Fan Junming, Ding Lu, Xia Dongmei, Chen Danyang, Jiang Pu, Ge Wenhua, Zhao Ru, Guo Jinbin, Fan Xiaofang, Xue Feng, Wang Yongyu, Mao Sunzhong, Hu Lianggang, Gong Yongsheng
Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Institute of Hypoxia Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
Brain Res Bull. 2017 Apr;130:67-74. doi: 10.1016/j.brainresbull.2017.01.005. Epub 2017 Jan 5.
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.
Apelin是一种小的生物活性肽，通过内源性配体APJ在情绪障碍的发病机制中发挥重要作用。尽管Apelin的抗焦虑作用已得到充分证实，但其机制尚不清楚。在本研究中，我们假设Apelin在慢性常压缺氧（CNH）诱导的小鼠焦虑样行为中发挥抗焦虑作用，这可能与抑制海马体中核因子-κB（NF-κB）的激活有关。为此，将小鼠置于常压缺氧舱中，吸入氧分数（FIO₂，约10%，每天23小时），同时给予或不给予Apelin-13（20 nmol/kg/d，腹腔注射），持续4周。通过高架十字迷宫和旷场试验检测焦虑样行为。检测在此病理过程中海马体中NF-κB、小胶质细胞的活性以及相关信号通路。我们发现，CNH处理降低了APJ但增加了Iba-1蛋白表达，以及海马体中p50和p65的核转位，而Apelin-13处理可使其逆转。此外，Apelin-13处理改善了CNH诱导的小鼠焦虑样行为，表明Apelin-13的致焦虑作用可能是通过抑制海马体小胶质细胞中NF-κB的激活介导的。此外，Apelin-13处理逆转了CNH处理下海马体中p-CAMKII的降低。Apelin-13处理对常氧对照小鼠的焦虑样行为和相关蛋白表达没有影响。最后，我们发现CNH处理的大鼠海马体中APJ表达降低而NF-κB激活增强，这进一步证明了我们之前报道的CNH诱导的大鼠焦虑样行为中海马体中NF-κB的激活可能与APJ活性的抑制有关。总之，目前的结果表明，海马体小胶质细胞中APJ的抑制和NF-κB激活的促进可能参与了CNH暴露小鼠的致焦虑作用，而Apelin-13改善CNH诱导的焦虑样行为可能与抑制NF-κB激活有关。
