School of Pharmacy, Key Laboratory of Natural Medicine and Immune Engineering, Henan University, Kaifeng, 475004, PR China.
Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, 999077, PR China.
Eur J Pharmacol. 2021 Oct 5;908:174357. doi: 10.1016/j.ejphar.2021.174357. Epub 2021 Jul 17.
Neuroinflammation is considered as an important mechanism of vascular dementia (VaD). Our primary study showed that the bisindole analogue (2-(2-(bis(5-chloro-1H-indol-3-yl)methyl)phenoxy)aniline, compound 4ae) had great anti-inflammation in zebrafish. Rat model of permanent occlusion of the bilateral common carotid arteries (2-vessel occlusion, 2VO) was utilized to evaluate the neuroprotective effect of 4ae. Our results showed that 4ae treatment effectively reduced Iba-1 positive microglia cells in cerebral cortex and hippocampus after cerebral ischemia. Compared with the model group, neuroinflammation characterized by Interleukin (IL)-6 and tumor necrosis factor (TNF)-α, oxidative stress characterized by reactive oxygen species (ROS) and superoxide dismutase (SOD) were both improved significantly after treatment with 4ae. Moreover, 4ae treatment significantly reversed ischemia-induced ACE enhancement, while notably increased the level of ACE2. To further elucidate the role of 4ae on neuroinflammation, we investigated the effects of 4ae on lipopolysaccharide (LPS)-induced inflammation in BV2 microglia cells, a kind of innate immune cells in central nervous system. The results demonstrated that the expressions of CD11b, TNFα and IL-6 and the level of ROS were up-regulated after treatment with LPS. More importantly, 4ae was able to block the activation of BV2 by reducing ROS production and the expression of inflammatory cytokines. In addition, our results suggested that 4ae inhibited the inflammatory response mediated by microglia cells by inhibiting NF-κB. This anti-inflammatory effect on microglia may be a potential mechanism for the neuroprotective effect of 4ae in VaD.
神经炎症被认为是血管性痴呆（VaD）的重要机制。我们的初步研究表明，双吲哚类似物（2-（2-（双（5-氯-1H-吲哚-3-基）甲基）苯氧基）苯胺，化合物 4ae）在斑马鱼中有很强的抗炎作用。利用双侧颈总动脉永久性闭塞（2 血管闭塞，2VO）大鼠模型来评估 4ae 的神经保护作用。我们的结果表明，4ae 治疗可有效减少脑缺血后大脑皮质和海马区的 Iba-1 阳性小胶质细胞。与模型组相比，4ae 治疗后，白细胞介素（IL）-6 和肿瘤坏死因子（TNF）-α 等神经炎症特征，活性氧（ROS）和超氧化物歧化酶（SOD）等氧化应激均得到显著改善。此外，4ae 治疗可显著逆转缺血诱导的 ACE 增强，同时显著增加 ACE2 的水平。为了进一步阐明 4ae 对神经炎症的作用，我们研究了 4ae 对脂多糖（LPS）诱导的 BV2 小胶质细胞炎症的影响，BV2 小胶质细胞是中枢神经系统中的一种固有免疫细胞。结果表明，LPS 处理后 CD11b、TNFα 和 IL-6 的表达以及 ROS 水平升高。更重要的是，4ae 通过减少 ROS 生成和炎症细胞因子的表达来阻断 BV2 的激活。此外，我们的结果表明，4ae 通过抑制 NF-κB 抑制小胶质细胞介导的炎症反应。这种对小胶质细胞的抗炎作用可能是 4ae 在 VaD 中具有神经保护作用的潜在机制。
