SIRT1 Mediates Apelin-13 in Ameliorating Chronic Normobaric Hypoxia-induced Anxiety-like Behavior by Suppressing NF-κB Pathway in Mice Hippocampus

We previously showed that apelin-13 ameliorates chronic normobaric hypoxia (CNH)-induced anxiety-like behavior in mice, the mechanism, however, is not well known. This study aims to investigate whether SIRT1 is involved in the anxiolytic effect of apelin-13 in CNH-treated mice, and to illustrate the potential underlying mechanism. We showed that apelin-13 treatment reversed a decrease in SIRT1 and an increase in acetylated p65 (lysine 310) proteins' expression in hippocampus of CNH-treated mice, indicating that apelin-13 inhibited NF-κB signaling pathway by activating SIRT1. Behaviorally, apelin-13 ameliorated CNH-induced anxiety-like behavior, EX-527 blocked the beneficial effect of apelin-13, and the anxiogenic effect of CNH was attenuated by resveratrol pretreatment, suggesting that SIRT1 was involved in the effect of apelin-13 against CNH-induced anxiety-like behavior in mice. We also showed that resveratrol treatment decreased IL-1β, IL-6, TNF-ɑ, PCNA, Bcl-2, and acetyl-p65 levels, but increased Bax and caspase 3 levels in hippocampus, suggesting a suppressive effect of resveratrol on cellular neuroinflammation and proliferation while a promotive effect on apoptosis of microglia in hippocampus. Finally, blockade of NF-κB activity by PDTC diminished CNH-induced anxiety-like behavior, indicating that NF-κB was involved in CNH-induced anxiety-like behavior in mice. In conclusion, this study provides the first evidence that SIRT1 mediates the anxiolytic effect of apelin-13 in CNH-treated mice through the inhibition of NF-κB pathway. These results imply that dysfunction of the apelin-SIRT1-NF-κB axis in hippocampus represents a potential mechanism that results in the induction of neuroinflammation and reduction in neuroprotection, thus induces anxiety-like behavior in CNH-treated mice.