Glutaminyl cyclase inhibitor exhibits anti-inflammatory effects in both AD and LPS-induced inflammatory model mice
Glutaminyl cyclase inhibitor exhibits anti-inflammatory effects in both AD and LPS-induced inflammatory model mice
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谷氨酰胺酰环化酶抑制剂在 AD 和 LPS 诱导的炎症模型小鼠中表现出抗炎作用
DOI：
10.1016/j.intimp.2019.105770
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发表时间：
2019
影响因子：
5.6
通讯作者：
Wu Haiqiang
中科院分区：
文献类型：
--
作者：
Wang Xiaojuan;Wang Li;Yu Xi;Li Yue;Li Zhigang;Zou Yongdong;Zheng Yizhi;He Zhendan;Wu Haiqiang
上调的谷氨酰胺酰环化酶 (QC) 在阿尔茨海默病 (AD) 和炎症介导的各种慢性疾病的引发中发挥着至关重要的作用。 QC 被认为是治疗这些疾病的新靶标。在这里，我们探索了二苯基共轭咪唑 (DPCI) 衍生物的抗炎作用，这些衍生物是我们实验室先前设计、合成和评估的用于 AD 治疗的新型 QC 抑制剂。对 AD 和脂多糖 (LPS) 诱导的炎症模型小鼠进行行为测试、QC 活性测定、组织学和 ELISA 分析。结果表明，用所选化合物 DPCI-23 治疗的 AD 小鼠的行为和认知表现显着增强。 AD小鼠脑内QC活性、pE-Aβ和Aβ斑块的形成以及星形胶质细胞和小胶质细胞的活化受到抑制，血清中IL-6、IL-1β和TNF-α等炎症因子的水平显着降低。此外，DPCI-23治疗后，炎症小鼠大脑中升高的QC活性也受到抑制，血清、肾脏和大脑中IL-1β、IL-1ra、TNF-α和CCL2的水平以及大脑中活化的星形胶质细胞和小胶质细胞的水平均受到显着抑制。本研究中观察到的这些发现证明了 DPCI-23 通过抑制 QC 活性在 AD 和炎症模式中具有抗炎功效，并可能有助于使用 QC 抑制剂来预防和治疗 AD 和其他炎症性疾病。
Up-regulated glutaminyl cyclase (QC) plays crucial roles in the initiation of Alzheimer's disease (AD) and kinds of chronic diseases mediated by inflammation. QC is supposed as a novel target for the therapeutics of these diseases. Here, we explored the anti-inflammation effects of diphenyl conjugated imidazole (DPCI) derivatives which were previously designed, synthesized and evaluated as novel QC inhibitors for AD treatment in our lab. Behavioral tests, QC activity assay, histology and ELISA analysis were conducted on both AD and lipopolysaccharides (LPS)-induced inflammatory model mice. It was shown that behavioral and cognitive performance in AD mice treated with the selected compound DPCI-23were enhanced notably. QC activity, the formation of pE-Aβ and Aβ plaques and the activation of astrocytes and microglia cells in AD mice brains were inhibited, and the levels of inflammatory factors such as IL-6, IL-1β and TNF-α in serum were reduced remarkably. Furthermore, elevated QC activity in inflammatory mice brains was also inhibited, and levels of IL-1β, IL-1ra, TNF-α and CCL2 in serum, kidneys and brains together with the activated astrocytes and microglia cells in brains were all repressed significantly after the treatment of DPCI-23. These findings observed in this research demonstrated the anti-inflammation potency ofDPCI-23in modal of AD and inflammation by inhibiting QC activity, and may contribute to the employment of QC inhibitors for the prevention and treatment of AD and other inflammatory diseases.