大黄素通过调节血清代谢改善神经病理性疼痛的机制研究

Mechanism of emodin in relieving neuropathic pain by regulating serum metabolism

采用非靶标代谢组学技术检测大黄素干预对慢性压迫性损伤(chronic constriction injury,CCI)模型血清样本中代谢轮廓的影响,探究大黄素镇痛作用的机制。将24只SD大鼠随机分为假手术组、CCI模型组及大黄素组。术后第1天开始,大黄素组大鼠按50 mg·kg^(-1)给予大黄素溶液灌胃治疗,每日1次,连续15 d。于造模前及大黄素给药后第3、7、11、15天进行机械缩足反射阈值(mechanical withdrawal threshold,MWT)及热缩足反射阈值(thermal withdrawal threshold,TWL)测定,15 d后腹主动脉采血,运用非靶标代谢组学技术筛选出不同处理组差异代谢物,并进行生物信息分析。结果发现,术后第3天开始,CCI组及大黄素组大鼠MWT及TWL显著降低,并维持在较低水平,与假手术组相比差异有统计学意义(P<0.01);术后15 d,大黄素组大鼠MWT及TWL高于CCI模型组,差异有统计学意义(P<0.05)。经非靶标代谢组学技术,CCI模型组与假手术组筛选出差异代谢物72个,其中上调41个、下调31个;大黄素组与CCI模型组筛选出差异代谢物26个,其中上调10个、下调16个。京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)富集分析提示大黄素组与CCI模型组差异代谢物主要参与鞘脂代谢、精氨酸生物合成、甘油磷脂代谢及色氨酸代谢等信号通路。经创新途径分析(ingenuity pathway analyses,IPA)平台对差异代谢物相互关系进行分析,共构建出1个代谢互作网络“脂质代谢、分子转运、小分子生物化学”。大黄素可通过调节鞘脂代谢及精氨酸生物合成发挥镇痛作用。

The present study investigated the effect of emodin on the serum metabolite profiles in the chronic constriction injury(CCI)model by non-target metabolomics and explored its analgesic mechanism.Twenty-four Sprague Dawley(SD)rats were randomly divided into a sham group(S),a CCI group(C),and an emodin group(E).The rats in the emodin group were taken emodin via gavage once a day for fifteen days(50 mg·kg^(-1))on the first day after the CCI surgery.Mechanical withdrawal threshold(MWT)and thermal withdrawal threshold(TWL)in each group were performed before the CCI surgery and 3,7,11,and 15 days after surgery.After 15 days,blood samples were collected from the abdominal aorta.The differential metabolites were screened out by non-target metabolomics and analyzed with Kyoto Encyclopedia of Genes and Genomes(KEGG)and ingenuity pathway analysis(IPA).From the third day after CCI surgery,the MWT and TWL values were reduced significantly in both CCI group and emodin group,compared with the sham group(P<0.01).At 15 days post-surgery,the MWT and TWL values in emodin group increased significantly compared with the CCI group(P<0.05).As revealed by non-target metabolomics,72 differential serum metabolites were screened out from the C-S comparison,including 41 up-regulated and 31 down-regulated ones,while 26 differential serum metabolites from E-C comparison,including 10 up-regulated and 16 down-regulated ones.KEGG analysis showed that the differential metabolites in E-C comparison were enriched in the signaling pathways,such as sphingolipid metabolism,arginine biosynthesis,glycerophospholipid metabolism,and tryptophan metabolism.IPA showed that the differential metabolites were mainly involved in the lipid metabolism-molecular transport-small molecule biochemistry network.In conclusion,emodin can exert an analgesic role via regulating sphingolipid metabolism and arginine biosynthesis.