Rutin ameliorates stress-induced blood‒brain barrier dysfunction and cognitive decline via the endothelial HDAC1‒Claudin-5 axis.

IF 5.9 1区医学 Q1 NEUROSCIENCES

Fluids and Barriers of the CNS Pub Date : 2025-04-02 DOI:10.1186/s12987-025-00639-8

Zhao-Wei Sun, Zhao-Xin Sun, Yun Zhao, Ling Zhang, Fang Xie, Xue Wang, Jin-Shan Li, Mao-Yang Zhou, Hong Feng, Ling-Jia Qian

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引用次数: 0

Abstract

Background: Emerging evidence suggests that chronic stress compromises blood‒brain barrier (BBB) integrity by disrupting brain microvascular endothelial cells (BMECs), contributing to the development of cognitive impairments. Thus, targeting the BBB is expected to be a promising treatment strategy. The biological function of rutin has been investigated in neurological disorders; however, its regulatory role in stress-induced BBB damage and cognitive decline and the underlying mechanisms remain elusive.

Methods: In a chronic unpredictable mild stress (CUMS) mouse model, a fluorescent dye assay and behavioral tests, including a novel object recognition test and Morris water maze, were performed to evaluate the protective effects of rutin on BBB integrity and cognition. The effects of rutin on BMEC function were also investigated in hCMEC/D3 cells (a human brain microvascular endothelial cell line) in vitro. Furthermore, the molecular mechanisms by which rutin restores BBB endothelium dysfunction were explored via RNA-seq, quantitative real-time PCR, western blotting, immunofluorescence and chromatin immunoprecipitation. Finally, biotinylated tumor necrosis factor-α (TNF-α) was employed to test the influence of rutin on the ability of circulating TNF-α to cross the BBB.

Results: We identified that rutin attenuated BBB hyperpermeability and cognitive impairment caused by the 8-week CUMS procedure. Moreover, rutin promoted the proliferation, migration and angiogenesis ability of BMECs, and the integrity of the cellular monolayer through positively regulating the expression of genes involved. Furthermore, rutin impeded histone deacetylase 1 (HDAC1) recruitment and stabilized H3K27ac to increase Claudin-5 protein levels. Ultimately, normalization of the hippocampal HDAC1‒Claudin-5 axis by rutin blocked the infiltration of circulating TNF-α into the brain parenchyma and alleviated neuroinflammation.

Conclusions: This work establishes a protective role of rutin in regulating BMEC function and BBB integrity, and reveals that rutin is a potential drug candidate for curing chronic stress-induced cognitive deficits.

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芦丁通过内皮细胞HDAC1-Claudin-5轴改善应激诱导的血脑屏障功能障碍和认知能力下降。

背景：越来越多的证据表明，慢性应激通过破坏脑微血管内皮细胞（BMECs）破坏血脑屏障（BBB）的完整性，导致认知障碍的发展。因此，靶向血脑屏障有望成为一种有前景的治疗策略。芦丁在神经系统疾病中的生物学功能已被研究；然而，其在应激诱导的血脑屏障损伤和认知能力下降中的调节作用及其潜在机制尚不清楚。方法：在慢性不可预测轻度应激（CUMS）小鼠模型中，采用荧光染色法和行为学实验，包括新的物体识别测试和Morris水迷宫，评估芦丁对血脑屏障完整性和认知的保护作用。在体外培养的人脑微血管内皮细胞系hCMEC/D3细胞中，研究芦丁对BMEC功能的影响。通过RNA-seq、实时荧光定量PCR、western blotting、免疫荧光和染色质免疫沉淀等方法探讨芦丁恢复血脑屏障内皮功能障碍的分子机制。最后，采用生物素化肿瘤坏死因子-α (TNF-α)检测芦丁对循环TNF-α穿过血脑屏障能力的影响。结果：我们发现芦丁可以减轻8周CUMS手术引起的血脑屏障高通透性和认知障碍。芦丁通过正向调节相关基因的表达，促进bmec的增殖、迁移和血管生成能力，以及细胞单层的完整性。此外，芦丁阻碍了组蛋白去乙酰化酶1 （HDAC1）的募集，稳定了H3K27ac，增加了Claudin-5蛋白水平。最终，芦丁对海马HDAC1-Claudin-5轴的正常化阻断了循环TNF-α向脑实质的浸润，减轻了神经炎症。结论：本研究确定了芦丁对BMEC功能和血脑屏障完整性的保护作用，揭示了芦丁是治疗慢性应激性认知缺陷的潜在候选药物。

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

Fluids and Barriers of the CNS Neuroscience-Developmental Neuroscience

CiteScore

10.70

自引率

8.20%

发文量

审稿时长

14 weeks

期刊介绍： "Fluids and Barriers of the CNS" is a scholarly open access journal that specializes in the intricate world of the central nervous system's fluids and barriers, which are pivotal for the health and well-being of the human body. This journal is a peer-reviewed platform that welcomes research manuscripts exploring the full spectrum of CNS fluids and barriers, with a particular focus on their roles in both health and disease. At the heart of this journal's interest is the cerebrospinal fluid (CSF), a vital fluid that circulates within the brain and spinal cord, playing a multifaceted role in the normal functioning of the brain and in various neurological conditions. The journal delves into the composition, circulation, and absorption of CSF, as well as its relationship with the parenchymal interstitial fluid and the neurovascular unit at the blood-brain barrier (BBB).