钩藤降压解郁方通过抑制p38 MAPK信号分子改善高血压并发抑郁症大鼠海马神经元损伤*

作者：黄铃格1，赵红霞2，冯 敏1，刘叶倩1，陈 蕾3，刘 检1，王志琪4，任卫琼1

单位：1.湖南中医药大学第一附属医院，湖南 长沙 410007； 2.广州中医药大学第二临床医学院，广东 广州 510000； 3.重庆市万州食品药品检验所，重庆 404000； 4.湖南中医药大学药学院，湖南 长沙 410208

引用：引用：黄铃格，赵红霞，冯敏，刘叶倩，陈蕾，刘检，王志琪，任卫琼.钩藤降压解郁方通过抑制p38 MAPK信号分子改善高血压并发抑郁症大鼠海马神经元损伤[J].中医药导报,2025,31(5):38-44.

DOI：10.13862/j.cn43-1446/r.2025.05.007

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摘要：目的：探讨钩藤降压解郁方（GTJYJYF）改善高血压并发抑郁症大鼠海马神经元损伤的作用机制。方法：将40只自发性高血压（SHR）大鼠按照体质量和尾动脉压随机分为模型组、阳性药组及中药低、中、高剂量组，每组8只，另取8只SD大鼠作为空白组。采用慢性应激联合孤养的方法复制高血压并发抑郁症大鼠模型。造模同时灌胃给药，中药低、中、高剂量组予不同剂量GTJYJYF（6.35、12.69、25.38 g/kg）灌胃，阳性药组灌胃临床等效剂量的苯磺酸左旋氨氯地平（0.45 mg/kg）与盐酸氟西汀（1.80 mg/kg），模型组和空白组予等体积蒸馏水灌胃，连续6周。用无创血压计测量尾动脉收缩压；通过Morris水迷宫、旷场实验检测大鼠抑郁行为；HE染色观察大鼠CA1区海马神经元的形态结构变化；透射电镜观察大鼠海马神经元突触的超微结构；酶联免疫吸附试验（ELISA）检测大鼠血清炎性因子白介素-4（IL-4）、白介素-1β（IL-1β）的水平；RT-qPCR法检测大鼠海马p38丝裂原活化蛋白激酶（p38 MAPK）mRNA含量；Western blotting法检测大鼠海马p38 MAPK、磷酸化p38 MAPK（p-p38 MAPK）蛋白表达。结果：与空白组比较，模型组大鼠尾动脉收缩压升高（P<0.01），穿过目标平台次数、目标象限停留时间、跨格次数及水平运动总路程均减少（P<0.05或P<0.01）；模型组大鼠海马CA1区神经元数量减少，神经元排列紊乱，胞体皱缩深染，海马神经元突触小泡减少，突触间隙模糊；模型组大鼠血清IL-4水平降低，IL-1β水平升高（P<0.01），p38 MAPK mRNA及p38 MAPK、p-p38 MAPK蛋白含量均升高（P<0.05或P<0.01）。与模型组比较，各给药组大鼠收缩压均降低（P<0.05或P<0.01）；阳性药组及中药高剂量组大鼠穿过原平台次数增加（P<0.05或P<0.01），各给药组目标象限停留时间、跨格次数及水平运动总路程均增加（P<0.05或P<0.01）；各给药组海马CA1区神经元数量增多，神经元排列有序，神经元损伤程度减轻；阳性药组及中药中、高剂量组海马神经元的突触小泡数量上升，突触前致密结构丰富，突触后膜厚度增大，海马神经元突触超微结构损伤程度减轻；各给药组大鼠血清IL-4含量均升高（P<0.05或P<0.01），IL-1β含量均降低（P<0.05或P<0.01）；各给药组海马组织p38 MAPK mRNA含量及p38 MAPK、p-p38 MAPK蛋白表达均减少（P<0.05或P<0.01）。结论：GTJYJYF可能通过抑制p38 MAPK信号分子，调控血清炎性因子水平，改善海马神经元损伤。

关键词：高血压并发抑郁症；钩藤降压解郁方；海马神经元损伤；p38丝裂原活化蛋白激酶；大鼠

Abstract：

Objective: To explore the effect and possible mechanism of Gouteng Jiangya Jieyu formula (GTJYJYF) on improving hippocampal neuron injury in rats with hypertension complicated with depression. Methods: Totally 40 spontaneously hypertensive rats (SHR) rats were randomly assigned into model group, positive medicine group, low dose Chinese medicine group, medium dose Chinese medicine group and high dose Chinese medicine group, and another 8 SD rats were taken as blank group. The method of chronic unpredictable mild stress combined with solitary raising was used to intervene SHR to replicate the model of hypertension complicated with depression. At the same time of modeling, low dose Chinese medicine group, medium dose Chinese medicine group and high dose Chinese medicine group were given different doses of GTJYJYF (6.35, 12.69 and 25.38 g/kg), and the positive drug group was given Levamlodipine Besylate (0.45 mg/kg) and Fluoxetine Hydrochloride (1.80 mg/kg). The model group and blank group received interventions using identical distilled water for 6 weeks. Tail artery systolic blood pressure was measured by non-invasive sphygmomanometer. The depression-like behavior of rats was evaluated by Morris water maze and open field test. HE staining was used to observe the morphological and structural changes in hippocampal neurons in the CA1 region of rats. Synapse ultrastructure in hippocampus neurons was observed under electron propagation microscopy. The levels of serum inflammatory factors interleukin-4 (IL-4) and IL-1β in rats were detected by ELISA. The content of p38 mitogen-activated protein kinase (p38 MAPK) mRNA in hippocampus was detected by RT-qPCR. The expression of p38 MAPK and phosphorylated p38 MAPK (p-p38 MAPK) in hippocampus was detected by Western blotting. Results: Compared with the blank group, the systolic blood pressure of the tail artery increased in model group (P<0.01), while the number of crossings through the target platform, the duration of stay in the target area, the number of crossings, and the total distance traveled decreased in model group (P<0.05 or P<0.01). The number of neurons in hippocampal CA1 area decreased and the arrangement of residual neurons was disordered in model group. The synaptic vesicles of hippocampal neurons decreased, and the synaptic space was blurred in model group. Compared with the blank group, the level of serum inflammatory factor IL-4 decreased in model group, while the level of IL-1β increased in model group (P<0.01). The expression of p38 MAPK mRNA and p38 MAPK, p-p38 MAPK protein increased in model group (P<0.05 or P<0.01). Compared to with the model group, the systolic blood pressure of the tail artery decreased in each dosing group (P<0.05 or P<0.01). The number of rats crossing the target platform increased in positive medicine group and high dose Chinese medicine group (P<0.05 or P<0.01), and the duration of stay in the target area, the number of crossings, and the total traveled distance increased in each dosing group (P<0.05 or P<0.01). The number of neurons in the hippocampal CA1 region increased in each dosing group, and the arrangement of neurons was orderly. The degree of ultrastructural damage was reduced in each dosing group. The synaptic vesicles increased in positive medicine group, medium dose Chinese medicine group and high dose Chinese medicine group, and presynaptic density increased. The postsynaptic membrane thickened and the damage degree of synaptic ultrastructure of hippocampal neurons was reduced in positive medicine group, medium dose Chinese medicine group and high dose Chinese medicine group. The levels of serum IL-4 increased in each dosing group (P<0.05 or P<0.01), while the levels of IL-1β decreased (P<0.05 or P<0.01). The content of p38 MAPK mRNA and levels of p38 MAPK and p-p38 MAPK protein in the hippocampus decreased in each dosing group (P<0.05 or P<0.01). Conclusion: Gouteng Jiangya Jieyu formula may regulate the level of serum inflammatory factors and improve the damage of hippocampal neurons by inhibiting p38 MAPK signaling molecules.

Key words：hypertension complicated with depression; Gouteng Jiangya Jieyu formula; hippocampal neuron injury; p38 mitogen-activated protein kinase; rats

发布时间：2025-12-30

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