、小胶质细胞相关的炎症细胞因子和血脑屏障（BBB）完整性。进行RNA-seq分析以确定Pol招募的潜在途径。采用原代皮质神经元、BV2小胶质细胞系和小鼠脑微血管内皮细胞系（bEnd.3）在体外探讨其作用机制。结果与tMCAO组比较，Pol可显著减轻小鼠神经功能缺损，降低梗死面积。体外和体内实验表明，Pol调节小胶质细胞极化，下调炎症因子（IL-6和TNF-α）水平，在维持紧密连接蛋白（ZO-1, claudin-5, occludin）表达的同时，减轻炎症介导的血脑屏障损伤。通过对其潜在机制的研究，结合RNA-seq分析和实验结果，我们在体外和体内均确定了Pol下调JAK/STAT3通路，并通过使用JAK抑制剂tofacitinib证实了这一点。结论pol通过下调JAK/STAT3信号通路调节缺血性卒中小胶质细胞极化，减轻小胶质细胞介导的炎症反应和血脑屏障破坏。

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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.