CSB6B prevents beta-amyloid-associated neuroinflammation and cognitive impairments via inhibiting NF-kappa B and NLRP3 in microglia cells
CSB6B prevents beta-amyloid-associated neuroinflammation and cognitive impairments via inhibiting NF-kappa B and NLRP3 in microglia cells
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CSB6B 通过抑制小胶质细胞中的 NF-κ B 和 NLRP3 来预防 β-淀粉样蛋白相关的神经炎症和认知障碍
DOI：
10.1016/j.intimp.2020.106263
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发表时间：
2020
影响因子：
5.6
通讯作者：
Cui Wei
中科院分区：
文献类型：
--
作者：
Yan Sicheng;Xuan Zhenquan;Yang Mengxiang;Wang Chuang;Tao Tao;Wang Qinwen;Cui Wei
病理性β-淀粉样蛋白（Aβ）诱导的小胶质细胞活化可导致阿尔茨海默病（AD）患者脑内慢性神经炎症，被认为是AD的主要病理事件之一。芝加哥天蓝6 B（CSB 6 B），一种用于生化染色的色素，已被报道在神经炎症相关疼痛模型中产生镇痛作用。我们以前发现CSB 6 B可以直接抑制Aβ聚集，防止Aβ在神经元中的毒性。然而，目前尚不清楚该化合物是否可以预防Aβ诱导的神经炎症以及AD模型中的学习和记忆障碍。在这项研究中，发现CSB 6 B可有效抑制Aβ寡聚体和脂多糖刺激的BV 2小胶质细胞中促炎细胞因子（包括肿瘤坏死因子-α和白细胞介素-1 β）的产生，而不影响细胞活力。CSB 6 B可显著降低诱导型一氧化氮合酶mRNA的表达，并增加一氧化氮合酶-1 mRNA的表达，提示CSB 6 B可促进BV 2细胞向M2表型分化。在Aβ寡聚体处理的小鼠中，海马注射CSB 6 B可预防认知障碍，并减弱促炎细胞因子的产生。此外，CSB 6 B在体外和体内均能抑制核转录因子-κB（NF-κB B）和抑制NOD样受体pyrin domain containing-3（NLRP 3）的活化。CSB 6 B可能通过抑制NF-κB B和NLRP 3而对抗Aβ诱导的认知障碍和神经炎症。结合以往的研究，我们预计CSB 6 B可能进一步发展成为一种潜在的抗AD药物，同时对神经元和小胶质细胞具有多种功能。
Pathological β-amyloid (Aβ)-induced microglial activation could cause chronic neuroinflammation in the brain of Alzheimer's disease (AD) patients, and has been considered as one of the main pathological events of this disease. Chicago sky blue 6B (CSB6B), a pigment used in biochemical staining, has been reported to produce analgesic effects in neuroinflammatory-associated pain models. We have previously found that CSB6B could directly inhibit Aβ aggregation and prevent Aβ toxicity in neurons. However, it remains unclear whether this compound could prevent Aβ-induced neuroinflammation and impairments of learning and memory in the AD models. In this study, CSB6B was found to effectively inhibit the production of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, without affecting cell viability in BV2 microglia cells stimulated by Aβ oligomer and lipopolysaccharide. Moreover, CSB6B significantly reduced mRNA expression of inducible nitric oxide synthase and increased mRNA expression of arginase-1, suggesting that CSB6B might promote the polarization of BV2 cells into M2 phenotype. In Aβ oligomer-treated mice, hippocampal injection of CSB6B prevented cognitive impairments, and attenuated pro-inflammatory cytokines production. In addition, CSB6B inhibited nuclear transcription factor-κB (NF-κB), and restrained the activation of NOD-like receptor pyrin domain containing-3 (NLRP3) bothin vitroandin vivo. According to our results, CSB6B may counteract Aβ-induced cognitive impairments and neuroinflammation by inhibiting NF-κB and NLRP3. Combined with previous studies, we anticipated that CSB6B may further develop into a potential anti-AD drug with multiple functions on neurons and microglia cells, concurrently.