【作者】 修丽娟；

【导师】 魏品康；

【作者基本信息】 第二军医大学 ， 中西医结合临床， 2009， 博士

【摘要】 目的:通过观察消痰解郁方(白龙解郁颗粒)对肿瘤并发抑郁症患者临床疗效,以及消痰解郁方对肿瘤并发抑郁症动物模型的行为学改变,探讨消痰解郁方治疗肿瘤并发抑郁症的的作用机制。方法:临床观察肿瘤并发抑郁症的病情分级的分布特点,并采用抑郁自评量表(SDS)及汉密尔顿他评量表(HAMD)进行评分,并随机分为中药组及空白对照组。观察消痰解郁方(白龙解郁颗粒)治疗4周后肿瘤并发抑郁症患者的SDS、HAMD评分的变化,通过HAMD量表减分率进行疗效评价。实验研究方面,随机分为应激组、应激荷瘤组、荷瘤组、应激荷瘤中药组、应激荷瘤西药组、正常对照组。观察接受慢性应激的荷瘤大鼠的行为学改变,建立肿瘤并发抑郁症动物模型。并观察消痰解郁方对肿瘤并发抑郁症动物模型的行为学、体重、血清蛋白、血清炎性细胞因子TNF-α、IL-6及海马组织中与神经发生障碍相关的Bcl-2、ERK1/2、CREB蛋白及基因的作用。结果:1.肿瘤并发抑郁症患者用药前中药组与空白对照组的SDS、HAMD评分差异无统计学意义,均P>0.05,用药后中药组的SDS、HAMD评分均低于空白对照组,差异有统计学意义,均P<0.05。疗效评价表明中药组的有效率为90.63%(29/32),空白对照组有效率为47.82%(11/23),差异有统计学意义。2.实验前各组大鼠的糖水摄食量、行为学得分及体重差异无统计学意义,均P>0.05,28d慢性应激后应激组、应激荷瘤组糖水摄食量、行为学得分、净体重、血清白蛋白、白球比均较对照组下降,均P<0.05,应激荷瘤组的行为学得分及净体重血清白蛋白下降最为明显,与其余各组差异均有统计学意义,均P<0.05。应激荷瘤组的肿瘤体积在第二周高于荷瘤组,而第三周、第四周的肿瘤体积及瘤重差异无统计学意义,均P>0.05。3.应激荷瘤中药组与应激荷瘤西药组的糖水摄食量、行为学得分高于应激荷瘤组,差异有统计学意义,均P<0.05,且应激荷瘤中药组与应激荷瘤西药组组间比较差异无统计学意义,均P>0.05;应激荷瘤中药组的动物净体重、血清白球比高于应激荷瘤组及应激荷瘤西药组,差异有统计学意义,均P<0.05。4.应激组、应激荷瘤组、荷瘤组大鼠血清的TNF-α、IL-6水平较正常对照组均升高,其中应激荷瘤组TNF-α升高水平最明显,与应激组及荷瘤组差异均有统计学意义(P<0.05),但应激组、应激荷瘤组及荷瘤组三组血清IL-6水平差异无统计学意义。应激荷瘤中药组大鼠的血清TNF-α、IL-6水平较应激荷瘤组下降,差异有统计学意义,与应激荷瘤西药组差异无统计学意义,P>0.05。5.应激组及应激荷瘤组的大鼠的海马Bcl-2mRNA及蛋白表达水平、p-ERK1/2蛋白、p-CREB蛋白较正常对照组明显下降,差异有显著的统计学意义,均P<0.05,应激荷瘤组的海马Bcl-2mRNA低于应激组,差异有统计学意义,P<0.05;应激荷瘤中药组的海马Bcl-2蛋白、p-ERK1/2蛋白、p-CREB与应激荷瘤组比较差异均有统计学意义(P<0.05);而应激荷瘤西药组大鼠海马Bcl-2蛋白、p-ERK1/2蛋白高于应激荷瘤组,与应激荷瘤中药组差异无统计学意义,但p-CREB蛋白表达水平则低于应激荷瘤中药组(P<0.05)。6.相关分析结果表明p-CREB蛋白与TNF-α呈显著负相关(r=-0.401,P=0.023),与Bcl-2蛋白及mRNA、p-ERK1/2存在明显正相关(r=0.613,P=0.000;r=0.486,P=0.005;r=0.488,P=0.006)。结论1、消痰解郁方(白龙解郁颗粒)能有效治疗肿瘤并发抑郁症,以方测证证明痰气互结是肿瘤并发抑郁症的重要病因病机之一。2、慢性应激能导致荷瘤大鼠行为学改变、净体重下降、血清白蛋白、白球比下降,表明荷瘤大鼠在慢性应激情况下比正常大鼠更容易出现抑郁状态,可以模拟临床肿瘤并发抑郁症的患者。肿瘤促进炎性反应,可以作为一种应激参与抑郁症的发病机制。3、慢性应激荷瘤大鼠海马p-CREB蛋白与血清TNF-α呈负相关,与海马Bcl-2蛋白及mRNA、p-ERK1/2呈正相关,p-CREB可能是肿瘤并发抑郁症中的一个关键作用靶点。4、消痰解郁方能够拮抗慢性应激导致的应激荷瘤大鼠的行为学改变、提高净体重及血清白蛋白及白球比,该方的作用机制与下调血清TNF-α、IL-6,上调海马p-CREB蛋白,激活p-ERK1/2蛋白,调节Bcl-2蛋白,保护神经细胞,维持海马正常功能有关。更多还原

【Abstract】 Object:The purpose of this study is to discuss on the influence of Xiaotan jieyu prescription on cancer related depression and discuss the effect of unpredictable chronic mild stress and Xiaotan-Jieyu prescription upon the behavior of Walker 256 tumor-bearing rats and its mechanism.Methods: In clinical study, cancer related depression patients were divided into Chinese medicine group and control group, were assessed by SDS and HAMD scores for four weeks. The effect was valued by score-reducing rate of HAMD.In experimental study, rats were divided into stress, tumor, S-T, ST-XTJY, ST-FLX, control group, observing the effect of chronic unpredicatable mild stress (CUMS) on the sucrose consumption, activity and body weight, so establishing the stressed tumor-brearing rat model. The levels of serum TNF-α, IL-6, hippocampal function and on the mRNA and protein levels of Bcl-2, ERK1/2 and CREB in their hippocampus were observed also.Results:1、Before treatment, no difference was found between Chinese medicine group and control group all P>0.05. The SDS and HAMD scores of Chinese medicine group were significantly lower than that before treatment, all P<0.05. Efficacy evaluation showed that effective rate of Chinese medicine group was 90.63%(29/32), and that of control group was 47.82%(11/23)(P<0.05).2、Before test, no difference was found between sucrose consumption, behavioral scores, and body weight, P>0.05. 28 days of CUMS can reduce the sucrose consumption, behavioral scores, body weight gain and serum Albumin and A/G of tumor-bearing rats. The stressed tumor-bearing rats had less body weight gain, lower behavioral scores and lower serum Albuminthan stressed non-tumor-bearing rats, all P<0.05. The tumor volume of S-T group was bigger than stress group 2 weeks later. But no difference was found between thus two group 3 weeks or 4 weeks later.3、After the exposure to CUMS for 4 weeks, the sucrose consumption, behavioral activities scores of rats in both ST-XTJY group and in ST-FLX group were higher than those of rats in S-T group, all P<0.05, and no difference was shown between ST-XTJY and ST-FLX. Great differences were shown both in body weight gain and serum Albumin between ST-XTJY and S-T groups, while no difference was shown between ST-FLX and S-T group. Xiaotan-Jieyu prescription can alleviate the CUMS-induced changes caused by CUMS.4、The level of serum TNF-αand IL-6 of S-T, Stress and Tumor groups were all higher than those in control group. The level of serum TNF-αin S-T group was higher than that in ST-XTJY and ST-FLX groups (P<0.05), while no difference was shown in serum IL-6 in the other three groups. The levels of serum TNF-αand IL-6 of ST-XTJY and ST-FLX were lower than that in S-T group, all P<0.05, and there was no difference between ST-XTJY and ST-Fluoxetine.5、A marked decrease in mRNA and protein levels of Bcl-2, p-ERK1/2 and p-CREB were found in the hippocampus of rats in stress group and S-T group compared with those in control group. The mRNA level of Bcl-2 in hippocampus in S-T group decreased more than that in stress group. The administration of Xiaotan-Jieyu prescription resulted in a significant increase in protein levels of Bcl-2, p-ERK1/2 and p-CREB. No difference was shown between ST-FLX and ST-XTJY in the levels of Bcl-2 protein and p-ERK1/2 in hippocampus of rats, but a difference in p-CREB proterin between them.6、The correlation analysis showed that p-CREB was correlated with serum TNF-αnegatively(r=-0.401,P=0.023), but correlated with Bcl-2 protein and mRNA and p-ERK1/2 in hippocampus positively (r=0.613,P=0.000;r=0.486,P=0.005;r=0.488,P=0.006).Conclusion:1、Xiaotan Jieyu prescription(Bailong jieyu particle) can treat cancer related depression effectively. That proved that the sputum-qi interplay is the mechanism of cancer related depression.2、CUMS can reduce the average sucrose consumption, behavioral scores, body weight gain and serum albumin, which indicated that tumor-bearing rats were prone to behave more depressively than non-tumor-bearing rats after being exposed to CUMS. Tumor, by increasing the inflammatory reaction, can be taken as a stressor, playing an important role in the pathogenesis of cancer related depression.3、A negative correlation was found between the expression of p-CREB in hippocampus proper and levels of serum TNF-α, while a positive correlation between the expression of p-CREB and Bcl-2 protein, mRNA and p-ERK1/2. The p-CREB protein maybe a target of treatment for cancer related depression. 4、Those changes caused by CUMS were relieved in stressed tumor-bearing rats administered with Xiaotan-Jieyu prescription. It can decrease serum TNF-αand IL-6 and increase p-CREB, p-ERK1/2 and Bcl-2 protein, which helps protect neurons and maintain the normal function of hippocampus.更多还原