百日咳毒素联合卡介苗诱导CD-1小鼠抑郁症模型研究  

The Co-administration of Pertussis Toxin and Bacillus Calmette Guerin Vaccine in CD-1 Mice Induces a Long-term Depressive Behavior,Peripheral Inflammation,and Neuroinflammation

作　　者：李岑[1,2] 赵苗 许祎宁 毕宏涛[1,2] 杨红霞[1,2] 肖远灿[1,2] 陈占娟 王嘉女 乔亚俊 周学青 魏立新[1,2] Li Cen;Zhao Miao;Xu Yining;Bi Hongtao;Yang Hongxia;Xiao Yuancan;Chen Zhanjuan;Wang Jianv;Qiao Yajun;Zhou Xueqing;Wei Lixin(CAS Key Laboratory of Tibetan Medicine Research,Northwest Institute of Plateau Biology of Chinese Academy of Sciences,Xining 810008,China;Qinghai Key Laboratory of Tibetan Medicine Pharmacology and Safety Evaluation,Northwest Institute of Plateau Biology of Chinese Academy of Sciences,Xining 810008,China;College of Pharmacy,Qinghai University,Xining 810016,China)

机构地区：[1]中国科学院西北高原生物研究所,中国科学院藏药研究重点实验室,西宁810008 [2]中国科学院西北高原生物研究所,青海省藏药药理学和安全性评价研究重点实验室,西宁810008 [3]青海大学药学院,西宁810016

出　　处：《青海科技》2023年第4期62-72,共11页Qinghai Science and Technology

基　　金：青海省应用基础研究项目“藏药佐太对抑郁症模型小鼠慢性神经炎症的改善作用及机制研究”(2019-ZJ-7030)。

摘　　要：为了构建具备良好的治疗性干预时间窗的新型抑郁症动物模型,本研究基于抑郁症发病的炎症假说,选用血脑屏障通透剂——百日咳毒素,联合低剂量免疫激活剂——卡介苗(牛结核分枝杆菌)对CD-1小鼠造模。实验发现,与单独低剂量卡介苗诱导相比,百日咳毒素联合低剂量卡介苗诱导可以增强小鼠的抑郁样行为,如行为绝望状态增加(悬尾实验中一动不动时间)、探索性行为降低(开场实验中的区域穿梭次数和抬头直立次数)、自发运动状态降低(开场实验总运动距离)等,促进小鼠中枢神经炎症和外周炎症(IL-1β、IL-6、IFN-γ等);同时,加剧脑中色氨酸-犬尿氨酸通路的激活,表现为其关键酶——吲哚胺2,3-双加氧酶1(IDO1)进一步显著升高。经口给予抗抑郁药丙咪嗪,可缓解百日咳毒素联合低剂量卡介苗诱导的小鼠抑郁样症状、炎症反应和激活的色氨酸-犬尿氨酸通路。另外,发现百日咳毒素联合低剂量卡介苗诱导的小鼠抑郁样症状可以从第7天至少持续到第28天。综上,本研究基于百日咳毒素和低剂量卡介苗构建的小鼠抑郁模型具有较好的表面效度、结构效度和预测效度,其长期持续性的抑郁表型可为抗抑郁疗法研究提供宝贵的治疗性干预时间窗。In order to establish a low-cost new animal model of depression with a good therapeutic intervention time window,based on the inflammatory hypothesis of the onset of depression,this study uses blood-brain barrier permeability agent-pertussis toxin combined with low dose of immunization activator-Bacillus Calmette Guerin Vaccine(bovine tuberculosis branch Bacillus)to model CD-1 mice.The experiment found that compared with induction by single low-dose pertussis vaccine,induction with pertussis toxin plus low-dose Bacillus Calmette Guerin(BCG)vaccine enhanced the depression-like behavior of mice,such as increased behavioral despair state in the tail-suspension test(immobility time),decreased exploratory behavior in the open-field test(the number of zone crossing,and head-up and stand-up times),and decreased spontaneous motility in the open-field test(total distance traveled).Meanwhile,it also promoted central neuroinflammation and peripheral inflammation(IL-1β,IL-6,IFN-γ,etc.)of mice.Moreover,the combined administration of pertussis toxin and low-dose BCG vaccine could further enhance the activation of tryptophan-kynurenine pathway in brain,with the further significant upregulation of its key enzyme-indoleamine 2,3-dioxygenase 1(IDO1;p<0.05).Administration of antidepressant drug fluoxetine alleviated the mouse depression-like behaviors,inflammatory response and the activation of tryptophan-kynurenine pathway induced by the combined administration of pertussis toxin and low-dose BCG vaccine.In addition,it was found that the depressive-like behaviors induced by the combined administration of pertussis toxin and low-dose BCG vaccine continued from the 7th day to the 28th day.In summary,the mouse depression model constructed from pertussis toxin and low-dose BCG vaccine has good face validity,construct validity and predictive validity,and its long-term persistent depression phenotype can provide a valuable therapeutic intervention time window for the study of anti-depression therapy.

关 键 词：抑郁症 动物模型 百日咳毒素 卡介苗 炎症 

分 类 号：R749.4[医药卫生—神经病学与精神病学]