Apelin-13 Ameliorates Chronic Stress-induced Depression-like Behavior In Rats By Regulating Microglial Polarization

[Background and Objective] Chronic stress causes microglial activation to produce large amounts of inflammatory mediators which contribute to depressive disorder.Concomitantly,microglia polarization has two phenotypes of M1/M2 that play an important role in the regulation of central nervous system inflammation,which involved in the development of depression.The mechanisms underlying Apelin-13 has antidepressant effects in a variety of depression model is not clear.In this study,from the perspective of microglia polarization to investigate the mechanism of Apelin-13 improve the depression-like behavior of rats induced by chronic stress.[Methods] Male Sprague-Dawley(SD)rats received 28 days of chronic water immersion restraint stress.Apelin-13 or vehicle i.c.v.administration into the rats was continued for 7 days.Adopt behavioral indexes the sucrose preference,forced swimming test and tail suspension test to detect depression-like behavior in rats.Western blot was used to detect the expression of M1-inducible nitric oxide synthase(iNOS)and its proinflammatory cytokines interleukin-6(IL-6)and interleukin-1β(IL-1β);microglial marker M2 arginase 1(Arg1)and its anti-inflammatory cytokines interleukin-4(IL-4),interleukin-10(IL-10)expression.Immunofluorescence double labeling was used to detect microglial marker Iba-1 and microglial polarization markers Arg1 and iNOS co-expression.N9 microglia were treated with lipopolysaccharide(LPS)(2 μg/mL)for 6 h,and then treated with Apelin-13(0.1 μM)for 24 h.The protein expression of i NOS and Arg1 was detected by Western blot.[Results] Chronic restraint immersion stress induced depression-like behavior in rats.Compared with the control group,in stress group Apelin-13 decreased the relative sucrose preference of rats and reduced forced swimming immobility time and tail-suspending time.Apelin-13 upregulated the expression of Arg1 and its anti-inflammatory cytokines IL-4 and IL-10 in rat hippocampus induced by chronic binding stress induced by water immersion(M1/M2).However,Apelin-13 down-regulates the iNOS-M1 marker in the hippocampus of rats and decreases the expression of pro-inflammatory cytokines IL-1β and IL-6.In the same test area,Apelin-13 reduced the co-localization density of Iba-1 and iNOS,but increased the co-localization density of Iba-1 and Arg1.Compared with the control group,the LPS group the protein expression of Arg1 was significantly decreased,and the iNOS protein expression was significantly increased.After treatment with Apelin-13,the Arg1 protein expression was significantly increased,while the iNOS protein expression was significantly reduced.[Conclusion] Apelin-13 improve the chronic stress-induced depression-like behavior in rats,and its mechanism may be related to the regulation of microglial polarization,which provides a new treatment program and new drugs for the treatment of depression.