黄芪活性成分芒柄花素靶向GSK-3β蛋白调控巨噬细胞/小胶质细胞极化抗心梗合并抑郁的作用及分子机制

心梗合并抑郁症发生率高达45%，严重影响患者预后，临床上尚无理想治疗药物。前期实验发现心脑疾病常用中药黄芪活性成分芒柄花素有潜在抗心梗和抑郁行为作用。初步机制研究发现芒柄花素可促进M2型巨噬细胞极化，并直接作用GSK-3β蛋白，抑制其活性。而M2型巨噬细胞和小胶质细胞在抗心梗合并抑郁症中发挥重要作用。因此，提出科学假设：黄芪活性成分芒柄花素可通过抑制GSK-3β调控巨噬细胞和小胶质细胞极化而抗心梗合并抑郁症。本课题拟利用小鼠心肌缺血合并抑郁症模型评价黄芪及芒柄花素抗心梗合并抑郁症作用；借助基因敲除、过表达等手段，研究GSK-3β在黄芪活性成分芒柄花素调控巨噬细胞和小胶质细胞极化中的作用；利用脑片培养和细胞清除方法研究M2型巨噬细胞和小胶质细胞在抗心梗合并抑郁症的作用。本课题为阐明黄芪抗心梗合并抑郁症的药效物质基础提供依据，也为开发以调控巨噬细胞/小胶质细胞抗心梗合并抑郁的药物提供新思路。

The incidence of myocardial infarction (MI) combined with depression was as high as 45%, which seriously affected the prognosis of patients. And there are no ideal drugs for treatment in clinical. Radix Astragali (RA) is widely used for treating cardiac and brain diseases with clinical efficacy. In our pilot study, experimental data showed that fomononetin has potential effect on improving myocardial ischemia-reperfusion injury and the behavior of depression. Preliminary mechanism study showed that formononetin promoted macrophage M2 polarization and directly bound to GSK-3β, inhibiting its activity. And M2 macrophage and microglia play important roles in the pathological processes of myocardial infarction and depression. Thus, we proposed the scientific hypothesis that RA and formononetin regulates macrophage/microglia M1/M2 polarization against myocardial infarction combined with depression targeting glycogen synthase kinase-3β. We will confirm the effect of RA and formononetin in treatment of MI combined depression by using the mouse myocardial ischemia model plus the chronic mild unpredictability stimulation model after MI; using gene knockout and overexpression technology to study the role of GSK-3β in regulating macrophage and microglia cell polarization; using brain tissue culture and macrophage/microglia scavenging methods to study the effect of M2 macrophage/microglia on improving myocardial ischemia combined with depression. This study will illustrate the efficacy and material base of RA on treating MI combined with depression, and also pave the avenue for the development of novel macrophage/microglia-targeting drugs for the treatment of MI combined with depression.