丹参多酚酸对抑郁症大鼠模型的治疗效果及机制研究

Therapeutic effect and mechanism of salvianolic acid on depression rat model

目的 基于非受体型酪氨酸蛋白激酶2/信号转导与转录激活因子3(JAK2/STAT3)信号通路探究丹参多酚酸对抑郁症模型大鼠海马神经元细胞及单胺类神经递质的影响。方法 将SD大鼠随机分为对照组、模型组、丹参多酚酸低剂量组(20 mg·kg^(-1))、丹参多酚酸高剂量组(40 mg·kg^(-1))、JAK2抑制药组(pacritinib, 10 mg·kg^(-1)),每组8只。除对照组外,其他各组采用慢性温和应激法建立抑郁症模型,再按剂量腹腔注射给药。用免疫组化法检测海马胶质纤维酸性蛋白(GFAP)和成纤维细胞生长因子(FGF)表达,用酶联免疫吸附法检测海马组织白细胞介素(IL)-6、IL-1β、肿瘤坏死因子α(TNF-α)、5-羟色胺(5-HT)、多巴胺(DA)和去甲肾上腺素(NE)水平,用蛋白质印迹法检测海马组织JAK2/STAT3信号通路相关蛋白表达。结果 对照组、模型组、丹参多酚酸低、高剂量组、pacritinib组海马组织GFAP表达分别为35.68±3.28、8.32±2.25、12.36±3.54、16.52±3.13和20.57±4.12;FGF表达分别为48.55±5.22、9.24±1.07、11.29±2.28、19.46±3.83和23.49±4.65;IL-6含量分别为(12.48±2.24)、(39.35±4.32)、(36.68±6.47)、(24.17±5.81)和(21.60±5.29)ng·mL^(-1);IL-1β含量分别为(17.42±3.14)、(52.78±6.82)、(48.63±5.71)、(33.25±6.34)和(29.92±4.65)ng·mL^(-1);TNF-α含量分别为(24.67±3.51)、(65.81±9.47)、(61.25±7.38)、(41.72±5.63)和(37.79±5.46)ng·mL^(-1);5-HT含量分别为(28.75±2.54)、(19.16±3.61)、(21.72±2.98)、(24.91±3.23)和(26.37±3.74)ng·mL^(-1);DA含量分别为(269.78±22.34)、(205.41±17.66)、(212.36±19.42)和(245.52±26.73)、(251.75±29.95)ng·mL^(-1);NE含量分别为(32.47±2.36)、(22.68±3.14),(25.13±3.50)、(27.89±3.27)和(28.95±2.57)ng·mL^(-1);p-JAK2/JAK2分别为0.92±0.09、1.44±0.12、1.38±0.13、1.13±0.11和1.08±0.15;p-STAT3/STAT3分别为0.94±0.07、1.62±0.18、1.57±0.20、1.11±0.15和1.04±0.12。上述指标,对照组与模型组比较,模型组与丹参多酚酸高剂量组、pacritinib组比较,差异均有统计学意义(均P<0.05)。结论 丹参多酚酸能有效改善大鼠抑郁样行为,可能通过抑制JAK2/STAT3信号通路,减轻神经炎症,调节单胺类神经递质水平,改善星形胶质细胞功能途径实现。

Objective To explore the influences of salvianolic acids on hippocampal neurons and monoamine neurotransmitters in depression rats based on Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)signaling pathways.Methods SD rats were divided into control group,model group,salvianolic acid-L group(20 mg·kg^(-1)),salvianolic acid-H group(40 mg·kg^(-1))and JAK2 inhibitor group(pacritinib,10 mg·kg^(-1))randomly,8 rats in each group.Except control group,depression models were constructed by chronic mild stress method in other groups,and then administered by intraperitoneal injection.Immunohistochemistry was used to detect expressions of glial fibrillary acidic protein(GFAP)and fibroblast growth factor(FF)in hippocampus.Enzyme-linked immunosorbent assay was used to detect levels of interleukin(IL)-6,IL-1β,tumor necrosis factor-α(TNF-α),5-hydroxytryptamine(5-HT),dopamine(DA)and norepinephrine(NE)in hippocampus.WWestern blot was used to detect expressions of JAK2/STAT3 signaling pathway related proteins in hippocampus.Results In control group,model group,salvianolic acid-L,salvianolic acid-H and pacritinib groups,expressions of CFAP in hippocampus were 35.68±3.28,8.32±2.25,12.36±3.54,16.52±3.13 and 20.57±4.12;the expressions of FGF were 48.55±5.22,9.24±1.07,11.29±2.28,19.46±3.83 and 23.49±4.65;IL-6 levels were(12.48±2.24),(39.35±4.32),(36.68±6.47),(24.17±5.81)and(21.60±5.29)ng·mL^(-1);IL-1β levels were(17.42±3.14),(52.78±6.82),(48.63±5.71),(33.25±6.34)and(29.92±4.65)ng·mL^(-1);TNF-αlevels were(24.67±3.51),(65.81±9.47),(61.25±7.38),(41.72±5.63)and(37.79±5.46)ng·mL^(-1);5-HT levels were(28.75±2.54),(19.16±3.61),(21.72±2.98),(24.91±3.23)and(26.37±3.74)ng·mL^(-1);DAlevels were(269.78±22.34),(205.41±17.66),(212.36±19.42),(245.52±26.73)and(251.75±29.95)ng·mL^(-1);NE levels were(32.47±2.36),(22.68±3.14),(25.13±3.50),(27.89±3.27)and(28.95±2.57)ng·mL^(-1);the expressions of p-JAK2/JAK2 were 0.92±0.09,1.44±0.12,1.38±0.13,1.13±0.11 and 1.08±0.15;the expressions of p-STAT3/STAT3 were 0.94±0.07,1.62±0.18,1.57±0.20,1.11±0.15 and 1.04±0.12,respectively.There were significant differences in the above indexes between control group and model group,between model group and salvianolic acid-H group,pacritinib group(P<0.05).Conclusion Salvianolic acids may relieve neuroinflammation,regulate levels of monoamine neurotransmitters and improve astrocyte function by inhibiting JAK2/STAT3 signaling pathways,and thus reducing depression-like behavior in rats.