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首页> 外文期刊>Molecules >Luteolin Inhibits Fibrillary β-Amyloid 1–40 -Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways
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Luteolin Inhibits Fibrillary β-Amyloid 1–40 -Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways

机译：木犀草素通过抑制p38 MAPK介导的NF-κB信号通路抑制人血脑屏障模型中原纤维β-淀粉样蛋白1–40诱导的炎症。

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Amyloid-β peptides (Aβ) exist in several forms and are known as key modulators of Alzheimer’s disease (AD). Fibrillary Aβ (fAβ) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAβ 1–40 . We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAβ 1–40 -damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAβ 1–40 , luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAβ 1–40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAβ 1–40 . Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAβ 1–40 -induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAβ 1–40 -induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAβ 1–40 -induced injury.
机译：淀粉样β肽（Aβ）有几种形式，被称为阿尔茨海默氏病（AD）的关键调节剂。已发现原纤维Aβ（fAβ）通过引发和促进炎症来破坏血脑屏障（BBB）。在这项研究中，木犀草素是一种天然存在的类黄酮，在中枢神经系统中显示出有益的特性，被评估为保留屏障功能并抑制受fAβ1-40损伤的BBB炎症反应的潜在药物。我们通过在fAβ1–40损伤的条件下共同培养人脑微血管内皮细胞（hBMEC）和人星形胶质细胞（hAs），建立了体外BBB模型，并通过分析细胞毒性，屏障功能，细胞因子产生和对木犀草素的作用来研究木犀草素的作用。炎症相关的细胞内信号通路。我们的结果表明，在被fAβ1–40损伤的细胞中，木犀草素增加了hBMEC和hAs的细胞活力。共培养物对fAβ1–40诱导的损伤的细胞保护作用在顶端和基底外侧也都得到了增强。木犀草素在人BBB模型中暴露于fAβ1–40后，可通过保留跨内皮电阻和缓解加剧的通透性来保护屏障功能。此外，在共培养的顶端和基底外侧，木犀草素都降低了fAβ1-40诱导的炎症介质和细胞因子的产生，包括环氧合酶2（COX-2），肿瘤坏死因子α（TNF-α），白介素1β（IL-1β），白介素6（IL-6）和白介素8（IL-8），但是在清除hBMEC和hAs中的细胞内活性氧（ROS）方面未显示出足够的作用。 BBB对抗fAβ1–40诱导的损伤的保护机制可能与调节炎症信号转导有关，包括抑制p38丝裂原活化蛋白激酶（MAPK）活化，磷酸化抑制性κB激酶（phosphor-IKK）的下调。水平，抑制性κBα（IκBα）降解的缓解，核因子κB（NF-κB）p65核移位的阻滞和炎性细胞因子释放的减少。此外，使用p38 MAPK和NF-κB抑制剂可逆转木犀草素介导的屏障功能和细胞因子释放。两者合计，木犀草素可通过抑制fAβ1-40诱导的损伤后的炎症而成为保护BBB的潜在治疗剂。

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