中药葛根有效成分葛根素抗抑郁和止痛的双效作用及机制研究

Depression and pain comorbidity affects 9-15% of the global population and may trigger the suicide.The pharmacological treatment of comorbid depression and pain still remains to be one of the unmet medical needs worldwide. Unexpectedly, we have for the first time found that puerarin may be a potential dual antidepressant and analgesic drug. Furthermore, we have employed Western blot, immunofluorescence staining and RNA-seq transcriptomic profiling to explore the underlying mechanisms. As a result, we discovered that puerarin boosted brain-derived nerve growth factor BDNF level while down-regulated small GTPase Rrag A expression in mouse models of depression and pain. These two targets play a significant role in the nerve system. Thus, we hypothesized that puerarin may exhibit dual antidepressant and analgesic activities via regulating BDNF and Rrag A. We will test this hypothesis through pursuing three specific aims: 1) to further confirm the antidepressant and analgesic activities of puerarin in the animal models; 2) to determine the roles of BDNF and Rrag A in the antidepressant and analgesic activities of puerarin; 3) to discover the effects of puerarin on the expression of the recently emerged biologically important lncRNAs. Our study will demonstrate the targets and mechanisms underlying the antidepressant and analgesic effects of puerarin. The results will not only provide evidences for the development of puerarin as a novel and promising antidepressant and analgesic drug but also pave the avenue to develop new antidepressant and analgesic drugs.

情志抑郁与疼痛并发症影响了全球9-15%的人口。患者可能自杀。目前的治疗方法不能同时有效治疗抑郁症和疼痛。本课题组最近首次发现中药葛根素是一个潜在的双效抗抑郁和止痛药物，并进一步用蛋白印迹、免疫荧光及RNA测序研究该药治疗抑郁症和疼痛的机理。结果表明葛根素主要上调脑源性神经营养因子BDNF及下调小分子三磷酸鸟苷水解酶Rrag A的表达。基于此二者在神经系统的重要作用，本课题提出如下科学假设： 葛根素可能通过调节BDNF及Rrag A来治疗抑郁症和疼痛。为验证此科学假设，本课题拟实现三个目的：1）在动物模型中明确葛根素抗抑郁和止痛的作用； 2）确定BDNF及Rrag A与葛根素抗抑郁和止痛的关系；3）探索葛根素对抑郁症和疼痛相关的长链非编码RNA (lncRNA)的影响。 本课题将阐明葛根素抗抑郁和止痛的作用靶标和分子机制，为研发基于葛根素的抗抑郁和止痛新药奠定基础，提供新思路。

抑郁症是一种精神疾病，影响了全球13%-20%的人的健康。超过75%的抑郁症患者同时患有疼痛。疼痛与抑郁症相互加重彼此的症状，并且会促进暴力和自杀的发生。我们前期研究首次发现中药葛根活性成分葛根素的双效抗抑郁和止痛效果。基于此前期研究结果，我们进一步构建小鼠坐骨神经保留性神经损伤（SNI）引发的抑郁症和疼痛模型和脂多糖（LPS）干预的抑郁症模型，来检测中药葛根素抗抑郁和止痛的作用。用蛋白印迹、免疫荧光、定量聚合酶链反应及RNA二代测序研究该药治疗抑郁症和疼痛的机理。我们发现在小鼠SNI引发的抑郁症和疼痛模型中，葛根素通过上调脑源性神经营养因子BDNF来抗抑郁和止痛。在小鼠脂多糖（LPS）干预的抑郁症模型中，葛根素通过下调小分子三磷酸鸟苷水解酶RragA的表达来抗抑郁。在LPS刺激的神经干细胞中，葛根素能抑制RragA的表达。葛根素并没有缓解RragA 转基因鼠的抑郁行为。我们在RragA转基因鼠抑郁模型中发现了195个差异长链非编码RNA（lncRNA）。总之，葛根素可能通过调节BDNF及RragA来抗抑郁和止痛。本课题首次阐明了葛根素抗抑郁和止痛的作用及分子机制，为研发抗抑郁和止痛的新药奠定基础，为治疗抑郁症和疼痛提供新思路。