丙泊酚调整抑郁大鼠电休克治疗效应及减轻其学习记忆损害的突触可塑性机制
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摘要
目的对比观测丙泊酚联合电休克治疗(Electroconvulsive therapy,ECT)中多因素(病因、ECT参数及用药)对抑郁大鼠行为、学习记忆及海马脑源性神经营养因子(Brain derived neurotrophic factor,BDNF)表达的影响及其可能交互作用,并进一步研究丙泊酚联合ECT对海马长时程增强(Long term potentiation,LTP)及相关突触蛋白、基因表达的影响,以期探讨丙泊酚对抑郁大鼠ECT治疗效应的调整及减轻其学习记忆损害的突触可塑性机制。
方法
第一部分:健康成年雄性Wistar大鼠88只,鼠龄2～3月,体重200～250 g。除随机选取正常对照组大鼠(C组,n=8)正常饲养相同时间外,其余大鼠采用慢性轻度不可预见性应激(Chronic unpredictable mild stresses,CUMS)方法建立抑郁模型。模型制备成功后,抑郁模型大鼠按(2×5)两因素析因设计进行随机分组、被施予ECT处理,一因素为用药情况(联合生理盐水或丙泊酚,2个水平),另一因素为ECT电量(0、60、120、180、240 mC,5个水平),分为两个大组:施以联合生理盐水(9 ml/kg)腹腔注射(Intraperitoneal injection,I.P.)ECT处理组记为E组,施以联合丙泊酚(9 ml/kg,I.P.,浓度10 mg/ml)ECT处理组记为M组;再各自按ECT的5个电量水平分为5个亚组,分别记为E0、E60、E120、E180、E240与M0、M60、M120、M180、M24(0注:0 mC组安装电极但不通电流,即被施予伪ECT处理()n=8)。ECT参数设置及疗程:双相矩形波,波幅0.8 A,波宽1.5 ms,125脉冲/s,时程0.4、0.8、1.2、1.6 s分别产生电量为60、120、180、240 mC的电刺激,1次/d,连续7 d。C组予以生理盐水(9 ml/kg,I.P.)后行伪ECT处理。于建模后第1 d、ECT全程完成后第1 d行糖水偏好实验(SPT),于建模后第2 d、ECT全程完成后第2 d行旷场实验(OFT),于建模后第3 d、ECT全程完成后第3 d行Morris水迷宫实验。第二次水迷宫实验完成后第1 d,处死大鼠,取海马组织以酶联免疫吸附测定法(Enzyme linked immunosorbent assay,ELISA)测定其BDNF蛋白表达。
第二部分:健康成年雄性Wistar大鼠45只、成年雄性Wistar Kyoto (WKY)大鼠36只,鼠龄2～3月,体重200～250 g。除正常对照组(C组,随机选取Wistar鼠,n=9)正常饲养相同时间外,其余Wistar大鼠采用CUMS方法建立环境性抑郁模型,WKY鼠(作为遗传性抑郁模型)正常饲养相同时间。模型制备成功后,抑郁模型大鼠按(2×2×2)三因素析因设计随机分为8组(n=9),一因素为抑郁模型(CUMS处理Wistar鼠或WKY鼠,2个水平),第二因素为ECT处理(或伪ECT处理,2个水平),另一因素为用药情况(联合生理盐水或丙泊酚,2个水平)。上述8组分别为:抑郁对照组(环境性抑郁模型组CD组、Wistar鼠,遗传性抑郁模型组KD组、WKY鼠)、单纯丙泊酚处理组(环境性抑郁模型组CP组、Wistar鼠,遗传性抑郁模型组KP组、WKY鼠)、单纯ECT组(环境性抑郁模型组CE组、Wistar鼠,遗传性抑郁模型组KE组、WKY鼠)、丙泊酚联合ECT组(环境性抑郁模型组CM组、Wistar鼠,遗传性抑郁模型组KM组、WKY鼠)。按分组行ECT处理(双相矩形波、波幅0.8 A、波宽1.5 ms、125脉冲/s、时程0.8 s、电量120 mC,1次/ d,连续7 d):CE、KE组予以生理盐水(9 ml/kg,I.P.)后行ECT;CM、KM组予以丙泊酚(9 ml/kg,I.P.,浓度10mg/ml)后行ECT;C组、CD组、KD组予以生理盐水(9 ml/kg,I.P.)后行伪ECT处理,1次/d,连续7 d;CP、KP组予以丙泊酚(9 ml/kg,I.P. ,浓度10mg/ml)后行伪ECT处理,1次/d,连续7 d。于建模后第1 d、ECT全程完成后第1 d行SPT,于建模后第2 d、ECT全程完成后第2 d行OFT,于建模后第3 d、ECT全程完成后第3 d行Morris水迷宫实验。第二次水迷宫实验完成后第1 d,处死大鼠,取海马组织。各组随机选取4只大鼠以尼氏染色观测海马CA1区、DG区神经元形态数量;各组其余5只大鼠以ELISA法测定其海马BDNF蛋白表达。
第三部分:健康成年雄性Wistar大鼠35只,成年雄性WKY大鼠20只,鼠龄2～3月,体重200～250 g。动物随机分组:C组(正常对照组,Wistar鼠,n=11),D、P、E、M组(各纳入WKY鼠5只和Wistar鼠6只)。D、P、E、M组中Wistar鼠采用CUMS方法建立抑郁模型,WKY鼠及C组Wistar鼠正常饲养相同时间。D组大鼠予以生理盐水(9 ml/kg,I.P.)后行伪ECT处理(1次/ d,连续7 d),P组大鼠予以丙泊酚(9 ml/kg,I.P.,浓度10 mg/ml)后行伪ECT处理(1次/ d,连续7 d);E组予以生理盐水(9 ml/kg,I.P.)后行ECT处理(双相矩形波、波幅0.8 A、波宽1.5 ms、125脉冲/s、时程0.8 s、电量120 mC,1次/ d,连续7 d);M组予以丙泊酚(9 ml/kg,I.P. ,浓度10mg/ml)后行ECT处理(方法、疗程同E组)。C组随机选取5只Wistar鼠、其余4组中的WKY鼠于ECT全程完成后第1 d制作海马脑片、以电生理方法检测CA1区LTP;C组余下6只、其余4组每组中6只Wistar鼠于ECT全程完成后第1 d取海马组织,以western blotting方法、实时定量荧光RT-PCR方法分别检测Synapsin I,PSD-95,GluR1,CREB(p-CREB),NR2A/B蛋白及其mRNA表达。
结果(1)大鼠CUMS抑郁模型建立后及(/或)伪ECT处理后,其糖水偏好、OFT指标、记忆功能、海马BDNF蛋白水平相对正常对照鼠均降低;单纯丙泊酚注射不能逆转上述变化;单纯ECT(即生理盐水联合ECT)可改善抑郁行为、提升海马BDNF水平,但损害学习、记忆功能;随ECT电量增大,单纯ECT对快感缺失行为(由SPT评估)的对抗效应未见进一步增大,对自发探索行为(由OFT评估)的兴奋效应先增大后减小,对学习、记忆功能的损害效应逐渐加重(在中高电量下未见进一步加重),而对海马BDNF水平的提升效应仅在180 mC下略有下降;丙泊酚在除OFT直立次数外其余所有指标上均与ECT电量发生交互作用,不同程度地调整不同电量ECT的效应:丙泊酚在低电量(60 mC)表现出对ECT对抗快感缺失行为、提升海马BDNF效应的削弱,在120 mC及以上电量表现出对上述效应的增强(但最高电量240 mC下丙泊酚对ECT提升BDNF效应的增强作用不显著);随ECT电量增大,丙泊酚对ECT兴奋动物自发探索行为效应的对抗作用以及其对ECT损害学习记忆效应的对抗作用亦均减弱;(2)不同抑郁模型(模型因素)、接受ECT与否(ECT处理因素),联合生理盐水或丙泊酚(用药因素)以及上述三种因素两两之间或三种共同作用可对抑郁模型动物的抑郁行为、学习记忆及海马BDNF蛋白水平等产生不同程度的交互效应:环境性抑郁模型和遗传性抑郁模型鼠相对正常大鼠,除学习功能、海马DG区神经元数量外,其余指标均不同程度降低;单纯丙泊酚注射不能逆转上述变化;单纯ECT处理后:除外遗传性抑郁模型鼠的OFT水平活动距离及海马BDNF无显著变化,两种模型鼠的SPT、OFT行为学及海马BDNF其余指标均显著改善;除外OFT直立次数,遗传性抑郁模型鼠其余上述指标均相对环境性抑郁模型鼠偏低;丙泊酚联合ECT下,除环境性抑郁模型鼠上SPT、海马BDNF指标改善效应优于单纯ECT,OFT水平活动距离改善效应差于单纯ECT外,其余上述指标在两种模型上相对单纯ECT无显著差异;丙泊酚对遗传性抑郁模型鼠SPT、BDNF指标的改善效应均相对环境性抑郁模型鼠偏弱;单纯ECT处理后:两种模型的学习、记忆功能均显著降低,遗传性抑郁模型鼠相对环境性抑郁模型鼠学习功能下降更为显著;丙泊酚联合ECT下,相对单纯ECT组,两种抑郁模型学习、记忆功能均显著改善,遗传性抑郁模型鼠上该改善效应弱于环境性抑郁模型鼠;各治疗组海马CA1区神经元数量并未相对于
未治疗组得到增加;(3)相对正常组,抑郁模型鼠海马LTP效应减弱,其相关突触蛋白表达及PSD-95、GluR1、NR2A的mRNA表达不同程度下调;单纯丙泊酚注射不能逆转上述变化;单纯ECT增大兴奋性突触后场电位(fEPSP)基础斜率、但不加重对LTP效应的减弱,可回升Synapsin I蛋白至正常组水平,进一步降低PSD-95、p-CREB蛋白水平,而不逆转其它蛋白表达的降低及相关蛋白mRNA表达的下调;相对单纯ECT,丙泊酚联合ECT下,LTP水平回复至正常组水平,除Synapsin I蛋白水平下降外,PSD-95、NR2A/B及p-CREB蛋白水平均上调(除外PSD-95,均上升至正常组水平),而PSD-95、NR2A的mRNA表达回复至正常组水平。
结论(1)丙泊酚与ECT电量发生交互作用,从行为学和分子水平均能调整不同电量ECT对抑郁模型动物的效应:丙泊酚在不同ECT电量下产生不同效应;丙泊酚联合下,中等电量MECT在既能达到有效抗抑郁疗效的同时,较好地改善ECT所致学习记忆功能损害,且不过度干扰ECT对自发探索行为的兴奋效应;(2)丙泊酚与抑郁动物模型不同抑郁成因、ECT发生交互作用,从行为学和分子水平均能调整ECT对不同成因抑郁模型动物的效应:相比环境性抑郁模型,遗传性抑郁模型对丙泊酚在ECT中的调整作用的反应较弱;(3)丙泊酚联合ECT不同程度地改善抑郁症、单纯ECT对突触传递可塑性、相关突触蛋白及其基因的过度效应。
Objective To investigate the effects of multiple factors [e.g. etiological factors, parameters of electroconvulsive therapy (ECT), and anesthetics] on behavior, learning and memory, and hippocampal brain derived neurotrophic factor (BDNF) expression in depressed rats undergoing ECT pretreated with propofol and the potential interaction. The effects of ECT pretreated with propofol on long term potentiation (LTP) in hippocampal slices and expression of mRNA and protein level of related synaptic proteins were also included, so as to study propofol’s regulation of ECT’s efficacy and improvement of ECT-induced learning and memory deficits in depressed rats, and the possible mechanism in the view of synaptic plasticity.
Methods
Part I: Healthy adult male Wistar rats (2-3 months, 200-250 g) were randomly divided into 11 groups (n=8). Except for the normal breeding of rats in the control group (group C) for 28 d, the other rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the rodent model of depression. The 10 groups of depressed rats were assigned to treatments according to (2×5) factorial design, with drug factor (normal saline or propofol) and stimulus intensities of ECT (0, 60, 120, 180, and 240 mC) as the two factors. These depressed rats were assigned into two major groups, each received ECTs with pretreatment with either propofol (10 g/l)(group M) or normal saline (group E) (9 ml/kg, i.p.). There were five sub-groups in each major group, the rats of which received ECTs with different stimulus intensities (0 mC, 60 mC, 120 mC, 180 mC, 240 mC) once daily for 7 days. Other parameters of ECT: square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.4, 0.8, 1.2, 1.6 s (for 60 mC, 120 mC, 180 mC, 240 mC). Sucrose preference test (SPT) and open field test (OFT) were performed to assess depressive behavior. Morris water maze task (MWM) was used to measure learning and memory. Hippocampal BDNF protein level was measured with enzyme linked immunosorbent assay (ELISA).
Part II: Healthy adult male Wistar rats and adult Wistar Kyoto (WKY) rats (2-3 months, 200-250 g) were randomly divided into 9 groups (n=9). Except for the normal breeding of rats in the control group (group C, Wistar rats) and WKY rats for 28 d, the other Wistar rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the environmental rodent model of depression. The 8 groups of depressed rats were assigned to treatments according to (2×2×2) factorial design, with (environmental or genetic factors), ECT (or sham ECT), and drug factor (normal saline or propofol) as the three factors. These groups were as following: depressed rats groups treated with normal saline (9 ml/kg, I.P., everyday for 7 d) (environmental: group CD with Wistar rats; genetic: group KD with WKY rats); depressed rats treated with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) (environmental: group CP with Wistar rats; genetic: group KP with WKY rats); depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with normal saline (9 ml/kg, I.P., everyday for 7 d) (environmental: group CE with Wistar rats; genetic: group KE with WKY rats); depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) (environmental: group CM with Wistar rats; genetic: group KM with WKY rats). SPT and OFT were performed to assess depressive behavior. MWM was used to measure learning and memory. Number of hippocampal neurons was observed with Nissl stain, and BDNF protein level was measured with ELISA.
Part III: Healthy adult male Wistar rats and adult Wistar Kyoto (WKY) rats (2-3 months, 200-250 g) were randomly divided into 5 groups (n=11, except for 11 Wistar rats in group C, each of the other 4 groups included 5 WKY rats and 6 Wistar rats). Except for the normal breeding of rats in the control group (group C, Wistar rats) and WKY rats for 28 d, the other Wistar rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the environmental rodent model of depression. These groups were as following: depressed rats groups treated with normal saline (9 ml/kg, I.P., everyday for 7 d) in group D; depressed rats treated with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) in group P; depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with normal saline (9 ml/kg, I.P., everyday for 7 d) in group E; depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) in group M. 5 Wistar rats in group C and the WKY rats in the other 4 groups were used for measuring LTP in hippocampus with electrophysiological methods; all the rest Wistar rats in each group were used for assaying mRNA and protein level of Synapsin I, PSD-95, GluR1, CREB (p-CREB), NR2A/B with western blotting and real-time RT-PCR.
Results
Part I: The CUMS-treated rats exhibited depressive behavior and impairment of learning and memory; Propofol injection (everyday for 7 d) could not reverse these changes; ECT could relieve depressive behavior, but aggravated deficits of learning and memory; When ECT was pretreated with propofol, by the increase of stimulus intensities, propofol’s effects on the anti-anhedonia efficacy and elevating effects on hippocampal BDNF of ECT were turnovered from weakening to strengthening; both the weakening effects on ECT’s improving effects on spontaneous exploring activities and protective effects against ECT’s impairment of learning and memory of propofol were weaken. Propofol and stimulus intensities interacted with each other to exert effects both in the behavioral and molecular level in depressed rats.
Part II: Both the environmental and genetic rodent model of depression exhibited depressive behavior, reduced number of hippocampal neurons and BDNF expression, and deficits of learning and memory. Propofol injection (everyday for 7 d) could not reverse these changes; ECT could relieve depressive behavior, but aggravated deficits of learning and memory; the improving effects of ECT on depressive behavior and hippocampal BDNF were weaker, while ECT-induced learning and memory deficits were more severe in WKY rats; When ECT was pretreated with propofol, propofol could enhance the anti-anhedonia, elevating hippocampal BDNF effects of ECT, and attenuate ECT’s improving effects on spontaneous exploring activities and ECT-induced learning and memory impairment, while these effects were weaker in WKY rats than CUMS-treated Wistar rats (except for effects on spontaneous exploring activities); all the treatments exerted no signinficant effects on hippocampal neurons: etiological factors for depression, ECT, and propofol interacted with each other to exert effects both in the behavioral and molecular level in depressed rats.
Part III: In the depressed rats, both hippocampal LTP and the expression of related synaptic protein and their mRNA were inhibited to different extent; Propofol injection (everyday for 7 d) could not reverse these changes; ECT could not relieve the changes of expression of mRNA of synaptic proteins; Without reversing the other proteins’lower expression, ECT recovered Synapsin I protein expression to the level as group C, but more severely inhibited LTP and down-regulated expression of PSD-95 and p-CREB proteins; When ECT was pretreated with propofol, propofol could up-regulate LTP and expression of mRNA of PSD-95 and NR2A to the level of group C, down-regulate expression of Synapsin I protein, and up-regulate expression of the other proteins to different extent (except for PSD-95, all the other proteins were regulated to the level of group C).
Conclusions Propofol has interaction with stimulus intensities to differently regulate ECT's efficacy and amnesic effects in both behavioral and molecular levels; Response to ECT and propofol’s regulation in ECT were less significant in genetic rodent model of depression than environmental model; Propofol’s regulation of ECT’s effects is exerted by regulation of hippocampal synaptic plasiticity and related synaptic proteins.
方法
第一部分:健康成年雄性Wistar大鼠88只,鼠龄2～3月,体重200～250 g。除随机选取正常对照组大鼠(C组,n=8)正常饲养相同时间外,其余大鼠采用慢性轻度不可预见性应激(Chronic unpredictable mild stresses,CUMS)方法建立抑郁模型。模型制备成功后,抑郁模型大鼠按(2×5)两因素析因设计进行随机分组、被施予ECT处理,一因素为用药情况(联合生理盐水或丙泊酚,2个水平),另一因素为ECT电量(0、60、120、180、240 mC,5个水平),分为两个大组:施以联合生理盐水(9 ml/kg)腹腔注射(Intraperitoneal injection,I.P.)ECT处理组记为E组,施以联合丙泊酚(9 ml/kg,I.P.,浓度10 mg/ml)ECT处理组记为M组;再各自按ECT的5个电量水平分为5个亚组,分别记为E0、E60、E120、E180、E240与M0、M60、M120、M180、M24(0注:0 mC组安装电极但不通电流,即被施予伪ECT处理()n=8)。ECT参数设置及疗程:双相矩形波,波幅0.8 A,波宽1.5 ms,125脉冲/s,时程0.4、0.8、1.2、1.6 s分别产生电量为60、120、180、240 mC的电刺激,1次/d,连续7 d。C组予以生理盐水(9 ml/kg,I.P.)后行伪ECT处理。于建模后第1 d、ECT全程完成后第1 d行糖水偏好实验(SPT),于建模后第2 d、ECT全程完成后第2 d行旷场实验(OFT),于建模后第3 d、ECT全程完成后第3 d行Morris水迷宫实验。第二次水迷宫实验完成后第1 d,处死大鼠,取海马组织以酶联免疫吸附测定法(Enzyme linked immunosorbent assay,ELISA)测定其BDNF蛋白表达。
第二部分:健康成年雄性Wistar大鼠45只、成年雄性Wistar Kyoto (WKY)大鼠36只,鼠龄2～3月,体重200～250 g。除正常对照组(C组,随机选取Wistar鼠,n=9)正常饲养相同时间外,其余Wistar大鼠采用CUMS方法建立环境性抑郁模型,WKY鼠(作为遗传性抑郁模型)正常饲养相同时间。模型制备成功后,抑郁模型大鼠按(2×2×2)三因素析因设计随机分为8组(n=9),一因素为抑郁模型(CUMS处理Wistar鼠或WKY鼠,2个水平),第二因素为ECT处理(或伪ECT处理,2个水平),另一因素为用药情况(联合生理盐水或丙泊酚,2个水平)。上述8组分别为:抑郁对照组(环境性抑郁模型组CD组、Wistar鼠,遗传性抑郁模型组KD组、WKY鼠)、单纯丙泊酚处理组(环境性抑郁模型组CP组、Wistar鼠,遗传性抑郁模型组KP组、WKY鼠)、单纯ECT组(环境性抑郁模型组CE组、Wistar鼠,遗传性抑郁模型组KE组、WKY鼠)、丙泊酚联合ECT组(环境性抑郁模型组CM组、Wistar鼠,遗传性抑郁模型组KM组、WKY鼠)。按分组行ECT处理(双相矩形波、波幅0.8 A、波宽1.5 ms、125脉冲/s、时程0.8 s、电量120 mC,1次/ d,连续7 d):CE、KE组予以生理盐水(9 ml/kg,I.P.)后行ECT;CM、KM组予以丙泊酚(9 ml/kg,I.P.,浓度10mg/ml)后行ECT;C组、CD组、KD组予以生理盐水(9 ml/kg,I.P.)后行伪ECT处理,1次/d,连续7 d;CP、KP组予以丙泊酚(9 ml/kg,I.P. ,浓度10mg/ml)后行伪ECT处理,1次/d,连续7 d。于建模后第1 d、ECT全程完成后第1 d行SPT,于建模后第2 d、ECT全程完成后第2 d行OFT,于建模后第3 d、ECT全程完成后第3 d行Morris水迷宫实验。第二次水迷宫实验完成后第1 d,处死大鼠,取海马组织。各组随机选取4只大鼠以尼氏染色观测海马CA1区、DG区神经元形态数量;各组其余5只大鼠以ELISA法测定其海马BDNF蛋白表达。
第三部分:健康成年雄性Wistar大鼠35只,成年雄性WKY大鼠20只,鼠龄2～3月,体重200～250 g。动物随机分组:C组(正常对照组,Wistar鼠,n=11),D、P、E、M组(各纳入WKY鼠5只和Wistar鼠6只)。D、P、E、M组中Wistar鼠采用CUMS方法建立抑郁模型,WKY鼠及C组Wistar鼠正常饲养相同时间。D组大鼠予以生理盐水(9 ml/kg,I.P.)后行伪ECT处理(1次/ d,连续7 d),P组大鼠予以丙泊酚(9 ml/kg,I.P.,浓度10 mg/ml)后行伪ECT处理(1次/ d,连续7 d);E组予以生理盐水(9 ml/kg,I.P.)后行ECT处理(双相矩形波、波幅0.8 A、波宽1.5 ms、125脉冲/s、时程0.8 s、电量120 mC,1次/ d,连续7 d);M组予以丙泊酚(9 ml/kg,I.P. ,浓度10mg/ml)后行ECT处理(方法、疗程同E组)。C组随机选取5只Wistar鼠、其余4组中的WKY鼠于ECT全程完成后第1 d制作海马脑片、以电生理方法检测CA1区LTP;C组余下6只、其余4组每组中6只Wistar鼠于ECT全程完成后第1 d取海马组织,以western blotting方法、实时定量荧光RT-PCR方法分别检测Synapsin I,PSD-95,GluR1,CREB(p-CREB),NR2A/B蛋白及其mRNA表达。
结果(1)大鼠CUMS抑郁模型建立后及(/或)伪ECT处理后,其糖水偏好、OFT指标、记忆功能、海马BDNF蛋白水平相对正常对照鼠均降低;单纯丙泊酚注射不能逆转上述变化;单纯ECT(即生理盐水联合ECT)可改善抑郁行为、提升海马BDNF水平,但损害学习、记忆功能;随ECT电量增大,单纯ECT对快感缺失行为(由SPT评估)的对抗效应未见进一步增大,对自发探索行为(由OFT评估)的兴奋效应先增大后减小,对学习、记忆功能的损害效应逐渐加重(在中高电量下未见进一步加重),而对海马BDNF水平的提升效应仅在180 mC下略有下降;丙泊酚在除OFT直立次数外其余所有指标上均与ECT电量发生交互作用,不同程度地调整不同电量ECT的效应:丙泊酚在低电量(60 mC)表现出对ECT对抗快感缺失行为、提升海马BDNF效应的削弱,在120 mC及以上电量表现出对上述效应的增强(但最高电量240 mC下丙泊酚对ECT提升BDNF效应的增强作用不显著);随ECT电量增大,丙泊酚对ECT兴奋动物自发探索行为效应的对抗作用以及其对ECT损害学习记忆效应的对抗作用亦均减弱;(2)不同抑郁模型(模型因素)、接受ECT与否(ECT处理因素),联合生理盐水或丙泊酚(用药因素)以及上述三种因素两两之间或三种共同作用可对抑郁模型动物的抑郁行为、学习记忆及海马BDNF蛋白水平等产生不同程度的交互效应:环境性抑郁模型和遗传性抑郁模型鼠相对正常大鼠,除学习功能、海马DG区神经元数量外,其余指标均不同程度降低;单纯丙泊酚注射不能逆转上述变化;单纯ECT处理后:除外遗传性抑郁模型鼠的OFT水平活动距离及海马BDNF无显著变化,两种模型鼠的SPT、OFT行为学及海马BDNF其余指标均显著改善;除外OFT直立次数,遗传性抑郁模型鼠其余上述指标均相对环境性抑郁模型鼠偏低;丙泊酚联合ECT下,除环境性抑郁模型鼠上SPT、海马BDNF指标改善效应优于单纯ECT,OFT水平活动距离改善效应差于单纯ECT外,其余上述指标在两种模型上相对单纯ECT无显著差异;丙泊酚对遗传性抑郁模型鼠SPT、BDNF指标的改善效应均相对环境性抑郁模型鼠偏弱;单纯ECT处理后:两种模型的学习、记忆功能均显著降低,遗传性抑郁模型鼠相对环境性抑郁模型鼠学习功能下降更为显著;丙泊酚联合ECT下,相对单纯ECT组,两种抑郁模型学习、记忆功能均显著改善,遗传性抑郁模型鼠上该改善效应弱于环境性抑郁模型鼠;各治疗组海马CA1区神经元数量并未相对于
未治疗组得到增加;(3)相对正常组,抑郁模型鼠海马LTP效应减弱,其相关突触蛋白表达及PSD-95、GluR1、NR2A的mRNA表达不同程度下调;单纯丙泊酚注射不能逆转上述变化;单纯ECT增大兴奋性突触后场电位(fEPSP)基础斜率、但不加重对LTP效应的减弱,可回升Synapsin I蛋白至正常组水平,进一步降低PSD-95、p-CREB蛋白水平,而不逆转其它蛋白表达的降低及相关蛋白mRNA表达的下调;相对单纯ECT,丙泊酚联合ECT下,LTP水平回复至正常组水平,除Synapsin I蛋白水平下降外,PSD-95、NR2A/B及p-CREB蛋白水平均上调(除外PSD-95,均上升至正常组水平),而PSD-95、NR2A的mRNA表达回复至正常组水平。
结论(1)丙泊酚与ECT电量发生交互作用,从行为学和分子水平均能调整不同电量ECT对抑郁模型动物的效应:丙泊酚在不同ECT电量下产生不同效应;丙泊酚联合下,中等电量MECT在既能达到有效抗抑郁疗效的同时,较好地改善ECT所致学习记忆功能损害,且不过度干扰ECT对自发探索行为的兴奋效应;(2)丙泊酚与抑郁动物模型不同抑郁成因、ECT发生交互作用,从行为学和分子水平均能调整ECT对不同成因抑郁模型动物的效应:相比环境性抑郁模型,遗传性抑郁模型对丙泊酚在ECT中的调整作用的反应较弱;(3)丙泊酚联合ECT不同程度地改善抑郁症、单纯ECT对突触传递可塑性、相关突触蛋白及其基因的过度效应。
Objective To investigate the effects of multiple factors [e.g. etiological factors, parameters of electroconvulsive therapy (ECT), and anesthetics] on behavior, learning and memory, and hippocampal brain derived neurotrophic factor (BDNF) expression in depressed rats undergoing ECT pretreated with propofol and the potential interaction. The effects of ECT pretreated with propofol on long term potentiation (LTP) in hippocampal slices and expression of mRNA and protein level of related synaptic proteins were also included, so as to study propofol’s regulation of ECT’s efficacy and improvement of ECT-induced learning and memory deficits in depressed rats, and the possible mechanism in the view of synaptic plasticity.
Methods
Part I: Healthy adult male Wistar rats (2-3 months, 200-250 g) were randomly divided into 11 groups (n=8). Except for the normal breeding of rats in the control group (group C) for 28 d, the other rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the rodent model of depression. The 10 groups of depressed rats were assigned to treatments according to (2×5) factorial design, with drug factor (normal saline or propofol) and stimulus intensities of ECT (0, 60, 120, 180, and 240 mC) as the two factors. These depressed rats were assigned into two major groups, each received ECTs with pretreatment with either propofol (10 g/l)(group M) or normal saline (group E) (9 ml/kg, i.p.). There were five sub-groups in each major group, the rats of which received ECTs with different stimulus intensities (0 mC, 60 mC, 120 mC, 180 mC, 240 mC) once daily for 7 days. Other parameters of ECT: square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.4, 0.8, 1.2, 1.6 s (for 60 mC, 120 mC, 180 mC, 240 mC). Sucrose preference test (SPT) and open field test (OFT) were performed to assess depressive behavior. Morris water maze task (MWM) was used to measure learning and memory. Hippocampal BDNF protein level was measured with enzyme linked immunosorbent assay (ELISA).
Part II: Healthy adult male Wistar rats and adult Wistar Kyoto (WKY) rats (2-3 months, 200-250 g) were randomly divided into 9 groups (n=9). Except for the normal breeding of rats in the control group (group C, Wistar rats) and WKY rats for 28 d, the other Wistar rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the environmental rodent model of depression. The 8 groups of depressed rats were assigned to treatments according to (2×2×2) factorial design, with (environmental or genetic factors), ECT (or sham ECT), and drug factor (normal saline or propofol) as the three factors. These groups were as following: depressed rats groups treated with normal saline (9 ml/kg, I.P., everyday for 7 d) (environmental: group CD with Wistar rats; genetic: group KD with WKY rats); depressed rats treated with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) (environmental: group CP with Wistar rats; genetic: group KP with WKY rats); depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with normal saline (9 ml/kg, I.P., everyday for 7 d) (environmental: group CE with Wistar rats; genetic: group KE with WKY rats); depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) (environmental: group CM with Wistar rats; genetic: group KM with WKY rats). SPT and OFT were performed to assess depressive behavior. MWM was used to measure learning and memory. Number of hippocampal neurons was observed with Nissl stain, and BDNF protein level was measured with ELISA.
Part III: Healthy adult male Wistar rats and adult Wistar Kyoto (WKY) rats (2-3 months, 200-250 g) were randomly divided into 5 groups (n=11, except for 11 Wistar rats in group C, each of the other 4 groups included 5 WKY rats and 6 Wistar rats). Except for the normal breeding of rats in the control group (group C, Wistar rats) and WKY rats for 28 d, the other Wistar rats were treated with chronic unpredictable mild stresses (CUMS) to replicate the environmental rodent model of depression. These groups were as following: depressed rats groups treated with normal saline (9 ml/kg, I.P., everyday for 7 d) in group D; depressed rats treated with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) in group P; depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with normal saline (9 ml/kg, I.P., everyday for 7 d) in group E; depressed rats treated with ECT (square wave, amplitude 0.8 A, width 1.5 ms, 125 pulses/s, duration of 0.8 s, 120 mC, everyday for 7 d) with propofol (9 ml/kg, I.P., 10mg/ml, everyday for 7 d) in group M. 5 Wistar rats in group C and the WKY rats in the other 4 groups were used for measuring LTP in hippocampus with electrophysiological methods; all the rest Wistar rats in each group were used for assaying mRNA and protein level of Synapsin I, PSD-95, GluR1, CREB (p-CREB), NR2A/B with western blotting and real-time RT-PCR.
Results
Part I: The CUMS-treated rats exhibited depressive behavior and impairment of learning and memory; Propofol injection (everyday for 7 d) could not reverse these changes; ECT could relieve depressive behavior, but aggravated deficits of learning and memory; When ECT was pretreated with propofol, by the increase of stimulus intensities, propofol’s effects on the anti-anhedonia efficacy and elevating effects on hippocampal BDNF of ECT were turnovered from weakening to strengthening; both the weakening effects on ECT’s improving effects on spontaneous exploring activities and protective effects against ECT’s impairment of learning and memory of propofol were weaken. Propofol and stimulus intensities interacted with each other to exert effects both in the behavioral and molecular level in depressed rats.
Part II: Both the environmental and genetic rodent model of depression exhibited depressive behavior, reduced number of hippocampal neurons and BDNF expression, and deficits of learning and memory. Propofol injection (everyday for 7 d) could not reverse these changes; ECT could relieve depressive behavior, but aggravated deficits of learning and memory; the improving effects of ECT on depressive behavior and hippocampal BDNF were weaker, while ECT-induced learning and memory deficits were more severe in WKY rats; When ECT was pretreated with propofol, propofol could enhance the anti-anhedonia, elevating hippocampal BDNF effects of ECT, and attenuate ECT’s improving effects on spontaneous exploring activities and ECT-induced learning and memory impairment, while these effects were weaker in WKY rats than CUMS-treated Wistar rats (except for effects on spontaneous exploring activities); all the treatments exerted no signinficant effects on hippocampal neurons: etiological factors for depression, ECT, and propofol interacted with each other to exert effects both in the behavioral and molecular level in depressed rats.
Part III: In the depressed rats, both hippocampal LTP and the expression of related synaptic protein and their mRNA were inhibited to different extent; Propofol injection (everyday for 7 d) could not reverse these changes; ECT could not relieve the changes of expression of mRNA of synaptic proteins; Without reversing the other proteins’lower expression, ECT recovered Synapsin I protein expression to the level as group C, but more severely inhibited LTP and down-regulated expression of PSD-95 and p-CREB proteins; When ECT was pretreated with propofol, propofol could up-regulate LTP and expression of mRNA of PSD-95 and NR2A to the level of group C, down-regulate expression of Synapsin I protein, and up-regulate expression of the other proteins to different extent (except for PSD-95, all the other proteins were regulated to the level of group C).
Conclusions Propofol has interaction with stimulus intensities to differently regulate ECT's efficacy and amnesic effects in both behavioral and molecular levels; Response to ECT and propofol’s regulation in ECT were less significant in genetic rodent model of depression than environmental model; Propofol’s regulation of ECT’s effects is exerted by regulation of hippocampal synaptic plasiticity and related synaptic proteins.
引文
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