从“脑心同治”途径探讨冠心II号的抗抑郁作用及其对海马BDNF、HPA轴通路的影响机制

The coronary heart disease (CHD) in patients complicated with depression exists at present and it was quite necessary to study. Modern medical research shows that hypothalamus-pituitary-adrenal (HPA) axis may be the common pathogenesis between CHD and depression, and the Hippocampus brain derived neurotrophic factor (BDNF) expression is related to depression and CHD. The previous research works about Guanxin II, a Traditional Chinese formula, exhibited an effect in the treatment of CHD. From “the double heart medical mode” and “treatment of the brain and heart”, we propose a hypothesis that there are “Qi stagnation and blood stasis- brain and heart” axis abnormality. We want to explore if oral administration of Guanxin II induces an antidepressant effect during depressed syndrome in rats, and to investigate whether or not the mechanism is related to BDNF expression and HPA axis. We plan to determinate serum drug and brain tissue ingredients of Guanxin II first, and then test whether or not Guanxin II induces an antidepressant effect during depressed syndrome in rats by behavioral experiment, as well as test cerebral blood flow. At last, we plan to determinate the mechanism is related to HPA axis and the BDNF expression. Our project embodies the homotherapy for heteropathy. It was a preliminary attempt and exploration that we use “activating blood circulation to dissipate blood stasis” decoctions to treatment depression. It was also have a certain clinical value that use “activating blood circulation to dissipate blood stasis” decoctions to treatment diseases in clinical.

目前冠心病（CHD）合并抑郁症的患者大量存在，因此研究二者共同的发病机制及治疗具有一定的科学意义。现代医学研究表明：下丘脑-垂体-肾上腺皮质（HPA）轴可能是联系CHD与抑郁症共同的发病机制，海马脑源性神经营养因子（BDNF）表达与CHD及抑郁症均相关。本立项从双心医学出发，在前期研究基础上（冠心II号对CHD有确切的治疗作用），基于“脑心同治”的中医理论构建“气滞血瘀—脑心轴异常”假说，探讨冠心II号方对抑郁模型大鼠是否有抗抑郁的作用，及其对海马BDNF表达及HPA轴功能的影响。本项目拟首先进行冠心II号复方的血清及脑组织药物成分测定，然后进行复方对抑郁症模型的行为学及脑血流量检测，验证其是否具有抗抑郁的作用，再进行海马—HPA轴的相关机制研究。本立项体现了中医学异病同治，是将活血化瘀药用于抗抑郁治疗的初步尝试和探索，对于活血化瘀类方药的临床应用具有一定的临床价值。

本立项从“双心疾病”出发，在前期冠心II（GXII）对冠心病（CHD）有确切治疗作用的基础上，基于中医理论“脑心同治”及现代医学“下丘脑-垂体-肾上腺皮质（HPA）轴可能是联系二者共同的发病机制”，采用慢性不可预见性应激（CUMS）联合高脂饮食（HFD）建立抑郁-冠状动脉粥样硬化大鼠模型；采用旷场和强迫游泳实验行为学评价；苏木精-伊红及油红染色观察心肌组织和动脉血管形态；Western blot测定大鼠海马脑源性神经营养因子（BDNF），下丘脑促肾上腺皮质激素释放因子（CRF），促肾上腺皮质激素（ACTH）蛋白表达；酶联免疫吸附法测定血清糖皮质激素（GC）表达，旨在探索GXII 对大鼠行为学及其HPA轴的影响。结果：与模型对照组相比，GXII（2.5 g/kg/d）增加旷场试验总距离，缩短强迫游泳不动时间；改善心肌损害及血管动脉粥样硬化；增加BDNF表达；降低CRF、ACTH和GC表达。结论：CUMS联合HFD能够构建较为理想抑郁-动脉粥样硬化模型。GXII号可能通过血液脑等靶点发挥作用，其有效成分是羟基红花黄色素A、阿魏酸、丹酚酸B。GXII具有改善抑郁行为的作用，能增加BDNF蛋白表达，其可能通过调节HPA轴发挥抗抑郁样作用。本研究丰富了中医“脑心同治”基础理论，拓展了GXII的治疗作用认识，为“双心疾病”提供治疗参考。