OBJECTIVES To explore the role of 5' adenosine monophosphate-activated protein kinase/sirtuin1-sirtuin3 (AMPK/SIRT1-SIRT3) signaling pathway in behavioral and neuroinflammation/oxidative stress alterations in unpredictable chronic mild stress (UCMS) model mice. METHODS Male ICR mice weighing 20-22 g were used in this study. Behavior performance was evaluated from the 14th day of drug treatment. Expression levels of AMPK, SIRT1, SIRT3, and NF-κBp65 were tested by immuno-blot analysis. Contents of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β) and interleukin 6 (IL-6) were detected by enzyme linked immunosorbent assay (ELISA). Reactive oxygen species (ROS), superoxide dismutase (SOD) and glutathione (GSH) expressions were tested by neurochemical and biochemical assays. RESULTS Behavioral disorders and decreases of AMPK, SIRT1 and SIRT3 induced by UCMS were all reversed by AICA Riboside (AICAR) treatment. These effects were correlated with alterations of oxidative stress (ROS, GSH, SOD) and inflammation (pNF-κBp65, TNF-α, IL-1β, IL-6) status. Co-treatment with SIRT3 inhibitor (3-TYP) in addition to AICAR abolished AICAR's effects on behavior and expression level of inflammation/oxidative stress-related factors of mice, without affecting the content of SIRT1. Contrarily, combining use of AICAR and SIRT1 inhibitor (Sirtinol or EX-527) increased SIRT3 level, which led to better alleviation of behavioral disorders, compared with single AICAR treatment. Interestingly, in normal or UCMS mice, up or down regulation of SIRT1 did not affect SIRT3 level. CONCLUSION Provided that AMPK is activated, SIRT1 inhibition could induce the increase of SIRT3, and SIRT3 exerts more beneficial function in alleviation of consequences of chronic stress than SIRT1.

中文翻译：

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AMPK / SIRT1-SIRT3信号通路在不可预测的慢性轻度应激小鼠情感障碍中的作用。

目的探讨5'腺苷单磷酸激活蛋白激酶/ sirtuin1-sirtuin3（AMPK / SIRT1-SIRT3）信号通路在不可预测的慢性轻度应激（UCMS）模型小鼠的行为和神经炎症/氧化应激改变中的作用。方法本研究使用体重为20-22 g的雄性ICR小鼠。从药物治疗的第14天开始评估行为表现。通过免疫印迹分析测试AMPK，SIRT1，SIRT3和NF-κBp65的表达水平。用酶联免疫吸附法（ELISA）检测肿瘤坏死因子α（TNF-α），白介素1β（IL-1β）和白介素6（IL-6）的含量。通过神经化学和生化分析检测了活性氧（ROS），超氧化物歧化酶（SOD）和谷胱甘肽（GSH）的表达。结果行为障碍和AMPK降低，UCMS诱导的SIRT1和SIRT3均被AICA核苷（AICAR）处理逆转。这些作用与氧化应激（ROS，GSH，SOD）和炎症（pNF-κBp65，TNF-α，IL-1β，IL-6）状态的改变有关。除AICAR以外，还与SIRT3抑制剂（3-TYP）共同处理消除了AICAR对小鼠行为和炎症/氧化应激相关因子表达水平的影响，而不影响SIRT1的含量。相反，与单一AICAR治疗相比，将AICAR和SIRT1抑制剂（Sirtinol或EX-527）组合使用可提高SIRT3水平，从而更好地缓解行为障碍。有趣的是，在正常或UCMS小鼠中，SIRT1的上调或下调不会影响SIRT3的水平。结论假设AMPK被激活，SIRT1的抑制作用可以诱导SIRT3的增加，