Resveratrol ameliorates lipopolysaccharide-induced anxiety-like behavior by attenuating YAP-mediated neuro-inflammation and promoting hippocampal autophagy in mice
Resveratrol ameliorates lipopolysaccharide-induced anxiety-like behavior by attenuating YAP-mediated neuro-inflammation and promoting hippocampal autophagy in mice
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白藜芦醇通过减轻 YAP 介导的神经炎症和促进小鼠海马自噬来改善脂多糖诱导的焦虑样行为
DOI：
10.1016/j.taap.2020.115261
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Junming Fan
中科院分区：
文献类型：
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作者：
Qiuyun Tian;Xiaofang Fan;Jianshe Ma;Yujiao Han;Dantong Li;Shan Jiang;Fukun Zhang;Hui Guang;Xiaoqiong Shan;Ran Chen;Ping Wang;Qing Wang;Jinge Yang;Yongyu Wang;Lianggang Hu;Yangping Shentu;Yongsheng Gong;Junming Fan
白藜芦醇是一种主要从葡萄皮中提取的天然多酚，据报道具有抗炎和抗焦虑作用。Yes相关蛋白（雅普）是Hippo信号通路的主要下游效应子，在炎症反应中起重要作用。本研究旨在探讨雅普通路是否参与白藜芦醇对脂多糖（LPS）诱导的C57 BL/6 J雄性小鼠的抗焦虑作用。LPS处理诱导焦虑样行为，降低sirtuin 1，同时增加海马雅普表达。白藜芦醇减弱LPS诱导的焦虑样行为，这被EX-527（sirtuin 1抑制剂）阻断。从机制上讲，白藜芦醇的抗焦虑作用伴随着海马中雅普、白细胞介素-1 β和离子钙结合接头分子1（Iba-1）的显著降低，而自噬蛋白表达的显著增加。利用雅普激活剂XMU-MP-1进行的药理学研究表明，激活雅普可诱导焦虑样行为和神经炎症，并减少海马自噬。此外，XMU-MP-1处理激活雅普减弱了白藜芦醇对LPS诱导的焦虑样行为的改善作用，而用雅普抑制剂verteporfin阻断雅普激活，减弱了LPS诱导的焦虑样行为和神经炎症以及海马自噬。最后，雷帕霉素介导的自噬促进减弱了LPS诱导的焦虑样行为，并降低了海马中白细胞介素-1 β和Iba-1的表达。这些结果表明，白藜芦醇通过抑制YAP介导的神经炎症和促进海马自噬来改善LPS诱导的焦虑样行为，提示阻断雅普通路可能是治疗神经炎症诱导的焦虑样行为的潜在靶点。
Resveratrol, a type of natural polyphenol mainly extracted from the skin of grapes, has been reported to protect against inflammatory responses and exert anxiolytic effect. Yes-associated protein (YAP), a major downstream effector of the Hippo signalingpathway, plays a critical role in inflammation. The present study aimed to explorewhether YAP pathway was involved in the anxiolytic effect of resveratrol in lipopolysaccharide (LPS)-treated C57BL/6J male mice. LPS treatment induced anxiety-like behavior and decreased sirtuin 1 while increased YAP expression in the hippocampus. Resveratrol attenuated LPS-induced anxiety-like behavior, which was blocked by EX-527 (a sirtuin 1 inhibitor). Mechanistically, the anxiolytic effects of resveratrol were accompanied by a marked decrease in YAP, interleukin-1β and ionized calcium binding adaptor molecule 1 (Iba-1) while a significant increase in autophagic protein expression in the hippocampus. Pharmacological study using XMU-MP-1, a YAP activator, showed that activating YAP could induce anxiety-like behavior and neuro-inflammation as well as decrease hippocampal autophagy. Moreover, activation of YAP by XMU-MP-1 treatment attenuated the ameliorative effects of resveratrol on LPS-induced anxiety-like behavior, while blockade of YAP activation with verteporfin, a YAP inhibitor, attenuated LPS-induced anxiety-like behavior and neuro-inflammation as well as hippocampal autophagy. Finally, rapamycin-mediated promotion of autophagy attenuated LPS-induced anxiety-like behavior and decreased interleukin-1β and Iba-1 expression in the hippocampus. Collectively, these results indicate that amelioration by resveratrol in LPS-induced anxiety-like behavior is through attenuating YAP-mediated neuro-inflammation and promoting hippocampal autophagy, and suggest that inhibof YAP pathway could be a potential therapeutic target for anxiety-like behavior induced by neuro-inflammation.