护肝方919糖浆对产后应激小鼠食欲及脑胃ghrelin通路的影响

Postpartum depression lead growth retardation of the offspring. As the western medicine is limited use due to lactation, a Traditional Chinese Medicine (TCM)patented invention,919 syrup, be agreed a good efficacy in postpartum diseases.Its detail mechanisms was advised in this study. ICR mice were used to establish postnatal restraint stress model in preliminary studies, showed that stress caused postnatal offspring to low body weight. Further study found that postpartum restraint stress leads to reduced food intake in dams. Because of ghrelin is directly related with the feeding. This study will explore the influences of therapy of liver protection using 919 syrup on the appetite and brain-gastric regulates appetite ghrelin pathway in mouse with maternal stress. Methord of high-throughput microarray was used to filter differential gene between 919 syrup group and the stressed group, analysising the targets of 919 syrup's action and its related signaling pathway. The experimental method including :5-HT2b receptor blockers,5-HT2c receptor blocker,through the hypothalamus stimulates the appetite - - NPY / AgRP nervous system and the suppress the appetite - - 5-HT/CRF nerveous system, comparing the acylated ghrelin of gastric and blood among experimental groups to explore the efficacy mechanism of 919 syrup on dams. Metabolites differences were detected between 5-HT receptor antagonist and 919 syrup's treatment groups using metabolomics, also HPLC analysis was used to analysis the relationship between the metabolites product and the main active compound of 919 syrup. This study further reveal the pharmacological and mechanism of 919 syrup, also making the patents' transformation shows important achievements.

产后抑郁症影响子代生长发育，因哺乳期慎用西药，临床发现护肝为主的中药发明专利方919糖浆治疗产后病疗效良好，本研究探索其疗效的具体机制。前期研究以ICR系小鼠建立产后束缚应激模型，发现产后束缚应激导致子代低体重。进一步发现产后束缚应激导致乳母摄食减少；因ghrelin与摄食直接相关。本课题从调节食欲及脑-胃ghrelin通路探索护肝法专利方919糖浆治疗产后应激的机制，应用高通量基因芯片筛选给药组及模型组的差异基因，分析919糖浆的作用靶点及相关信号通路，采用受体阻断法：5-HT2b/2c受体阻断、从下丘脑促进食欲系统NPY/AgRP神经与抑制食欲系统5-HT/CRF神经ghrelin通路来探索919糖浆疗效的具体机制，并用代谢组学检测5-HT受体阻断及919糖浆治疗后代谢产物差异，HPLC法分析差异产物，并分析该方中的主要有效单体，揭示919糖浆的机制与药理，对转化专利成果有重要意义。

该项目研究产后抑郁症对母子都有影响。具体从产后应激对食欲及脑胃ghrelin通路的机制，及护肝为主的中药发明专利方919糖浆的疗效。项目进展顺利，圆满完成了预期目标。根据前期建立的小鼠产后束缚应激模型，从脑胃ghrelin通路观察胃中食欲调节相关基因（ghrelin、GHSR、Leptin、5-HT2bR）及下丘脑相关食欲调节基因（NPY/AgRP、POMC、5-HT2cR）及蛋白水平的表达（2015，Int J Clin Exp Pathol ），采用高通量基因测序，发现产后模型组与正常组差异基因上调基因55基因，下调36基因（2018，Sci Rep）。发现给予护肝方919糖浆治疗后，可以改善上述基因的异常表达，HPLC法分析差异产物，并分析该方中的主要有效单体为丹参酮、陈皮苷等（2017，Int J Clin Exp Med）。为进一步分析919糖浆的有效机制，采用5-HT2R受体阻断/激动法，发现919糖浆通过5-HT2b/2CR激动剂(D101)来发挥调节食欲的具体机制（2018，Int J Clin Exp Med）。本课题揭示了919糖浆的疗效机制与有效单体，对转化专利方919糖浆有重要意义。