Role of AMPK/SIRT1-SIRT3 signaling pathway in affective disorders in unpredictable chronic mild stress mice

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. 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. 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. 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.