益母草碱通过抑制核因子-κB表达治疗子宫腺肌病疼痛的机制研究

Pain is one of the most crucial symptoms of adenomyosis(ADM). Most patients choose drug therapy and reserve the pregnant ability. However, mechanisms of the pain in ADM still remain unclear, and drug therapy is far from satisfaction. In former studies, 1) we found a group of ADM related factors, and most of them were regulated by NF-κB. And 2) NF-κB inhibitor andrographolide relieved hyperalgesia in mice, prevented NF-κB against binding to the DNA, downregulated the expression of COX-2, VEGF, and TF, and thus inhibited the growth of ADM endometrial stromal cell. These results suggest that NF-κB might be the crucial promoter of the pain in ADM , and NF-κB inhibitor might be therapeutic on the hyperalgesia in ADM. The preliminary schemes of this study: 1) to investigate in vitro how the NF-κB inhibitor leonurine influence the activity of endometrial stromal cell and the myometrial smooth muscle cells, and how the leonurine regulate the NF-κB pathways and thus treating the pain in ADM; 2) to evaluate in vivo the therapeutic effect of leonurine on the pain of ADM mice; and 3) to carry out a small scale clinical trial on the effect of the OTC drug--extractum leonuri inspissatum in treating ADM patients with pain. Elucidation of these problems might provide new clues of mechanisms of the ADM pain, and might provide theoretical and experimental basis for new drugs treating the hyperalgesia in ADM.

疼痛是子宫腺肌病（ADM）患者的重要临床症状之一，但目前ADM疼痛发生机制不清，药物疗效欠佳。前期我们发现1）一系列与ADM疼痛相关的因子，并且很多因子都受到核因子-κB（NF-κB）的调控2）NF-κB抑制剂穿心莲内酯可改善ADM小鼠痛觉过敏，并可降低NF-κB与DNA结合能力,下调COX-2、VEGF和TF表达，从而抑制ADM异位内膜间质细胞生长。提示NF-κB是ADM疼痛产生的关键信号传导枢纽，NF-κB抑制剂可打破此通路发挥治疗作用。本研究拟1）体外研究NF-κB抑制剂益母草碱对ADM异位内膜间质细胞和子宫平滑肌细胞活性的影响及对NF-κB和其相关因子的影响，从而来解析益母草碱是如何对NF-κB通路进行调控，最终达到治疗ADM疼痛的目的。2）体内评价益母草碱对ADM小鼠疼痛的作用。为开发新的治疗ADM的药物提供理论依据和实验基础。

疼痛是子宫腺肌病（ADM）患者的重要临床症状之一，但目前ADM疼痛发生机制不清，药物疗效欠佳。在本研究中：1）我们用免疫组化的方法发现GM-CSFR表达、巨噬细胞数、微血管数都与痛经程度呈正相关。微血管数与月经量呈正相关。 因此炎症和血管生成参与子宫腺肌症的发生，进一步猜测其与痛经及月经量有关，为ADM的治疗提供了新的指导。2）体内实验中，我们发现ADM小鼠痛域低于正常对照小鼠，益母草碱可以减少子宫收缩，提高ADM小鼠的痛域，还可以减少异位内膜在肌层的浸润深度。益母草碱还可以上升PR-B的表达，降低P-P65，COX-2和OTR的表达。3）槲皮素是植物界分布最广的生物类黄酮 , 可在体外抑制多种肿瘤细胞的生长有抗氧化、抑制抗凋亡蛋白、缓解系统性炎症、抑制血管增生、调节免疫等功能，在治疗癌症、子宫内膜异位症等疾病中都有较好的效果。我们发现在小鼠实验中，ADM小鼠背根神经节（DRG）L6和S1中TRPV1, p p38 and p ERK的表达上升。槲皮素可以减少子宫收缩，提高腺肌病小鼠的痛域，还可以减少异位内膜在肌层的浸润深度。并且可以下调小鼠L6和S1中TRPV1, p p38 and p ERK的表达。本课题的研究结果为ADM发病机制的研究提供了新思路，并为开发新的治疗ADM药物靶点提供了理论依据及实验基础。