加减薯蓣丸对轻、中度阿尔茨海默病的临床疗效及外周血IL-1β、NF-κB、miR-146a表达的影响

Clinical Efficacy of Modified Shuyu Pill for Mild and Moderate Alzheimer′s Disease and Its Effects on Expressions of IL-1β/NF-κB/miR-146a in Peripheral Blood

目的探讨加减薯蓣丸治疗轻、中度阿尔茨海默病(Alzheimer′s disease, AD)的临床疗效及对外周血白细胞介素-1β(interleukin-1β, IL-1β)、核因子-κB(nuclear factor-kappa B, NF-κB)、血清微小核糖核酸-146a(microRNA-146a, miR-146a)表达的影响。方法 52例轻、中度AD患者随机分为治疗组(加减薯蓣丸浓缩汤剂,15 mL/次,1日2次)和对照组(盐酸多奈哌齐片,5 mg/次,睡前1次),每组26例,两组疗程均为12周。于治疗前后对患者进行简易精神状态量表(Mini-mental State Examination, MMSE)、阿尔茨海默病评定量表-认知(Alzheimer′s Disease Assessment Scale-Cognitive Subscale, ADAS-Cog)及日常生活能力量表(Activity of Daily Living Scale, ADL)评分;评定阿尔茨海默病证候要素量表(Pattern and Element of Syndrome of Alzheimer′s Disease, AD-PES-11)积分;评定中医证候临床疗效;采用Spearman相关系数分析法对AD-PES-11积分与神经心理测验量表评分之间进行相关性分析;采用ELISA法检测血清IL-1β、NF-κB水平;采用荧光定量PCR法检测miR-146a表达;观察治疗过程中的不良反应。结果与本组治疗前比较,两组治疗后MMSE评分明显升高(P<0.01),ADAS-Cog及ADL评分明显降低(P<0.01);与治疗前比较,治疗组治疗后AD-PES-11量表总积分、肾虚、脾虚、髓减、痰浊、血瘀积分明显降低(P<0.05,P<0.01),对照组治疗后脾虚积分明显升高(P<0.05);与对照组比较,治疗组治疗后量表总积分、肾虚、脾虚、痰浊、血瘀积分明显降低(P<0.01);治疗组总有效率69.23%(18/26),对照组总有效率7.69%(2/26),两组比较差异有统计学意义(P<0.01);相关性分析显示,MMSE评分与脾虚积分及总积分呈负相关(P<0.05,P<0.01),ADAS-Cog、ADL评分与脾虚、髓减积分及总积分呈正相关(P<0.05,P<0.01);与治疗前比较,两组治疗后IL-1β及NF-κB含量均降低(P<0.05,P<0.01),以治疗组降低更为明显(P<0.05);与治疗前比较,两组治疗后miR-146a水平均降低(P<0.05,P<0.01);两组患者治疗期间均未出现明显不良反应。结论加减薯蓣丸能有效改善轻、中度AD患者认知功能和日常生活能力,改善中医症状及体征,其机制可能与抑制外周血IL-1β、NF-κB、miR-146a的表达,阻断炎症反应相关。

Objective To explore the clinical efficay of Modified Shuyu Pill(MSP) for treatment of mild and moderate Alzheimer′s disease(AD) and its effect on the expressions of interleukin-1β(IL-1β)/nuclear factor-kappa B(NF-κB)/microRNA-146a(miR-146a) in peripheral blood. Methods Totally 52 patients with mild and moderate AD were randomly assigned to the treatment group and the control group, 26 in each group. Patients in the treatment group took MSP, 15 mL each time, twice a day, while those in the control group took Donepezil, 5 mg each time, once before bedtime. The therapeutic course for all was 12 weeks. Mini-mental State Examination(MMSE) scale, Alzheimer′s Disease Assessment Scale-Cognitive Subscale(ADAS-Cog), and Activity of Daily Living(ADL) scale were evaluated before and after treatment. Pattern and Element of Syndrome of Alzheimer′s Disease(AD-PES-11) scale and clinical efficacy of TCM syndromes were assessed. Spearman correlation analysis was used to analyze the correlation between the score of AD-PES-11 scale and neuropsychological test scales. Serum levels of IL-1β and NF-κB were detected using enzyme linked immunosorbent assay(ELISA). The level of miR-146a was detected by fluorescence quantitative PCR. Besides, adverse reactions were observed during the treatment. Results Compared with before treatment in the same group, the score of MMSE significantly increased after treatment(P<0.01), and the scores of ADAS-Cog and ADL significantly decreased in the two groups after treatment(P<0.01). Compared with before treatment, the scores of AD-PES-11 scale, scores of Shen deficiency, Pi deficiency, medullary decrease, phlegm turbidity, and blood stasis significantly decreased after treatment in the treatment group(P<0.05, P<0.01). In the control group, the score of Pi deficiency increased significantly after treatment(P<0.05). Compared with the control group, the scores of AD-PES-11 scale, Shen deficiency, Pi deficiency, phlegm turbidity, and blood stasis decreased significantly in the treatment group after treatment(P<0.01). The total effective rate was 69.23%(18/26 cases) in the treatment group, with statistical difference as compared with that of the control group [7.69%(2/26 cases)]. Statistical difference existed in clinical efficacy between the two groups(P<0.01). Correlation analysis showed that there was a negative correlation between MMSE score and Pi deficiency score/total scores(P<0.05,P<0.01). There was a positive correlation between ADAS-Cog score/ADL score and Pi deficiency/medullary decrease/total scores(P<0.05, P<0.01). Compared with before treatment, the levels of IL-1β and NF-κB decreased in both groups after treatment(P<0.05,P<0.01). The treatment group was superior to the control group in reducing IL-1β and NF-κB content(P<0.05). Compared with before treatment, the level of miR-146a decreased after treatment in the two groups(P<0.05,P<0.01). No obvious adverse reactions were observed during the treatment. ConclusionMYP could effectively improve the cognitive function and ADL of mild and moderate AD patients, improve their TCM symptoms and signs, and its mechanism might be related to inhibiting the expressions of IL-1β/NF-κB/miR-146a in peripheral blood and blocking inflammatory reactions.