GSK-3β基因表达在抑郁障碍治疗前后行为模式中的作用
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摘要
目的：
选取抑郁障碍建模成功的糖原合成酶激酶-3β（GSK-3β）过表达的转基因小鼠，按其是否给予慢性轻性不可预见性刺激（CMS）和选择性5-羟色胺再摄取抑制剂（SSRIs）进行分组，给予急性期和慢性期的干预，比较小鼠抑郁样行为的变化以及海马神经元细胞凋亡的情况，分析海马损伤指标的差异与抑郁样行为指标差异之间的相关性，初步探讨GSK-3β与抑郁障碍的发展及转归的关系。
方法：
1、按照随机分组的方法，将40只C57BL/6J小鼠（清华大学提供）按是否给予慢性轻性不可预见性刺激(CMS)和选择性5-羟色胺再摄取抑制剂（SSRI）随机分为5组,每组8只，分别为①正常对照组（control）②GSK3β过表达组（Lvx-GSK3β）、③GSK3β过表达+CMS组（Lvx-GSK3β+CMS）、④GSK3β过表达+氟西汀组（Lvx-GSK3β+fluoxetine）⑤GSK3β过表达+CMS+氟西汀组（Lvx-GSK3β+CMS+fluoxetine）。2.急性期干预：药物组按设计剂量20mg/kg的剂量，注射一次，非药物组不进行药物干预，其他处理同药物组，半小时后，通过强迫游泳实验和悬尾实验评估小鼠的抑郁行为。3.慢性期干预：药物组按设计剂量12mg/kg/d，干预时间14天。对照组不进行药物干预，其他处理同干预组。于第15天，评估其整体行为学指标。同时断头处死小鼠，取海马组织做冰冻切片，检测海马齿状回神经前体细胞凋亡情况。最后用SPSS16.0统计软件包进行数据分析。
结果：
1、单次给药30分钟后，强迫游泳实验及悬尾实验结果均显示：与正常组相比，过表达GSK-3β组（Lvx-GSK3β）和过表达GSK3β应激组（Lvx-GSK3β+CMS），相对于正常对照组（control），其不动时间明显增加,差别有统计学意义（P＜0.05）；Lvx-GSK3β+CMS组相对于Lvx-GSK3β组，其不动时间明显增加，差别有统计学意义（P＜0.05）；同时发现Lvx-GSK3β组及Lvx-GSK3β+CMS组与其相对应的给予氟西汀处理组（Lvx-GSK3β+fluoxetine组和Lvx-GSK3β+CMS+fluoxetine组）相比，差别无统计学差异（P＞0.05）。
2、连续给予氟西汀处理两周后，于次日行强迫游泳实验及悬尾实验，结果显示：与正常组相比，过表达GSK-3β组（Lvx-GSK3β）及过表达GSK3β应激组（Lvx-GSK3β+CMS），相对于正常对照组（control），其不动时间明显增加,差别有统计学意义（P＜0.05）；Lvx-GSK3β+CMS组相对于Lvx-GSK3β组，其不动时间明显增加，差别有统计学意义（P＜0.05）；同时发现Lvx-GSK3β组及Lvx-GSK3β+CMS组与其相对应的给予氟西汀处理组（Lvx-GSK3β+fluoxetine组和Lvx-GSK3β+CMS+fluoxetine组）相比，差别有统计学意义（P＜0.01）；Lvx-GSK3β+fluoxetine组与Lvx-GSK3β+CMS+fluoxetine组相比较，差别有统计学意义（P＜0.05）；Lvx-GSK3β+fluoxetine组和Lvx-GSK3β+CMS+fluoxetine组分别与control组比较，差别无统计学意义（P＞0.05）。
3、灌注处死小鼠，取其海马组织做冰冻切片，观察小鼠海马齿状回区神经前体细胞（NeuralprecursorcellsNPCs）的凋亡情况。
TUNEL染色结果（绿色）：Lvx-GSK3β小鼠海马齿状回区TUNEL阳性细胞较空白组数量多（P＜0.01）；Lvx-GSK3β+CMS组相对于Lvx-GSK3β组小鼠海马齿状回区TUNEL阳性细胞数量多（P＜0.05）；Lvx-GSK3β+fluoxetine组较Lvx-GSK3β组相比，TUNEL阳性细胞数量少（P＜0.01）；Lvx-GSK3β+CMS+fluoxetine组与Lvx-GSK3β+CMS组相比TUNEL阳性细胞数量少（P＜0.01）。
DAPI定位结果示（蓝色）：Lvx-GSK3β小鼠海马齿状回区活性细胞较空白组数量少（P＜0.01）；Lvx-GSK3β+CMS组相对于Lvx-GSK3β组小鼠海马齿状回区活性细胞数量少（P＜0.05）；Lvx-GSK3β+fluoxetine组较Lvx-GSK3β组相比活性细胞数量多（P＜0.01）；Lvx-GSK3β+CMS+fluoxetine组与Lvx-GSK3β+CMS组相比活性细胞数量多（P＜0.01）。
结论：
1、GSK-3β可能与抑郁障碍的发展与转归有关；
2、慢性应激性刺激可能是影响抑郁障碍预后的一个危险因素;
3、GSK-3β可能参与了小鼠海马神经可塑性调节。
目的：
通过检测重性抑郁障碍患者（MDD）治疗前后以及正常对照外周血有核细胞糖原合成酶激酶-3β（GSK-3β）的表达水平，以及自身丝氨酸磷酸化GSK-3β(p-Ser9-GSK-3β)的活性，比较其差异，初步探讨GSK-3β与抑郁障碍发生发展以及转归的关系。
方法：
采用病例对照研究以及前瞻性追踪治疗研究设计的方法。以17例重性抑郁障碍患者（患者组）和与之性别年龄相匹配的17例健康志愿者（对照组）为研究对象，患者组给予8周选择性5-羟色胺再摄取抑制剂（SSRI）氟西汀分散片的治疗，采用免疫印迹法，检测重性抑郁障碍患者治疗前后以及正常对照组，外周血有核细胞中GSK-3β及p-Ser9-GSK-3β的表达水平，最后由SPSS16.0统计软件包进行数据的处理。
结果：
1、重性抑郁障碍患者的临床疗效：重性抑郁障碍患者治疗前，汉密顿焦抑郁量表(HAMD(17项)评分：26.12±1.73分，治疗后其评分为：10.06±2.59分。治疗前后差别有统计学意义。（P＜0.001）。汉密顿焦抑郁量表减分比（治疗前－治疗后/治疗前）为67%±8.9%。重性抑郁障碍患者抑郁障碍状均明显好转（减分率≥50%）。
2、通过蛋白免疫印迹（westernblotting）的方法，检测受试者外周血中GSK-3β的蛋白表达情况，结果示：
三组间用单因素方差分析的方法检测其组间差异具有统计学意义（p=0.017）；治疗前患者组外周血中GSK-3β的蛋白表达明显高于正常组差别有统计学意义（p=0.006）；经过氟西汀分散片抗抑郁治疗后，其外周血中GSK-3β的蛋白表达与治疗前相比，差异有统计学意义（p=0.039）；和正常对照组相比，差别无统计学意义（p＞0.05）。
3、通过蛋白免疫印迹（westernbloating）的方法，检测受试者外周血中p-Ser9-GSK-3β的蛋白表达情况，结果示：
三组间用单因素方差分析的方法检测其组间差异具有统计学意义（p=0.046）；治疗前患者外周血中p-Ser9-GSK-3β的蛋白表达明显高于正常对照组差别有统计学意义（p=0.038）；经过氟西汀分散片抗抑郁治疗后，其外周血中p-Ser9-GSK-3β的蛋白表达与治疗前相比，差异有统计学意义（p=0.027）；和正常对照组相比，差异亦有统计学意义（p=0.015）
结论：
1、GSK-3β可能参与了重性抑郁障碍的发生及发展；
2、调节自身丝氨酸磷酸化的GSK-3β的信号传导通路可能参与了抑郁障碍的发展；
3、氟西汀分散片可以通过磷酸化GSK-3β使其失活，进而发挥药理学作用。
Objective:
To use animal models of depression, transgenic mice with the Glycogen synthase kinase-3β(GSK-3β) over-expressed,and they were grouped by chronic unpredictable mild stress (CMS) or fluoxetine or not.The acute phases of intervention and long term were undertaken on the basis of treatment allocation., to compare the difference between groups in depressed behavior, to find out the correlation between the damage of cells in mice hippocampal and depressed behavior, and to explore the relationship between GSK-3β and the development of depression.
Methods:
1.40C57BL/6J mice were randomly divided into five groups, according to chronic unpredictable mild stress (CMS) or fluoxetine or not, normal group (contributor), GSK3β over-expression group (Lvx-GSK3β),over-expression GSK3β group with CMS (Lvx-GSK3β+CMS), over-expression GSK3β group with fluoxetine (Lvx-GSK3β+fluoxetine),over-expression GSK3β group with CMS and fluoxetine (Lvx-GSK3β+CMS+fluoxetine).2. The acute phases of intervention:the group with fluoxetine was injected only once with fluoxetine (20mg/kg), the group with non-fluoxetine was injected only once with saline wate (20mg/kg),30minutes later, the forced swimming test and tail suspension test were used to evaluate the depressed behavior.3. The long term intervention:the group with fluoxetine was injected with fluoxetine (12mg/kg/d), the group with non fluoxetine was injected with saline wate (12mg/kg/d),14days later, the forced swimming test and tail suspension test were also used to evaluate the depressed behavior, the mice were killed, brain tissues from the brain and hippocampal gyrus were sliced into frozen sections.the apoptosis and proliferation of neural precursor cells were observed by immunofluorescence.Then, all the collected data was analyzed by SPSS16.0for data statistics and analysis.
Results:
1. The acute phases of intervention,the immobility time of the forced swimming test and tail suspension test:LVX-GSK3β group and Lvx-GSK3β+CMS group showed obviously to be longer than normal control groups (P<0.05), Lvx-GSK3β+CMS group showed obviously to be longer than LVX-GSK3β group (P<0.05), But it is not found differences between GSK3β+CMS+fluoxetine group and LVX-GSK3β.(P>0.05), T test showed no corresponding difference between LVX-GSK3β+CMS+fluoxetine group and LVX-GSK3β+CMS (P>0.05)
2. The long term intervention, the immobility time of the forced swimming test and tail suspension test:Lvx-GSK3β+fluoxetine group showed significantly to be shorter than LVX-GSK3β group (P<0.05),.LVX-GSK3β+CMS group show significantly to be shorter than LVX-GSK3β+CMS+fluoxetine group (P<0.01), LVX-GSK3β+CMS+fluoxetine group showed significantly to be longer than Lvx-GSK3β+fluoxetine group (P<0.01),But T test showed no corresponding difference between Lvx-GSK3β+fluoxetine and normal controls (P>0.05), it is not found differences between LVX-GSK3β+CMS+fluoxetine group and normal controls (P>0.05)
3.The results from immunofluorescence:GFP (green),TUNEL positive cells in the hippocampal. gyrusdentatus zone was calculated under a fluorescent microscope:The number of apoptotic cells in LVX-GSK3β group was more than in normal controls,(P<0.01), The number of apoptotic cells in Lvx-GSK3β+CMS group was more than in LVX-GSK3β group (P <0.05), Lvx-GSK3β+fluoxetine group showed significantly to be less than LVX-GSK3β group (P<0.01),and the same result was showed between LVX-GSK3β+CMS+fluoxetine group and LVX-GSK3β+CMS group (P<0.01); The fluorescence intensity was observed in DAPI staining, a true measure of the viable cells. The number of the viable cells in LVX GSK3β group was less than in normal controls,(P<0.01), The number of the viable cells in Lvx-GSK3β+CMS group was less than in LVX-GSK3β group (P<0.05), Lvx-GSK3β+fluoxetine group showed significantly to be more than LVX-GSK3β group (P<0.01),and the same result was showed between LVX-GSK3β+CMS+fluoxetine group and LVX-GSK3p+CMS group (P<0.01)
Conclusion:
1. GSK-3β may be linked to the development of depression.2. CMS may be one of the important factors affecting prognosis.3. GSK-3β may be take part in the regulation of the hippocampal synaptic plasticity in mice.
Objective:
Major depressive disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3β (GSK-3β). The antidepressant medicines inhibit GSK-3β in vitro and in mice brain,we tested whether fluoxetine modified GSK-3β in vivo in peripheral blood mononuclear cells (PBMCs) from healthy control and major depressive disorder subjects, and to explore the relationship between GSK-3β and the development of depressive disorder.
Methods:
1. A case control study and prospective study were conducted., the PBMCs were obtained from17major depressive disorder subjects and17healthy control subjects matched for age and sex, major depressive disorder subjects were treated with fluoxetine therapy for8weeks.2.Immunoblot analyses were used to measure GSK-3β and the inhibited, serine9-phosphorylated GSK-3p.
Results:
1. The level of GSK-3β was increased in major depressive disorder subjects, compared to healthy controls (p=0.006), the level of GSK-3β was decreased by in vivo fluoxetine treatment.(p=0.039), but GSK-3β levels between fluoxetine treatment group and healthy controls was no corresponding difference (p>0.05)
2. Phos-pho-Ser9-GSK3β levels were higher in PBMCs from fluoxetine-treated major depressive disorder subjects than before the treatment (p=0.027) and healthy controls (p=0.015).
Conclusion:
1.GSK-3β may be linked to the development of depressive disorder.
2.Signaling pathways regulating serine9-phosphorylation of GSK-3β is associated with depressive disorder.
3.fluoxetine treatment is associated with a large increase in phospho-Ser9-GSK-3β in PBMCs,the inhibitory serine9-phosphorylation of GSK-3β in human PBMCs may provide a biochemical marker to evaluate the association between GSK-3β inhibition and therapeutic responses to fluoxetine treatment.
选取抑郁障碍建模成功的糖原合成酶激酶-3β（GSK-3β）过表达的转基因小鼠，按其是否给予慢性轻性不可预见性刺激（CMS）和选择性5-羟色胺再摄取抑制剂（SSRIs）进行分组，给予急性期和慢性期的干预，比较小鼠抑郁样行为的变化以及海马神经元细胞凋亡的情况，分析海马损伤指标的差异与抑郁样行为指标差异之间的相关性，初步探讨GSK-3β与抑郁障碍的发展及转归的关系。
方法：
1、按照随机分组的方法，将40只C57BL/6J小鼠（清华大学提供）按是否给予慢性轻性不可预见性刺激(CMS)和选择性5-羟色胺再摄取抑制剂（SSRI）随机分为5组,每组8只，分别为①正常对照组（control）②GSK3β过表达组（Lvx-GSK3β）、③GSK3β过表达+CMS组（Lvx-GSK3β+CMS）、④GSK3β过表达+氟西汀组（Lvx-GSK3β+fluoxetine）⑤GSK3β过表达+CMS+氟西汀组（Lvx-GSK3β+CMS+fluoxetine）。2.急性期干预：药物组按设计剂量20mg/kg的剂量，注射一次，非药物组不进行药物干预，其他处理同药物组，半小时后，通过强迫游泳实验和悬尾实验评估小鼠的抑郁行为。3.慢性期干预：药物组按设计剂量12mg/kg/d，干预时间14天。对照组不进行药物干预，其他处理同干预组。于第15天，评估其整体行为学指标。同时断头处死小鼠，取海马组织做冰冻切片，检测海马齿状回神经前体细胞凋亡情况。最后用SPSS16.0统计软件包进行数据分析。
结果：
1、单次给药30分钟后，强迫游泳实验及悬尾实验结果均显示：与正常组相比，过表达GSK-3β组（Lvx-GSK3β）和过表达GSK3β应激组（Lvx-GSK3β+CMS），相对于正常对照组（control），其不动时间明显增加,差别有统计学意义（P＜0.05）；Lvx-GSK3β+CMS组相对于Lvx-GSK3β组，其不动时间明显增加，差别有统计学意义（P＜0.05）；同时发现Lvx-GSK3β组及Lvx-GSK3β+CMS组与其相对应的给予氟西汀处理组（Lvx-GSK3β+fluoxetine组和Lvx-GSK3β+CMS+fluoxetine组）相比，差别无统计学差异（P＞0.05）。
2、连续给予氟西汀处理两周后，于次日行强迫游泳实验及悬尾实验，结果显示：与正常组相比，过表达GSK-3β组（Lvx-GSK3β）及过表达GSK3β应激组（Lvx-GSK3β+CMS），相对于正常对照组（control），其不动时间明显增加,差别有统计学意义（P＜0.05）；Lvx-GSK3β+CMS组相对于Lvx-GSK3β组，其不动时间明显增加，差别有统计学意义（P＜0.05）；同时发现Lvx-GSK3β组及Lvx-GSK3β+CMS组与其相对应的给予氟西汀处理组（Lvx-GSK3β+fluoxetine组和Lvx-GSK3β+CMS+fluoxetine组）相比，差别有统计学意义（P＜0.01）；Lvx-GSK3β+fluoxetine组与Lvx-GSK3β+CMS+fluoxetine组相比较，差别有统计学意义（P＜0.05）；Lvx-GSK3β+fluoxetine组和Lvx-GSK3β+CMS+fluoxetine组分别与control组比较，差别无统计学意义（P＞0.05）。
3、灌注处死小鼠，取其海马组织做冰冻切片，观察小鼠海马齿状回区神经前体细胞（NeuralprecursorcellsNPCs）的凋亡情况。
TUNEL染色结果（绿色）：Lvx-GSK3β小鼠海马齿状回区TUNEL阳性细胞较空白组数量多（P＜0.01）；Lvx-GSK3β+CMS组相对于Lvx-GSK3β组小鼠海马齿状回区TUNEL阳性细胞数量多（P＜0.05）；Lvx-GSK3β+fluoxetine组较Lvx-GSK3β组相比，TUNEL阳性细胞数量少（P＜0.01）；Lvx-GSK3β+CMS+fluoxetine组与Lvx-GSK3β+CMS组相比TUNEL阳性细胞数量少（P＜0.01）。
DAPI定位结果示（蓝色）：Lvx-GSK3β小鼠海马齿状回区活性细胞较空白组数量少（P＜0.01）；Lvx-GSK3β+CMS组相对于Lvx-GSK3β组小鼠海马齿状回区活性细胞数量少（P＜0.05）；Lvx-GSK3β+fluoxetine组较Lvx-GSK3β组相比活性细胞数量多（P＜0.01）；Lvx-GSK3β+CMS+fluoxetine组与Lvx-GSK3β+CMS组相比活性细胞数量多（P＜0.01）。
结论：
1、GSK-3β可能与抑郁障碍的发展与转归有关；
2、慢性应激性刺激可能是影响抑郁障碍预后的一个危险因素;
3、GSK-3β可能参与了小鼠海马神经可塑性调节。
目的：
通过检测重性抑郁障碍患者（MDD）治疗前后以及正常对照外周血有核细胞糖原合成酶激酶-3β（GSK-3β）的表达水平，以及自身丝氨酸磷酸化GSK-3β(p-Ser9-GSK-3β)的活性，比较其差异，初步探讨GSK-3β与抑郁障碍发生发展以及转归的关系。
方法：
采用病例对照研究以及前瞻性追踪治疗研究设计的方法。以17例重性抑郁障碍患者（患者组）和与之性别年龄相匹配的17例健康志愿者（对照组）为研究对象，患者组给予8周选择性5-羟色胺再摄取抑制剂（SSRI）氟西汀分散片的治疗，采用免疫印迹法，检测重性抑郁障碍患者治疗前后以及正常对照组，外周血有核细胞中GSK-3β及p-Ser9-GSK-3β的表达水平，最后由SPSS16.0统计软件包进行数据的处理。
结果：
1、重性抑郁障碍患者的临床疗效：重性抑郁障碍患者治疗前，汉密顿焦抑郁量表(HAMD(17项)评分：26.12±1.73分，治疗后其评分为：10.06±2.59分。治疗前后差别有统计学意义。（P＜0.001）。汉密顿焦抑郁量表减分比（治疗前－治疗后/治疗前）为67%±8.9%。重性抑郁障碍患者抑郁障碍状均明显好转（减分率≥50%）。
2、通过蛋白免疫印迹（westernblotting）的方法，检测受试者外周血中GSK-3β的蛋白表达情况，结果示：
三组间用单因素方差分析的方法检测其组间差异具有统计学意义（p=0.017）；治疗前患者组外周血中GSK-3β的蛋白表达明显高于正常组差别有统计学意义（p=0.006）；经过氟西汀分散片抗抑郁治疗后，其外周血中GSK-3β的蛋白表达与治疗前相比，差异有统计学意义（p=0.039）；和正常对照组相比，差别无统计学意义（p＞0.05）。
3、通过蛋白免疫印迹（westernbloating）的方法，检测受试者外周血中p-Ser9-GSK-3β的蛋白表达情况，结果示：
三组间用单因素方差分析的方法检测其组间差异具有统计学意义（p=0.046）；治疗前患者外周血中p-Ser9-GSK-3β的蛋白表达明显高于正常对照组差别有统计学意义（p=0.038）；经过氟西汀分散片抗抑郁治疗后，其外周血中p-Ser9-GSK-3β的蛋白表达与治疗前相比，差异有统计学意义（p=0.027）；和正常对照组相比，差异亦有统计学意义（p=0.015）
结论：
1、GSK-3β可能参与了重性抑郁障碍的发生及发展；
2、调节自身丝氨酸磷酸化的GSK-3β的信号传导通路可能参与了抑郁障碍的发展；
3、氟西汀分散片可以通过磷酸化GSK-3β使其失活，进而发挥药理学作用。
Objective:
To use animal models of depression, transgenic mice with the Glycogen synthase kinase-3β(GSK-3β) over-expressed,and they were grouped by chronic unpredictable mild stress (CMS) or fluoxetine or not.The acute phases of intervention and long term were undertaken on the basis of treatment allocation., to compare the difference between groups in depressed behavior, to find out the correlation between the damage of cells in mice hippocampal and depressed behavior, and to explore the relationship between GSK-3β and the development of depression.
Methods:
1.40C57BL/6J mice were randomly divided into five groups, according to chronic unpredictable mild stress (CMS) or fluoxetine or not, normal group (contributor), GSK3β over-expression group (Lvx-GSK3β),over-expression GSK3β group with CMS (Lvx-GSK3β+CMS), over-expression GSK3β group with fluoxetine (Lvx-GSK3β+fluoxetine),over-expression GSK3β group with CMS and fluoxetine (Lvx-GSK3β+CMS+fluoxetine).2. The acute phases of intervention:the group with fluoxetine was injected only once with fluoxetine (20mg/kg), the group with non-fluoxetine was injected only once with saline wate (20mg/kg),30minutes later, the forced swimming test and tail suspension test were used to evaluate the depressed behavior.3. The long term intervention:the group with fluoxetine was injected with fluoxetine (12mg/kg/d), the group with non fluoxetine was injected with saline wate (12mg/kg/d),14days later, the forced swimming test and tail suspension test were also used to evaluate the depressed behavior, the mice were killed, brain tissues from the brain and hippocampal gyrus were sliced into frozen sections.the apoptosis and proliferation of neural precursor cells were observed by immunofluorescence.Then, all the collected data was analyzed by SPSS16.0for data statistics and analysis.
Results:
1. The acute phases of intervention,the immobility time of the forced swimming test and tail suspension test:LVX-GSK3β group and Lvx-GSK3β+CMS group showed obviously to be longer than normal control groups (P<0.05), Lvx-GSK3β+CMS group showed obviously to be longer than LVX-GSK3β group (P<0.05), But it is not found differences between GSK3β+CMS+fluoxetine group and LVX-GSK3β.(P>0.05), T test showed no corresponding difference between LVX-GSK3β+CMS+fluoxetine group and LVX-GSK3β+CMS (P>0.05)
2. The long term intervention, the immobility time of the forced swimming test and tail suspension test:Lvx-GSK3β+fluoxetine group showed significantly to be shorter than LVX-GSK3β group (P<0.05),.LVX-GSK3β+CMS group show significantly to be shorter than LVX-GSK3β+CMS+fluoxetine group (P<0.01), LVX-GSK3β+CMS+fluoxetine group showed significantly to be longer than Lvx-GSK3β+fluoxetine group (P<0.01),But T test showed no corresponding difference between Lvx-GSK3β+fluoxetine and normal controls (P>0.05), it is not found differences between LVX-GSK3β+CMS+fluoxetine group and normal controls (P>0.05)
3.The results from immunofluorescence:GFP (green),TUNEL positive cells in the hippocampal. gyrusdentatus zone was calculated under a fluorescent microscope:The number of apoptotic cells in LVX-GSK3β group was more than in normal controls,(P<0.01), The number of apoptotic cells in Lvx-GSK3β+CMS group was more than in LVX-GSK3β group (P <0.05), Lvx-GSK3β+fluoxetine group showed significantly to be less than LVX-GSK3β group (P<0.01),and the same result was showed between LVX-GSK3β+CMS+fluoxetine group and LVX-GSK3β+CMS group (P<0.01); The fluorescence intensity was observed in DAPI staining, a true measure of the viable cells. The number of the viable cells in LVX GSK3β group was less than in normal controls,(P<0.01), The number of the viable cells in Lvx-GSK3β+CMS group was less than in LVX-GSK3β group (P<0.05), Lvx-GSK3β+fluoxetine group showed significantly to be more than LVX-GSK3β group (P<0.01),and the same result was showed between LVX-GSK3β+CMS+fluoxetine group and LVX-GSK3p+CMS group (P<0.01)
Conclusion:
1. GSK-3β may be linked to the development of depression.2. CMS may be one of the important factors affecting prognosis.3. GSK-3β may be take part in the regulation of the hippocampal synaptic plasticity in mice.
Objective:
Major depressive disorder has been linked to alterations in the multifunctional enzyme glycogen synthase kinase-3β (GSK-3β). The antidepressant medicines inhibit GSK-3β in vitro and in mice brain,we tested whether fluoxetine modified GSK-3β in vivo in peripheral blood mononuclear cells (PBMCs) from healthy control and major depressive disorder subjects, and to explore the relationship between GSK-3β and the development of depressive disorder.
Methods:
1. A case control study and prospective study were conducted., the PBMCs were obtained from17major depressive disorder subjects and17healthy control subjects matched for age and sex, major depressive disorder subjects were treated with fluoxetine therapy for8weeks.2.Immunoblot analyses were used to measure GSK-3β and the inhibited, serine9-phosphorylated GSK-3p.
Results:
1. The level of GSK-3β was increased in major depressive disorder subjects, compared to healthy controls (p=0.006), the level of GSK-3β was decreased by in vivo fluoxetine treatment.(p=0.039), but GSK-3β levels between fluoxetine treatment group and healthy controls was no corresponding difference (p>0.05)
2. Phos-pho-Ser9-GSK3β levels were higher in PBMCs from fluoxetine-treated major depressive disorder subjects than before the treatment (p=0.027) and healthy controls (p=0.015).
Conclusion:
1.GSK-3β may be linked to the development of depressive disorder.
2.Signaling pathways regulating serine9-phosphorylation of GSK-3β is associated with depressive disorder.
3.fluoxetine treatment is associated with a large increase in phospho-Ser9-GSK-3β in PBMCs,the inhibitory serine9-phosphorylation of GSK-3β in human PBMCs may provide a biochemical marker to evaluate the association between GSK-3β inhibition and therapeutic responses to fluoxetine treatment.
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