GSK650394对慢性应激抑郁症模型大鼠行为及海马神经营养的调节作用

Regulating effects of GSK650394 on behavior and hippocampal neurotrophy in chronic stress model of depression in rats

目的探讨血清和糖皮质激素调节蛋白激酶1(SGK1)抑制剂GSK650394对抑郁症模型大鼠抑郁样行为及海马神经营养的调节作用。方法将SD大鼠随机分为对照组、抑郁模型(慢性温和不可预见性应激加孤养)组、GSK650394(2.8 g/L,按1 mL/kg腹腔注射)干预组;采用强迫游泳、糖水消耗、Morris水迷宫实验观察模型动物的情绪行为变化;用ELISA检测大鼠海马血浆和血清中皮质酮(CORT)、5-羟色胺(5-HT)、去甲肾上腺素(NE)含量;用Western blot检测海马中脑源性神经营养因子(BDNF)、神经营养素3(NT-3)、神经生长因子(NGF)的表达。结果与对照组比较,模型组大鼠蔗糖水偏食度显著降低、游泳不动时间增加(P<0.01)、逃避潜伏期(EL)、目标象限的潜伏时间(Lat.T)均显著延长(P<0.05或P<0.01);血浆CORT显著升高(P<0.01)、血清5-HT、NE和海马NT-3、BDNF、NGF表达显著降低(P<0.05或P<0.01)。与模型组比较,GSK650394可显著增加蔗糖水偏食度、降低游泳不动时间(P<0.05或P<0.01)、缩短EL、Lat.T(P<0.05)、降低血浆CORT的含量(P<0.01)、增加血清5-HT、NE的含量(P<0.05或P<0.01);促进海马NT-3、BDNF、NGF的表达(P<0.05)。结论SGK1抑制剂GSK650394可显著改善抑郁样行为,其机制可能与促进海马神经营养有关。

Objective To investigate the protective effect of serum and glucocorticoid-regulated kinase 1(SGK1)inhibitor GSK650394 on depression-like behaviors and hippocampus neurotrophy in depressive model rats.MethodsSD rats were randomly divided into control group,depression model group and GSK650394 group.Depression model was established by chronic mild unpredictable stress.The behavioral changes of the SD rats were observed by forced swimming,1%sugar consumption test and Morris water maze.The changes of corticosterone(CORT)and monoamine neurotransmitters in plasma and serum were observed by ELISA.The changes of BDNF,NT-3 and NGFin hippocampus were detected by Western blot.ResultsCompared with the control group,the model group showed that sucrose preference decreased and swimming immobility time increased significantly(P<0.01).Escape latency(EL)and latency time(Lat.T)prolonged significantly(P<0.05 or P<0.01)and the content of CORT in plasma increased significantly(P<0.01).The content of 5-HT,NE in serum and the expression of BDNF,NT-3,NGF in hippocampus significant increased in the model group.Compared with model group,GSK650394 significantly increased sucrose preference,decreased immobility time(P<0.05 or P<0.01),shortened EL and Lat.T(P<0.05),decreased the content of CORT in plasma(P<0.01)and enhanced the level of 5-HT and NE in serum(P<0.01)and also promoted the expression of NT-3,BDNF and NGF in hippocampus.Conclusions SGK1 inhibitor GSK650394 can significantly relieve depression like behavior potentially through improving the nutrition profile of neurotrophin in hippocampus.