类风湿关节炎伴发抑郁症模型大鼠制备与评价探讨

Establishment and evaluation of a rat model of rheumatoid arthritis with depression

目的 制备并评价类风湿关节炎伴发抑郁症动物模型。方法 32只大鼠随机分为正常组(N组)、抑郁组(D组)、关节炎组(RA组)、模型组(RAD组),每组8只。N组正常饲养,D组施加1周孤养与3周慢性不可预知温和刺激(chronic unpredictable mild stress, CUMS),RA组予胶原诱导性关节炎(collagen-induced arthritis, CIA)方法建立关节炎模型,RAD组在建立CIA动物模型基础上施加1周孤养与3周CUMS建立RAD动物模型。通过观测大鼠足趾容积、关节炎指数(arthrits index, AI),滑膜、踝关节病理和血清白介素-1β(interleukin-1β,IL-1β)、白介素-6(interleukin-6,IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)水平评价大鼠类风湿关节炎模型是否制备成功;通过测定体重、摄食量、糖水偏好率、旷场行为学(运动总格数、直立次数),血清促肾上腺皮质激素释放激素(corticotropin-releasing hormone, CRH)、促肾上腺皮质激素(adrenocorticotropic hormone, ACTH)、皮质酮(corticosterone, CORT)水平及海马病理变化评价大鼠抑郁状态。模型大鼠同时符合上述抑郁状态与类风湿关节炎相关指标检测,则表明RAD动物模型制备成功。结果 与N组比较,RA组与RAD组大鼠足趾容积、AI评分及血清IL-1β、IL-6水平显著增加(P<0.05),关节间隙增宽,滑膜增生明显并延伸至关节腔,可见大量炎细胞浸润,D组与RAD组大鼠体重、摄食量、运动总格数、直立次数、糖水偏好率有不同程度降低,血清CRH、ACTH、CORT水平有不同程度升高,神经元细胞减少,伴有部分细胞核萎缩,模型组尤为明显(P<0.05)。结论 胶原诱导性关节炎联合孤养与CUMS可较好地模拟RAD模型动物外在表现与内在指标变化,可为RAD疾病的研究提供动物模型参考。

Objective To establish and evaluate an animal model of rheumatoid arthritis with depression.Methods Thirty-two rats were randomly divided into normal group(N group),depression group(D group),arthritis group(RA group)and model group(RAD group),with eight rats in each group.The N group was fed normally,and the D group was fed under solitary rearing for 1 week and chronic unpredictable mild stress(CUMS)for 3 weeks.The RA group was subjected to collagen-induced arthritis(CIA)to establish the arthritis model.In the RAD group,the RAD animal model was established on the basis of the CIA animal model with 1 week of solitary rearing and 3 weeks of CUMS.Toe volume,arthritis index(AI),synovial and anklejoint pathology,and serumlevelsof interleukin-1β(IL-1β),interleukin-6(IL-6),and tumor necrosis factor-α(TNF-α)were used to evaluate whether the rat model of RA was successfully established.The depression status of rats was evaluated by measuring body weight,food intake,sugar water preference rate,open field behavior(total number of motion cells and number of standing uprights),serum levels of corticotropin-releasing hormone(CRH),adrenocorticotropic hormone(ACTH),andcorticosterone(CORT),and pathological changes in the hippocampus.The RAD animal model was successfully established when both depression and RA were present in the rats.Results Compared with the N group,the toe volume,AI score,and serum levels of IL-1βand IL-6 in RA and RAD groups were significantly increased(P<0.05),joint space had widened,synovial hyperplasia was obvious and extended to the joint cavity,and a large number of inflammatory cells were seen.In D and RAD groups,body weight,food intake,total number of motion cells,number of standing uprights,and sugar water preference rate were decreased by various degrees,serum levels of CRH,ACTH,and CORT were increased by various degrees,and neuronal cells were reduced,accompanied by partial nuclear atrophy,especially in the model group(P<0.05).Conclusions CIA combined with solitary rearing and CUMS better simulates the changes in external manifestations and internal indicators of RAD model animals,which provides a reference to study RAD disease animal models.