周翠红; 薛姗姗; 白洁; 彭正午; 谭庆荣; 王化宁

doi:10.3760/cma.j.issn.1006-7884.2019.05.007

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重复经颅磁刺激通过调节海马的核因子转录因子抗氧化信号通路改善慢性不可预见应激大鼠的抑郁样行为

中华精神科杂志, 2019,52(5) : 331-338. DOI: 10.3760/cma.j.issn.1006-7884.2019.05.007

摘要

目的

探讨重复经颅磁刺激（rTMS）对慢性不可预见应激（CUS）大鼠抑郁行为及海马区核因子转录因子（Nrf2）抗氧化基因表达的影响。

方法

将24只SD雄性大鼠按安全随机法分为对照组、CUS组、CUS+rTMS组，每组各8只。适应性饲养7 d后，CUS组、CUS+rTMS组大鼠给予CUS刺激，然后给予CUS+rTMS组大鼠5 Hz的rTMS刺激干预7 d，其他组接受假刺激。最后一次rTMS干预结束24 h后进行糖水偏好、旷场和强迫游泳测试，随后处死动物，通过实时定量PCR（RT-PCR）和蛋白免疫印迹法检测海马的Nrf2、血红素加氧酶1（HO-1）和超氧化物歧化酶1（SOD-1）的表达变化。将另外24只大鼠按安全随机法分为3组：对照病毒+CUS组、对照病毒+CUS+rTMS组、Nrf2下调病毒（shNrf2）+CUS+rTMS组，每组各8只；对照病毒+CUS组、对照病毒+CUS+rTMS组大鼠海马注射对照病毒，shNrf2+CUS+rTMS组大鼠海马注射shNrf2。注射病毒2周后，均接受CUS刺激，然后给予rTMS（5 Hz）或假刺激干预7 d。干预结束24 h后进行行为学及分子生物学检测。

结果

（1）与对照组相比，CUS组大鼠糖水偏好减少[（39.33±11.85）%比（77.31±4.69）%；F=8.32，P<0.01]，旷场中心活动时间减少[（14.70±4.27）s比（52.49±1.07）s；F=3.84，P<0.05）]，强迫游泳不动时间增加[（38.70±4.27）s比（24.19±1.07）s；F=10.31，P<0.01）]，海马Nrf2、HO-1和SOD-1表达下调（P<0.05）；（2）与CUS组相比，CUS+rTMS组大鼠的糖水偏好和旷场中心活动时间增加（均P<0.05），强迫游泳不动时间减少（P<0.05），海马Nrf2、HO-1和SOD-1表达上调（P<0.05）。（3）与对照病毒+CUS+rTMS组相比，shNrf2+CUS+rTMS组大鼠海马Nrf2及下游靶基因HO-1和SOD-1表达下调（P<0.05），大鼠的糖水偏好和旷场中心活动时间减少（均P<0.05），强迫游泳不动时间增加（P<0.05）。

结论

rTMS通过调节CUS大鼠海马Nrf2及其下游分子HO-1和SOD-1表达而缓解CUS大鼠的抑郁行为，发挥抗抑郁效果。

引用本文: 周翠红, 薛姗姗, 白洁, 等. 重复经颅磁刺激通过调节海马的核因子转录因子抗氧化信号通路改善慢性不可预见应激大鼠的抑郁样行为 [J] . 中华精神科杂志, 2019, 52(5) : 331-338. DOI: 10.3760/cma.j.issn.1006-7884.2019.05.007.

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抑郁症是目前临床上最常见的精神疾患之一，其发病率呈逐年上升的趋势，严重影响着人类的健康和生活质量，也给社会带来了沉重的经济负担^[1]。目前药物治疗为抑郁症的主要治疗手段，但还存在以下2个棘手的问题，一是药物治疗起效慢、有效率低、需要维持治疗较长时间等，使治疗难以达到满意效果^[2]；二是复发率高，首次发病患者康复后复发几率高达50%，第2次发病后康复患者的复发率高达70%，对于第3次以上发病的患者，复发率上升到80%^[3]。为此，众多研究者致力于寻找到更有效的抑郁症治疗方法。重复经颅磁刺激（rTMS）作为非侵入性脑刺激疗法之一，目前已被广泛用于治疗精神疾病。rTMS对抑郁症的治疗效果已在临床试验中得到很好的证实^[4,5,6]。此外，rTMS治疗妊娠期抑郁症的可能性也得到证实^[7,8]。本研究组既往的随机对照试验还证实rTMS可以预防抑郁症复发和复发性抑郁症^[9,10]，但rTMS治疗抑郁症的潜在分子机制仍需要进一步阐述。

贡献者信息

周翠红

空军军医大学第一附属医院心身科，西安　710032

薛姗姗

空军军医大学第一附属医院心身科，西安　710032

白洁

空军军医大学第一附属医院心身科，西安　710032

彭正午

空军军医大学第一附属医院心身科，西安　710032

谭庆荣

空军军医大学第一附属医院心身科，西安　710032

王化宁

空军军医大学第一附属医院心身科，西安　710032

通信作者

王化宁

空军军医大学第一附属医院心身科，西安　710032

Email：13609161341@163.com

关键词

经颅磁刺激; 应激; 核因子转录因子; 血红素加氧酶1; 超氧化物歧化酶1;

基金项目

国家自然科学基金面上项目（81571309）

国家自然科学基金重点项目（81630032）

利益冲突

利益冲突　所有作者均声明不存在利益冲突

历史

出版日期：2019-10-05

收稿日期：2019-05-03

本文编辑

安京媛常静

Stress Disorders

Repetitive transcranial magnetic stimulation ameliorates chronic unpredictable stress-induced depressive-like behaviors in rats model through enhancing hippocampal nuclearfactor-E2-related factor2 antioxidant signaling

Cuihong Zhou, Shanshan Xue, Jie Bai, Zhengwu Peng, Qingrong Tan, Huaning Wang

Published 2019-10-05

Cite as Chin J Psychiatry, 2019, 52(5): 331-338. DOI: 10.3760/cma.j.issn.1006-7884.2019.05.007

Abstract

Objective

To investigate the antidepressive-like effect of repetitive transcranial magnetic stimulation (rTMS) on the rats model exposing chronic unpredictable stress (CUS) and their nuclearfactor-E2-related factor2 (Nrf2) gene expression in hippocampus.

Methods

(1) SD rats were randomly assigned to the following 3 groups (n=8 for each group): Sham, CUS, CUS+ rTMS. The Sham group received only Sham stimulation. The rats in the CUS and CUMS+ rTMS group were subjected to CUS stimulus, followed by 5Hz rTMS or Sham rTMS for 7 days. 24 h after the last stimulation, rats were given a sucrose preference test, an open filed test and a forced swim test. Finally the gene expression of Nrf2, HO-1 and SOD-1 in the hippocampus were determined by real-time PCR and western blot. (2) SD rats were randomly assigned to another 3 groups (n=8 for each group): scramble+CUS, scramble+ CUS+ rTMS and shNrf2+ CUS+ rTMS. Rats were injected with scramble or shNf2 lentivirus into the dentate gyrus. Two weeks later, all rats were subjected to CUS followed by rTMS or Sham rTMS stimulus for 7 days. Finally rats were given the series behavior tests, and the gene expression of hippocampal Nrf2, HO-1 and SOD-1 were then determined after being sacrificed.

Results

(1) In comparison with Sham, the rat in CUS group showed significant lower sucrose preference ((77.31±4.69)% vs. (39.33±11.85)%; F_{2, 21}=8.32, P<0.01) and shorter centre time ((52.49±1.07) s vs. (14.70±4.27) s; F_{2, 21}=3.84, P<0.01)) in the open filed test, but longer freezing time in the forced swim test ((24.19±1.07 s vs. (38.70±4.27); F_{2, 21}=10.31, P<0.05) ; the expression of Nrf2, HO-1 and SOD-1 in the hippocampus was inhibited in the CUS rats. (2) Compared with CUS group, the rat in CUS+rTMS group showed significant better sucrose preference (P<0.05), longer centre time (P<0.05 in open filed test), while shorter freezing time in the forced swim test (P<0.05); the expression of Nrf2, HO-1 and SOD-1 in the hippocampus in CUS+rTMS rats was up-regulated (P<0.05); (3) Rats in shNrf2+CUS+ rTMS group showed lower sucrose preference (P<0.05), shorter centre time (P<0.05) in the open filed test and longer freezing time in the forced swim test (P<0.05) and their expression of Nrf2, HO-1 and SOD-1 in the hippocampus (P<0.05) was down-regulated than rats in scramble+CUS+rTMS group.

Conclusion

rTMS administration may reverse depressive-like behaviors in rats under CUS paradigm and may restore the gene expression of Nrf2, HO-1 and SOD-1 in the hippocampus.

Key words:

Transcranial Magnetic Stimulation; Stress; Nuclearfactor-E2-related factor 2; Hemeoxygenase-1; Superoxide Dismutase-1

Contributor Information

Cuihong Zhou

Department of Psychosomatic, Xijing Hospital, Fourth Military Medical University, Xi′an 710032, China

Shanshan Xue

Jie Bai

Zhengwu Peng

Qingrong Tan

Huaning Wang

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