Microglia polarization of hippocampus is involved in the mechanism of Apelin-13 ameliorating chronic water immersion restraint stress-induced depression-like behavior in rats

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.