温阳解郁汤对肾阳虚型抑郁大鼠PI3K/Akt信号通路及神经递质的影响

Effects of Wenyang jieyu decoction on PI3K/Akt signaling pathway and neurotransmitters in kidney-yang deficiency depressed rats

目的探讨温阳解郁汤对肾阳虚抑郁症大鼠磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(Akt)信号通路及神经递质的影响。方法将雄性SD大鼠分为空白组、模型组、氟西汀组(西药阳性对照,4.17 mg/kg)、逍遥散组(中药阳性对照,1.88 g/kg)和温阳解郁汤低、中、高剂量组(1.25、2.50、5.00 g/kg),每组15只。除空白组外,其余各组均皮下注射皮质酮20 mg/kg以复制肾阳虚型抑郁大鼠模型,并同时灌胃相应药液,每天1次,连续28 d。观察大鼠的一般情况,检测其糖水偏好率、强迫游泳静止不动时间,计算其脏器指数,检测其血清中神经递质水平/含量,检测其海马组织中PI3K/Akt通路相关蛋白的表达量和树突棘数量。结果与空白组比较,模型组大鼠出现了掉毛、畏冷扎堆、蜷缩等症状,糖水偏好率,肾上腺、胸腺、脾指数,血清环磷酸腺苷(cAMP)、脑源性神经营养因子、γ氨基丁酸水平,cAMP与环磷酸鸟苷比值,去甲肾上腺素、多巴胺、5-羟色胺含量,PI3K、Akt、哺乳动物雷帕霉素靶蛋白的表达量,以及海马组织中树突棘数量均显著降低(P<0.01);静止不动时间、谷氨酸水平、糖原合成酶激酶3β蛋白的表达量均显著延长或升高(P<0.01)。与模型组比较,各药物组大鼠的抑郁症状有所改善,上述指标大部分逆转(P<0.05或P<0.01)。结论温阳解郁汤可改善大鼠的抑郁样行为和肾阳虚状态,调节神经递质的分泌,并可激活PI3K/Akt信号通路,从而起到保护海马神经元的作用。

OBJECTIVE To investigate the effects of Wenyang jieyu decoction on phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)signaling pathway and neurotransmitters in rats with kidney-yang deficiency depression.METHODS The SD rats were divided into blank group,model group,fluoxetine group(positive control of western medicine,4.17 mg/kg),Xiaoyao powder group(positive control of TCM,1.88 g/kg)and Wenyang jieyu decoction low-dose,medium-dose and high-dose groups(1.25,2.50,5.00 g/kg),with 15 rats in each group.Except for blank group,the other groups were treated with corticosterone 20 mg/kg subcutaneously to induce kidney-yang deficiency depressed model,meanwhile the mice were given relevant medicine intragastrically,once a day,for 28 consecutive days.The general conditions of rats were observed.The sucrose preference rate and the static time of forced swimming were detected,and organ indexes of rats were calculated.The levels/contents of neurotransmitters in serum were detected,the expressions of PI3K/Akt pathway-related proteins in hippocampus were detected,and the number of dendritic spines was determined.RESULTS Compared with blank group,model group suffered from the symptoms such as hair loss,fear of cold,curling up;sucrose preference rate,indexes of adrenal gland,thymus gland and spleen,serum levels of cyclic adenosine phosphate(cAMP),brainderived neurotrophic factor and gamma-aminobutyric acid,the ratio of cAMP to cyclic guanosine monophosphate,the contents of norepinephrine,dopamine and 5-hydroxy-tryptamine,the expressions of PI3K,Akt,mammalian target of rapamycin,and the number of dendritic spines in the hippocampus were significantly decreased(P<0.01).The time of immobility,level of glutamic acid and protein expression of glycogen synthetase kinase-3βwere prolonged and increased(P<0.01).Compared with model group,depression symptoms of rats in each administration group were improved,and the above indexes were mostly reversed(P<0.05 or P<0.01).CONCLUSIONS Wenyang jieyu decoction can improve depression-like behavior and the deficiency of kidney-yang,regulate the secretion of neurotransmitters,and activate PI3K/Akt signaling pathway,thus playing a role in protecting hippocampal neurons.