| Objectives：Studies have shown that Apelin have antidepressant effect in FST and LH models.This research we used the forced swimming model of WKY rats、tail suspension model ofKM mouse and unexpected chronic mild stress model of rats to study the antidepressanteffects of Apelin. The behavior pharmacology、 immunohistochemical andimmunefluorescence double-labeling methods were used to detect the role ofhippocampal neurogenesis in antidepressant effects of Apelin.Methods：1、To assess antidepressant effect of Apelin in WKY rats forced swimmingmodelMale WKY rats and Wistar rats were implanted with guide cannulae aimed atlateral ventricle under anesthesia, rats were allowed a total of7days recovery time. TheWKY rats were divided into three groups: Control vehicle group, IMI group and Apelingroup。The Wistar rats were divided into three groups: Control vehicle group，IMI groupand Apelin group。The rats were microiniected three times either vehicle, imipramine(200μg/rat) or Apelin-13(2μg/rat) were performed before FST. After24hours, theWistar rats were microiniected once vehicle, imipramine (200μg/rat) or Apelin-13(2μg/rat) were performed before the second FST. The total accumulative immobility timeduration of immobility was scored during the FST.2、To assess antidepressant effect of Apelin in mouse tail suspension modelMale KM mouse were implanted with guide cannulae aimed at lateral ventricleunder anesthesia, mouse were allowed a total of7days recovery time. The mouse weredivided into three groups: Control vehicle group, IMI group and Apelin group. Themouse were microiniected three times either vehicle, imipramine (200μg/rat) orApelin-13(2μg/rat) were performed before TST. After24hours, the mouse were microiniected once vehicle, imipramine (200μg/rat) or Apelin-13(2μg/rat) wereperformed before the second TST. The total accumulative immobility time duration ofimmobility was scored during the TST.3、To assess antidepressant effect of Apelin in rats chronic mild stress modelMale Wistar rats were implanted with guide cannulae aimed at lateral ventricleunder anesthesia, rats were allowed a total of7days recovery time. The rats were dividedinto four groups: Control/vehicle group, Str/vehicle group, Str/IMI group and Str/Apelingroup。It consisted of a varying of stressors applied randomly and at varying times of theday for5weeks. At3weeks after the beginning of the CUS procedure, the rats weremicroiniected once either vehicle, imipramine (200μg/rat) or Apelin-13(2μg/rat) everyday.The weight and sucrose preference were tested at every week.4、To assess antidepressant effect of Apelin in rats chronic mild stress model1)The influence of Apelin on the proliferation, differentiation of hippocampalneural sterm cell and the survival of newly proliferating cellsMale Wistar rats were implanted with guide cannulae aimed at lateral ventricleunder anesthesia, rats were allowed a total of7days recovery time. The rats weremicroinjected vehicle or Apelin-13(2μg/rat)2weeks.(1) The effect of Apelin on theproliferation of hippocampal neural sterm cell. BrdU was used to label proliferating cells.The BrdU were given intraperitoneally (50mg/kg) to the rats every day, lasting7days,until the end of Apelin treatment. The rats were killed24h after the last BrdUtreatment. The brains were removed and fixed. The paraffin sections were used forimmunohistochemistry.(2) The effect of Apelin on the differentiation of hippocampalneural sterm cell. BrdU was used to label differentiation cells. Four injections of BrdUwere given intraperitoneally (75mg/kg) to the rats every2h every day, lasting two days.The rats were killed28days after the last BrdU treatment. The brains were removed andfixed. The paraffin sections were used for immunofluorescence (BrdU/NeuN).(3) Theeffect of Apelin on the ohippocampal newly proliferating cell. BrdU was used to labelnewly proliferating cells. Four injections of BrdU were given intraperitoneally (75mg/kg)to the rats every2h every day, lasting two days. The rats were killed28days after the lastBrdU treatment. The brains were removed and fixed. The paraffin sections were used for immunofluorescence (BrdU/NeuN).2) The influence of Apelin on CMS supression hippocampal neurogenesisMale Wistar rats were implanted with guide cannulae aimed at lateral ventricleunder anesthesia, rats were allowed a total of7days recovery time. The rats were dividedinto four groups: Control/vehicle group, Str/vehicle group and Str/Apelin group.Itconsisted of a varying of stressors applied randomly and at varying times of the day for5weeks. At3weeks after the beginning of the CUS procedure, the rats were microiniectedonce either vehicle or Apelin-13(2μg/rat) every day. BrdU was used to label proliferatingcells. The BrdU were given intraperitoneally (50mg/kg) to the rats every day, lasting7days, until the end of Apelin treatment. The rats were killed24h after the last BrdUtreatment. The brains were removed and fixed. The paraffin sections were used forimmunohistochemistry.3) Involvement of hippocampal neurogenesis in mediating the antidepressanteffect of ApelinMale Wistar rats were implanted with guide cannulae aimed at lateral ventricleunder anesthesia, rats were allowed a total of7days recovery time. The rats were dividedinto five groups: Control/vehicle group, Str/vehicle group, Str/AZT group, Str/Apelingroup and Str/Apelin+AZT group. It consisted of a varying of stressors applied randomlyand at varying times of the day for5weeks. At3weeks after the beginning of the CUSprocedure, the rats were microiniected once either vehicle or Apelin (2μg/rat) every day,lasting2weeks. The rats were microiniected AZT (1μmol/rat)2h before microinjectionApelin, lasting2weeks. The BrdU were given intraperitoneally (50mg/kg) to the ratsevery day, lasting7days, until the end of Apelin treatment. The sucrose preference weretested at every week. The rats were killed24h after the last sucrose preference test. Thebrains were removed and fixed. The paraffin sections were used forimmunohistochemistry.Results：1、To assess antidepressant effect of Apelin in WKY rats forced swimmingmodelDuring the first FST, the immobility time of WKY rats Vehicle group significantly higher than the Wistar rats Vehicle group. Compared with WKY rats Vehicle group,WKY rats IMI group and Apelin group significantly decrease immobility time of WKYrats. Compared with Wistar rats Vehicle group, Wistar rats IMI group significantlydecrease immobility time. During the second FST, Compared with Wistar rats Vehiclegroup, Wistar rats IMI group and Apelin group significantly decrease immobility time ofWistar rats.2、To assess antidepressant effect of Apelin in mouse tail suspension modelDuring the first TST, the immobility time of KM mouse IMI group significantlylower than Vehile group, but there are no significantly difference between KM mouseApelin group and Vehicle group. During the second TST, KM mouse Apelin group andIMI group significantly decrease immobility time compared with Vehicle group.3、To assess antidepressant effect of Apelin in rats chronic mild stress modelAfter chronic mild stress treat one week, the body weight significant decrease inStr/Veh group, Str/IMI group and Str/Apelin group compared with Con/Veh group. Stresstreat3weeks, Stress group had a significantly lower preference for sucrose solution thanControl group. In the forth week, the sucrose preference of Str/IMI group significantlyhigher than Str/Veh group. In the fifth week, the sucrose preference of Str/IMI group andStr/Apelin group significantly higher than Str/Veh group, but no significantly differencecompared with Con/Veh group.4、To assess antidepressant effect of Apelin in rats chronic mild stress model1) Effects of Apelin on proliferation, differentiation, survive of adulthippocampal neural stem cellCompared with Vehicle group, Apelin group significantly increase the number ofBrdU-positive cells in the hippocampus, in proliferation of hippocampal neural stem cell.In differentiation of hippocampal neural stem cell, the number of BrdU-positive cellsdouble-labeled for neuronal nuclei (NeuN) in Apelin group, significant higher than theVehicle group. In survive of hippocampal neural stem cell, Apelin group significantlyincrease the number of BrdU-positive cells double-labeled for neuronal nuclei (NeuN)than the Vehicle group.2) The influence of Apelin on CMS inhibits hippocampal neurogenesis In proliferation of hippocampal neural stem cell, compared with Con/Veh group,Str/Veh group significantly increase the number of BrdU-positive cells in thehippocampus. Str/Apelin group significantly increased the total number of BrdU-positivecells compared with Str/Veh.3) Involvement of hippocampal neurogenesis in mediating the antidepressanteffect of ApelinStress were treated2weeks, Stress group had a significantly lower preference for sucrosesolution than Control group. In the forth and fifth week, Str/Apelin group rats had a significantlyhigher sucrose preference than Str/Veh group, but no significantly difference compared with Con/Vehgroup. There are no significantly difference between Str/Apelin+AZT and Str/Veh group. Inproliferation of hippocampal neural stem cell, compared with Con/Veh group, Str/Veh group, Str/AZTgroup and Str/Apelin+AZT group significantly increase the number of BrdU-positive cells in thehippocampus. Str/Apelin group significantly increased the total number of BrdU-positive cellscompared with Str/Veh. There are no significantly difference between Str/Apelin and Con/Veh group.Conclusion：Apelin have antidepressive behavior in various of depressed models of animal.During the chronic mild stress model, hippocampal neurogenesis contributes to theantidepressant-like behavioral effect of Apelin. |
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