目的 探讨血府逐瘀胶囊对卒中后抑郁（post-stroke depression，PSD）大鼠抑郁症状的改善作用，并基于神经再生关键通路脑源性神经营养因子（brain derived neurotrophic factor，BDNF）/酪氨酸激酶受体B（tyrosine kinase receptor，TrkB）/磷酸化环腺苷酸应答元件结合蛋白（phosphorylated cAMP response element-binding protein，p-CREB）探讨其机制。方法 采用短暂大脑中动脉梗塞（transient middle cerebral artery occlusion，tMCAO）复合慢性不可预知应激（chronic unpredictable mild stimulation，CUMS）方法复制PSD大鼠模型。大鼠随机分为假手术组、模型组及血府逐瘀低、高剂量（0.43、0.86 g/kg）组和氟西汀（1.8 mg/kg）组，每组18只。连续给予药物干预28 d，利用神经功能评分、糖水偏好实验、旷场实验、强迫游泳实验考察血府逐瘀胶囊对PSD大鼠神经功能损伤以及抑郁症状的改善作用；高效液相色谱-电化学检测法检测额叶皮质及海马神经递质多巴胺（dopamine，DA）和5-羟色胺（5-hydroxytryptamine，5-HT）含量；免疫荧光染色检测海马5-溴脱氧尿嘧啶核苷（5-bromo-2-deoxyuridine，BrdU）、双皮质素（doublecortin，DCX）和巢蛋白（neuroepithelial stem cell protein，Nestin）表达评价神经再生情况；Western blotting检测海马BDNF/TrkB/p-CREB蛋白表达。结果 与假手术组比较，模型组大鼠神经功能评分显著提高（P<0.001），糖水偏好率显著下降（P<0.05），强迫游泳不动时间显著增长（P<0.05）；前额叶皮质、海马组织DA以及海马组织5-TH含量明显减少（P<0.05）；BrdU、DCX阳性细胞数量明显降低（P<0.05、0.01），Nestin阳性细胞数量减少；海马BDNF、TrkB、p-CREB表达显著降低（P<0.05、0.01）。与模型组比较，血府逐瘀胶囊组神经功能评分显著降低（P<0.01），糖水偏好率明显升高（P<0.05），强迫游泳的不动时间明显减少（P<0.05、0.01）；前额叶皮质和海马DA、5-TH含量均显著增加（P<0.05、0.01）；BrdU、Nestin、DCX阳性细胞数量明显增加（P<0.05、0.01）；海马BDNF表达有增加的趋势，TrkB、p-CREB表达均明显增加（P<0.05）。结论 血府逐瘀胶囊可通过BDNF/TrkB/p-CREB通路促进神经再生进而发挥治疗PSD作用。

Objective To explore the improvement effect of Xuefu Zhuyu Capsule (血府逐瘀胶囊) on depression symptoms in post-stroke depression (PSD) rats, and explore its mechanism based on the key pathway of neural regeneration[brain derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB)/phosphorylated cAMP response element binding protein (p-CREB)]. Methods The rats model of PSD was established by transient middle cerebral artery occlusion (tMCAO) and chronic unpredictable mild stimulation (CUMS). Rats were randomly divided into sham group, model group, Xuefu Zhuyu Capsule low-and high-dose (0.43, 0.86 g/kg) groups and fluoxetine (1.8 mg/kg) group, with 18 rats in each group. Continuous medication intervention was given for 28 d, and the improvement effect of Xuefu Zhuyu Capsule on neurological function damage and depressive symptoms in PSD rats was investigated by neurological function scores, sugar preference experiments, open field experiments and forced swimming experiments; High performance liquid chromatography-electrochemical detection method was used to detect the contents of neurotransmitters dopamine (DA) and 5-hydroxytryptamine (5-HT) in frontal cortex and hippocampus; Immunofluorescence staining was used to detect the expressions of 5-bromo-2-deoxyuridine (BrdU), doublecortin (DCX) and neuroepithelial stem cell protein (Nestin) in hippocampus to evaluate nerve regeneration; Western blotting was used to detect the expressions of BDNF/TrkB/p-CREB protein. Results Compared with sham group, neurological deficit score of rats in model group was significantly increased (P < 0.001), the sugar water preference rate was significantly decreased (P < 0.05), and duration of forced swimming immobility was significantly increased (P < 0.05). The levels of DA in prefrontal cortex and hippocampus and 5-TH in hippocampus were significantly reduced (P < 0.05). The number of BrdU and DCX positive cells were significantly decreased (P < 0.05, 0.01), while the number of Nestin positive cells was decreased. The expressions of BDNF, TrkB and p-CREB in hippocampus were significantly reduced (P < 0.05, 0.01). Compared with model group, neurological deficit score in Xuefu Zhuyu Capsule group was significantly reduced (P < 0.01), the sugar water preference rate was significantly increased (P < 0.05), and the immobility time of forced swimming was significantly reduced (P < 0.05, 0.01). The levels of DA and 5-HT in prefrontal cortex and hippocampus were significantly increased (P < 0.05, 0.01). The number of BrdU, Nestin and DCX positive cells were significantly increased (P < 0.05, 0.01). The expression of BDNF in hippocampus showed an increasing trend, and the expressions of TrkB and p-CREB were significantly increased (P < 0.05). Conclusion Xuefu Zhuyu Capsule can promote nerve regeneration through BDNF/TrkB/p-CREB pathway and thus exert therapeutic effects on PSD.

R285.5

国家自然科学基金资助项目（81873192）