Chronic stress induces the activation of hippocampal microglia, which produces many inflammatory mediators and mediates the occurrence of depression. Two phenotypes of microglia polarization, the classical M1 and alternative M2, play important regulatory roles in neuroinflammation and are involved in the occurrence and development of depression. Apelin is derived from a precursor peptide consisting of 77 amino acids and is a natural ligand for the orphan G-protein-coupled receptor APJ. Apelin-13 is one of the subtypes of Apelin and has a wide range of biological effects. Studies have shown that Apelin-13 has an antidepressant effect, but its specific mechanism has not been elucidated. In this study, the purpose of this study is to explore the possible mechanism of Apelin-13 to improve depression-like behaviors induced by chronic stress in rats from the perspective of microglial polarization in vivo. Adult male Sprague Dawley (SD) rats received 28 days of chronic water immersion restraint stress (CWIRS). Apelin group was injected with Apelin-13 (2 μg/2 μL) through the intracerebroventricular for 7 days. The results showed that CWIRS can induce depression-like behaviors in rats. Compared with the CWIRS + saline group, the CWIRS + Apelin-13 group was significantly improved the depression-like behaviors in rats. Compared with the CWIRS + saline group, the CWIRS + Apelin-13 group was significantly down-regulated the protein expression of M1-type marker iNOS and the pro-inflammatory factors IL-1β and IL-6 secret by microglia decreased. Compared with the CWIRS + saline group, the protein expression of M2-type marker Arg1 and anti-inflammatory factors IL-4 and IL-10 secreted by microglia was significantly increased in CWIRS + Apelin-13 group. Double-labelling immunofluorescence co-localization showed that, compared with the CWIRS + saline group, CWIRS + Apelin-13 group significantly inhibited the co-localization expression of Iba-1 and iNOS, and promoted the co-localization expression of Iba-1 and Arg1 in hippocampus microglia. Taken together, our study suggests that Apelin-13 improves depression-like behavior in rats induced by CWIRS and its mechanism may be related to the regulation of microglial polarization.

中文翻译：

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海马小胶质细胞极化参与Apelin-13改善慢性水浸束缚应激诱导大鼠抑郁样行为的机制

慢性应激诱导海马小胶质细胞活化，产生多种炎症介质，介导抑郁症的发生。小胶质细胞极化的两种表型，经典 M1 和替代 M2，在神经炎症中起着重要的调节作用，并参与抑郁症的发生和发展。Apelin 来源于由 77 个氨基酸组成的前体肽，是孤儿 G 蛋白偶联受体 APJ 的天然配体。Apelin-13是Apelin的亚型之一，具有广泛的生物学效应。研究表明Apelin-13具有抗抑郁作用，但其具体机​​制尚未阐明。在这项研究中，本研究的目的是从体内小胶质细胞极化的角度探讨Apelin-13改善慢性应激诱导的大鼠抑郁样行为的可能机制。成年雄性 Sprague Dawley (SD) 大鼠接受 28 天的慢性浸水束缚应激 (CWIRS)。Apelin组经脑室内注射Apelin-13（2 μg/2 μL）7 d。结果表明，CWIRS可诱导大鼠出现抑郁样行为。与CWIRS+生理盐水组相比，CWIRS+Apelin-13组显着改善了大鼠的抑郁样行为。与CWIRS+生理盐水组相比，CWIRS+Apelin-13组显着下调M1型标志物iNOS的蛋白表达，小胶质细胞分泌的促炎因子IL-1β和IL-6降低。与CWIRS+生理盐水组相比，CWIRS+Apelin-13组M2型标志物Arg1和小胶质细胞分泌的抗炎因子IL-4和IL-10的蛋白表达显着增加。双标免疫荧光共定位显示，与CWIRS+生理盐水组相比，CWIRS+Apelin-13组显着抑制了Iba-1和iNOS的共定位表达，促进了Iba-1和iNOS的共定位表达。海马小胶质细胞中的 Arg1。总之，我们的研究表明 Apelin-13 改善了 CWIRS 诱导的大鼠抑郁样行为，其机制可能与调节小胶质细胞极化有关。CWIRS+Apelin-13组M2型标志物Arg1和小胶质细胞分泌的抗炎因子IL-4和IL-10的蛋白表达显着增加。双标免疫荧光共定位显示，与CWIRS+生理盐水组相比，CWIRS+Apelin-13组显着抑制了Iba-1和iNOS的共定位表达，促进了Iba-1和iNOS的共定位表达。海马小胶质细胞中的 Arg1。总之，我们的研究表明 Apelin-13 改善了 CWIRS 诱导的大鼠抑郁样行为，其机制可能与调节小胶质细胞极化有关。CWIRS+Apelin-13组M2型标志物Arg1和小胶质细胞分泌的抗炎因子IL-4和IL-10的蛋白表达显着增加。双标免疫荧光共定位显示，与CWIRS+生理盐水组相比，CWIRS+Apelin-13组显着抑制了Iba-1和iNOS的共定位表达，促进了Iba-1和iNOS的共定位表达。海马小胶质细胞中的 Arg1。总之，我们的研究表明 Apelin-13 改善了 CWIRS 诱导的大鼠抑郁样行为，其机制可能与调节小胶质细胞极化有关。CWIRS+Apelin-13组显着抑制Iba-1和iNOS的共定位表达，促进Iba-1和Arg1在海马小胶质细胞中的共定位表达。总之，我们的研究表明 Apelin-13 改善了 CWIRS 诱导的大鼠抑郁样行为，其机制可能与调节小胶质细胞极化有关。CWIRS+Apelin-13组显着抑制Iba-1和iNOS的共定位表达，促进Iba-1和Arg1在海马小胶质细胞中的共定位表达。总之，我们的研究表明 Apelin-13 改善了 CWIRS 诱导的大鼠抑郁样行为，其机制可能与调节小胶质细胞极化有关。