Apelin-13 Ameliorateds Chronic Water Immersion Restrant Stress-induced Depressive Behaviors Through BDNF-mediated Glucocorticoid Receptor Nuclear Translocation

[Backgroud and Objective] Depression, as a mental illness featured by persistent low mood, affects 14 percent of the population in the world. Therefore, researches about the neuropathology mechanisms, prevention and treanment of depression have very vital significance. Chronic stress induces the dysfunction of GR by inhibiting GR nuclear translocation in hippocampus neurons, which is related to the dysfunction of HPA axis and the development of depression. Brain derived neurotrophic factor(BDNF) regulated the function of GR by affecting on GR nuclear translocation through crosstalk mechanism. The BDNF protein level was decreased in depression patients. Apelin is an endogenous ligand of the G-protein-coupled Apelin receptor(APJ). Apelin-13 was found to exhibit the highest activity to the APJ receptors followed by Apelin-17 then Apelin-36. Prior researches of our lab showed that Apelin-13 had antidepressant effect in a variety of depression models,but the mechanism is not clear. Therefore, we investigate whether the potentially antidepressant mechanism of Apelin-13 is to improve the dysfunction of GR nuclear translocation induced by chronic water immersion restraint stress(CWIRS) through regulating BDNF function. [Methods] In this experiment, the expressions of Apelin and APJ were measured by Western Blot in CWIRS rat models. The sucrose preference test, forced swimming test and tail suspension test were used to measure depressive behavior induced by CWIRS. The effects of Apelin-13 on CWIRS-induced dysfunction of HPA axis feedback were studied by dexamethasone suppression test and calculating of adrenal weight ratio. The GR protein levels of the cytoplasm and nucleus in hippocampus were measured to study the effects of Apelin-13 on dysfunction of GR nuclear translocation in CWIRS rat models. The effects of Apelin-13 on CWIRS-induced decrease of BDNF, CREB and p CREB were measured by Western Blot. The effects of BDNF antagonist ANA-12 on GR nuclear translocation, depressive behavior and dysfunction of HPA axis feedback recovered by Apelin-13 were measured by Western Blot, the sucrose preference test and adrenal weight ratio. [Results] The levels of Apelin and APJ were significantly increased in the CWIRS group compared to the no stressed group. The CWIRS-induced reduction of sucrose consumption was ameliorated by Apelin-13 i.c.v administration. The CWIRS-induced increase of immobility time in the forced swimming test and tail suspension test were ameliorated by Apelin administration. In the dexamethasone suppression test, the CWIRS-induced corticosterone secretion was significantly decreased by Apelin-13 i.c.v administration. The CWIRS-induced increase of adrenal weight per body weight was ameliorated by Apelin-13 i.c.v administration. Apelin-13 improved the decrease of ratio of cytoplasm GR/nucleus GR in the hippocampus induced by CWIRS. The CWIRS-induced decreases of BDNF and p CREB in the hippocampus were ameliorated by Apelin-13 i.c.v administration. ANA-12 blocked the ameliorative effect of Apelin on the reduction of sucrose consumption, increase of adrenal weight per body weight and decrease of ratio of nucleus GR/cytoplasm GR induced by CWIRS. [Conclusion] Apelin-13 ameliorats the CWIRS-induced depression behavior and the dysfunction of GR nuclear translocation, and this effects relay on the activation of the BDNF/Trk B signal pathway.