Amelioration of apelin-13 in chronic normobaric hypoxia-induced anxiety-like behavior is associated with an inhibition of NF-κB in the hippocampus.

Apelin, a small bioactive peptide, plays an important role in the pathogenesis of mood disorders through the endogenous ligand APJ. Although the anxiolytic effect of apelin is well established, the mechanisms are poorly understood. In this study, we hypothesized that apelin played an anxiolytic role in chronic normobaric hypoxia (CNH)-induced anxiety like behavior in mice, which might be associated with an inhibition of nuclear factor-κB (NF-κB) activation in the hippocampus. To this end, mice were exposed in a normobaric hypoxic chamber with a fraction of inspired oxygen (FIO, ∼10%, 23h/d) with or without apelin-13 application (20 nmolkgd, i.p.), for 4 weeks. The anxiety-like behavior was tested by elevated plus maze and open field. Activities of NF-κB, microglial, and related signaling pathways in the hippocampus during this pathological process were examined. We found that CNH treatment decreased APJ but increased Iba-1 proteins expression, as well as nucleus translocation of p50 and p65 in the hippocampus, which were reversed by apelin-13 treatment. In addition, apelin-13 treatment ameliorated CNH-induced anxiety-like behavior in mice, suggesting anxiogenic effect of apelin-13 might be mediated by an inhibition of NF-κB activation in microglial of the hippocampus. Furthermore, apelin-13 treatment reversed p-CAMKII decrease in the hippocampus under CNH treatment. Apelin-13 treatment did not affect anxiety-like behavior and relative proteins expression in normoxia control mice. Finally, we found that rats with CNH treatment decreased APJ expression while enhanced NF-κB activation in the hippocampus, providing additional evidences that NF-κB activation in hippocampus in CNH-induced anxiety-like behavior in rats we reported previously might be associated with an inhibition of APJ activity. In conclusion, the present results illustrated that inhibition of APJ and promotion of NF-κB activation in the microglial of hippocampus might be involved in anxiogenic effect in CNH-exposed mice, and apelin-13 ameliorates CNH-induced anxiety-like behavior might be associated with an inhibition of NF-κB activation.