逍遥抗癌解郁方通过调控COX通路对乳腺癌并发抑郁模型小鼠的治疗作用及机制研究  

Therapeutic effect and mechanism of Xiaoyao Kangai Jieyu Recipe on mice with breast cancer related depression through regulating COX pathway

作　　者：何璎 邹蔓姝 任廷婷 李萍[2] 刘洋[2] 韩远山[1,3] HE Ying;ZOU Man-shu;REN Ting-ting;LI Ping;LIU Yang;HAN Yuan-shan(the First Hospital of Hunan University of Chinese Medicine,Changsha 410007,China;Science and Technology Innovation Center,Hunan University of Chinese Medicine,Changsha 410208,China;Hunan Provincial Key Laboratory of Traditional Chinese Medicine Prevention and Treatment of Depression,Changsha 410208,China)

机构地区：[1]湖南中医药大学第一附属医院,湖南长沙410007 [2]湖南中医药大学科技创新中心,湖南长沙410208 [3]抑郁类疾病中医药防治湖南省重点实验室,湖南长沙410208

出　　处：《中国中药杂志》2023年第14期3874-3881,共8页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金青年基金项目(82104846);湖南省科药联合基金项目(2022JJ80092);湖南省自然科学基金青年基金项目(2022JJ40323);长沙市自然科学基金项目(kq2202266);湖南省研究生科研创新项目(CX20220796);湖南省中药粉体与创新药物研究省部共建国家重点实验室培育基地开放基金项目(2022FTKFJJ12)。

摘　　要：研究逍遥抗癌解郁方对乳腺癌并发抑郁模型小鼠海马小胶质细胞和神经元损伤的干预作用及其机制。采用腋下接种4T1乳腺癌细胞联合皮下注射皮质酮(30 mg·kg^(-1))的方法构建乳腺癌并发抑郁小鼠模型,将造模成功的小鼠随机分为模型组,阳性药组[卡培他滨(60 mg·kg^(-1))+氟西汀(19.5 mg·kg^(-1))],逍遥抗癌解郁方组(19.5 g·kg^(-1)),每组6只,另取6只正常小鼠作为正常组。各给药组灌胃相应药物,正常组和模型组给予等体积蒸馏水,每日1次,连续给药21 d。采用糖水消耗实验、旷场实验和新奇摄食实验评价小鼠抑郁行为;苏木素-伊红(hematoxylin eosin,HE)染色和抑瘤率评价腋下肿瘤变化情况;实时荧光定量PCR(quantitative real-time PCR,qRT-PCR)法检测小鼠海马白细胞介素-1β(interleukin-1β,IL-1β)、白细胞介素-18(interleukin-18,IL-18)、环氧酶-2(cyclooxyganese-2,COX-2)、前列腺素受体(glutamyl-prolyl-tRNA synthetase,EPRs)mRNA表达;免疫组化检测海马IL-1β、IL-18、COX-2、EPRs蛋白的相对表达量,免疫荧光检测海马小胶质细胞活化标志分子CD11b的平均荧光强度;尼氏染色观察海马神经元形态变化;透射电镜观察海马神经元的超微形态变化。结果显示,与正常组比较,模型组小鼠糖水消耗、矿场总活动数均显著降低(P<0.05,P<0.01),新奇摄食实验首次摄食时间显著上升(P<0.01),抑郁样行为显著;海马中IL-1β、IL-18、COX-2、EPRs表达显著升高(P<0.05,P<0.01),海马小胶质细胞活化,神经元明显损伤。与模型组相比,阳性药和逍遥抗癌解郁方给药后小鼠抑郁行为均明显改善;海马IL-1β、IL-18、COX-2、EPRs含量均明显降低,海马小胶质细胞激活和神经元损伤情况得以缓解;阳性药抑瘤率为40.32%,逍遥抗癌解郁方抑瘤率为48.83%,肿瘤生长速度都慢于模型组。综上所述,逍遥抗癌解郁方可能通过COX信号通路的激活改善乳腺癌并发抑郁症模型小鼠海马小胶�This study aimed to investigate the intervention effect and mechanism of Xiaoyao Kangai Jieyu Recipe(XKJR)on hip-pocampal microglia and neuronal damage in mice with breast cancer related depression.The mouse model of breast cancer related depression was established by inoculation of 4T1 breast cancer cells in axilla and subcutaneous injection of corticosterone(30 mg·kg^(-1)).The successfully modeled mice were randomly divided into a model group,a positive drug group(capecitabine 60 mg·kg^(-1)+fluoxetine 19.5 mg·kg^(-1)),and XKJR group(19.5 mg·kg^(-1)crude drug),with 6 in each group.Another 6 normal mice were taken as a normal group.The administration groups were given corresponding drugs by gavage,while the normal and model groups were given an equal volume of distilled water,once a day for 21 consecutive days.The depressive behavior of mice was assessed by glucose consumption test,open field test and novelty-suppressed feeding test.Hematoxylin and eosin(HE)staining and tumor suppression rate were used to evaluate the changes of axillary tumors.The mRNA expressions and the relative protein expressions of interleukin-1β(IL-1β),interleukin-18(IL-18),cyclooxyganese-2(COX-2)and glutamyl-prolyl-tRNA synthetase(EPRs)in the hippocampus of mice were determined by quantitative real-time polymerase chain reaction(qRT-PCR)and immunohistochemistry,respectively.Immunofluorescence was performed to detect the mean fluorescence intensity of CD11b,a marker of hippocampal microglia activation.Nissler staining and transmission electron microscopy were employed to observe the morphological changes and the ultramorphological changes of hippocampal neurons,respectively.The experimental results indicated that compared with the normal group,the model group had reduced glucose consumption and lowered number of total activities in open field test(P0.05,P0.01),prolonged first feeding latency in no-velty-suppressed feeding test(P0.01),and significant depression-like behavior;the contents of IL-1β,IL-18,COX-2,and EPRs in hippocampus w

关 键 词：逍遥抗癌解郁方 乳腺癌并发抑郁症 COX信号通路 小胶质细胞 海马神经元 

分 类 号：R285.5[医药卫生—中药学]