丹酚酸B对慢性应激抑郁症模型大鼠端粒长度的影响

Effect of salvianolic acid B on the telomere length in a chronic mild stress rat model of depression

目的探讨慢性温和应激(chronic mild stress,CMS)抑郁症模型大鼠血液及脑中端粒长度的变化及丹酚酸B对其的影响。方法采用随机数字表法将45只Sprague-Dawley雄性大鼠随机分为5组:对照组、CMS组、氟西汀组、丹酚酸B组、联合用药组,每组9只,CMS共6周;在抑郁症模型造模成功后(入组后第22~42天),分别按照分组给大鼠腹腔注射0.9%生理盐水、氟西汀(每天20 mg/kg)、丹酚酸B(每天40 mg/kg)。每组在入组前和入组后每周末检测体质量,分别于入组前(第1和第2天),造模后(第21、22天)、干预后(第42、43天)通过检测强迫游泳测试和蔗糖偏爱测试评估抑郁症样行为。通过RT-PCR分析各组大鼠外周血、海马、皮质和小脑的相对端粒长度。采用两因素重复方差分析5组体质量、蔗糖偏爱值和强迫游泳不动时间的差异,Kruskal-Wallis H检验比较5组相对端粒长度的差异。采用Spearman相关分析不同部位端粒长度与体质量、蔗糖偏爱值和强迫游泳不动时间的相关性。结果干预3周后,与CMS组相比,丹酚酸B组、氟西汀组、联合用药组大鼠体质量增加(P=0.049、0.008、0.036),蔗糖偏爱值增加(P=0.089、0.094、0.041)以及强迫游泳不动时间缩短(均P<0.01)。与对照组相比,CMS组外周血相对端粒长度缩短,差异有统计学意义[8.53(3.95)与0.12(0.23),P<0.01,Bonferroni校正P=0.002],双侧海马、皮质和小脑的相对端粒长度差异无统计学意义。与CMS组相比,丹酚酸B组(P=0.005,Bonferroni校正P=0.051)、氟西汀组(P<0.01,Bonferroni校正P=0.005)和联合用药组(P=0.001,Bonferroni校正P=0.007)外周血相对端粒长度显著增加,但在不同脑区差异无统计学意义。Spearman相关分析不同部位的端粒长度与干预后体质量、蔗糖偏爱值、强迫游泳不动时间均无相关性。结论CMS抑郁症模型大鼠外周血端粒长度缩短并不能反映脑内端粒长度的变化,丹酚酸B可使大鼠血液中端粒长度缩短,与氟西汀效果相当。

Objective This study aims to explore the change of blood and brain telomere length and the effect of salvianolic acid B on it in a rat chronic mild stress(CMS)model of depression.Methods A total of 45 Sprague-Dawley(SD)male rats were randomly divided into 5 groups using a random number table,which were the control group,CMS group,fluoxetine group,salvianolic acid B group,and combined medication group,with nine rats in each group.All rats received CMS for 6 weeks.After successfully establishing the depression model(day 22 to day 42 after enrollment),each rat was intraperitoneally injected with 0.9%normal saline,salvianolic acid B(40 mg·kg-1·d-1),and/or fluoxetine(20 mg·kg-1·d-1)respectively according to its belonging group.The body mass of each group was tested before admission and every weekend after admission.The depressant-like behaviors were evaluated using sucrose preference test(SPT)and forced swimming test(FST)before(day-1 and-2)and after the depression model established(day 21 and 22)and after treatment(day 42 and 43)respectively.The relative telomere length in the blood,hippocampus,cortex,and cerebellum were analyzed using RT-PCR,respectively.Two-factor repeated analysis of variance was used to analyze the differences in body mass,sucrose preference,and immobility time among the five groups.The Kruskal-Wallis H test was used to compare the relative telomere length among the five groups.The Spearman's rank correlation test was used to analyze the correlation between the telomere length and body mass,sucrose preference,and immobility time at different body parts.Results After 3 weeks of intervention,compared with those in the CMS group,rats in the salvianolic acid B group,fluoxetine group,and combination medication group showed increased body mass(P=0.049,P=0.008,P=0.036),raised sucrose preference value(P=0.089,P=0.094,P=0.041),and shortened forced swimming immobility time(all P<0.01).Compared with the control group,the CMS group presented statistically significantly shortened blood relative telomere length(8.53(3.95)vs.0.12(0.23),P<0.01,Bonferroni adjusted P=0.002).The relative telomere length of the bilateral hippocampus,cortex,and cerebellum did not significantly differ between the control group and the CMS group.Compared with the CMS group,the relative telomere length in the salvianolic acid B group(P=0.005,Bonferroni adjusted P=0.051),fluoxetine group(P<0.01,Bonferroni adjusted P=0.005),and combined medication group(P=0.001,Bonferroni adjusted P=0.007)increased significantly in the blood sample but not in different brain regions.Spearman correlation analysis showed that there was no correlation between the telomere length of different body parts and the body weight,sucrose preference value,and forced swimming immobility time that assessed after the intervention.Conclusion The shortened telomeres length in the peripheral blood in depression model rats cannot indicate the change of telomere length in the brain.Salvianolic acid B can block the shortening of blood telomere length in depression model rats,with comparable efficacy of fluoxetine.