Circumdatin D Exerts Neuroprotective Effects by Attenuating LPS-Induced Pro-Inflammatory Responses and Downregulating Acetylcholinesterase Activity In Vitro and In Vivo
Circumdatin D Exerts Neuroprotective Effects by Attenuating LPS-Induced Pro-Inflammatory Responses and Downregulating Acetylcholinesterase Activity In Vitro and In Vivo
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DOI：
10.3389/fphar.2020.00760
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发表时间：
2020-05
影响因子：
5.6
通讯作者：
Chan-juan Zhang;Likun Hu;Dong Liu;Jian Huang;Wenhan Lin
中科院分区：
文献类型：
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作者：
Chan-juan Zhang;Likun Hu;Dong Liu;Jian Huang;Wenhan Lin
阿尔茨海默病（Alzheimer's disease，AD）是一种多因素引起的神经退行性疾病，其中全身性炎症反应在AD的神经退行性变中起重要作用，而乙酰胆碱酯酶（acetylcholinesterase，AChE）是诱导胆碱能传递的靶蛋白。针对炎症和靶向AChE的抑制剂被认为在AD治疗中促进中枢神经系统的胆碱能信号传导。在从海洋提取物中寻找神经保护剂的过程中，从珊瑚共生真菌赭曲霉LZDX-32-15中提取的7种环孢菌素型生物碱对脂多糖（LPS）诱导的一氧化氮（NO）产生、NF-κB报告基因的激活沿着AChE活性均有较强的抑制作用。结果表明，环孢菌素D对AChE活性和NO生成的抑制作用最强。AD样线虫模型的体内实验表明，circumdatin D通过抑制AChE活性和炎症相关基因的表达，有效地延迟CL 4176蠕虫在温度升高时的麻痹。此外，环孢菌素D通过抑制LPS诱导的BV-2和原代小胶质细胞中促炎细胞因子的分泌来干扰炎症反应。在LPS刺激的BV-2细胞中，环孢菌素D调节Toll样受体4（TLR 4）介导的NF-κB、MAPK和JAK/STAT炎症通路，保护原代神经元细胞免受LPS诱导的神经毒性。因此，环孢菌素D是一种潜在的多靶点神经保护剂。
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with multifactorial causes, of which systemic inflammation may play a key role to promote neurodegeneration, and acetylcholinesterase (AChE) is a target protein to induce cholinergic transmission. Inhibitors toward inflammation and targeting AChE are regarded to promote cholinergic signaling of the central nervous system in AD therapy. During the search for neuroprotection agents from marine-derived compounds, seven circumdatin-type alkaloids from a coral-associated fungus Aspergillus ochraceus LZDX-32-15 showed potent inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) production and activation of NF-κB report gene along with anti-AChE activities. Among the tested compounds, circumdatin D showed the most potent inhibitory effect against AChE activity and NO production. In vivo experiments using AD-like nematode models demonstrated that circumdatin D effectively delayed paralysis of CL4176 worms upon temperature up-shift via suppression of AChE activity and inflammatory-related gene expression. Moreover, circumdatin D interfered with inflammatory response by inhibiting the secretion of pro-inflammatory cytokines in LPS-induced BV-2 and primary microglia cells. Mechanistically, circumdatin D modulated Toll-like receptor 4 (TLR4)-mediated NF-κB, MAPKs and JAK/STAT inflammatory pathways in LPS-stimulated BV-2 cells, and protected primary neurons cells from LPS-induced neurotoxicity. Thus, circumdatin D is a potential agent for neuroprotective effects by the multi-target strategy.