基于血清代谢组学研究牛蒡苷元对大鼠脑缺血-再灌注损伤的保护作用及其分子机制

目的 探讨牛蒡苷元对脑缺血-再灌注损伤模型大鼠血清中代谢物的影响，阐明牛蒡苷元对脑缺血-再灌注损伤保护作用的分子机制。 方法 将18只SPF SD大鼠随机分成假手术组、模型组和牛蒡苷元组，每组6只。牛蒡苷元组大鼠灌胃给予100 mg·kg^－1牛蒡苷元，假手术组和模型组大鼠灌胃给予相同剂量生理盐水，连续灌胃14 d。采用改良线栓法制备脑缺血-再灌注大鼠模型。再灌注24 h后，评估各组大鼠神经功能缺损评分，HE染色观察各组大鼠大脑皮层缺血半暗带组织病理形态表现，代谢组学技术检测各组大鼠血清中代谢物水平。 结果 与假手术组比较，模型组大鼠神经功能缺损评分明显升高（P<0.05），脑组织形态明显改变并可见少量胶质细胞增生，血清中14个代谢物包括3，3'，4'，5-四羟基二苯乙烯和二十二碳六烯酸（DHA）等水平明显降低（P<0.05），12个代谢物包括肌肽等水平明显升高（P<0.05）；与模型组比较，牛蒡苷元组大鼠神经功能缺损评分明显降低（P<0.05），神经元损伤得到改善，血清中14个代谢物包括3，3'，4'，5-四羟基二苯乙烯和DHA等水平明显升高（P<0.05），12个代谢物包括肌肽等水平明显降低（P<0.05）。 结论 牛蒡苷元可能通过调控DHA、3，3'，4'，5-四羟基二苯乙烯和肌肽等代谢物参与组氨酸代谢及精氨酸和脯氨酸代谢等氨基酸代谢通路起到抗脑缺血-再灌注损伤作用。

Protective effect of arctigenin on cerebral ischemia- reperfusion injury based on serum metabolomics and its molecular mechanism

Objective To investigate the effect of arctigenin on the metabolites in serum of the cerebral ischemia-reperfusion injury model rats， and to clarify the molecular mechanism of arctigenin for protection of cerebral ischemia-reperfusion injury. Methods A total of 18 SPF SD rats were randomly divided into sham operation group， model group and arctigenin group， with six rats in each group. The rats in arctigenin group were administered with 100 mg·kg^－1 arctigenin by gavage，and the rats in sham operation group and model group were administrated with saline at the same volume lasted for 14 d， then the cerebral ischemia-reperfusion rat models were established by improved line embolization. After 24 h of reperfusion， the neurological deficit scores of the rats in various groups were assessed， HE staining was used to observe the pathomorphology of ischemic penumbra of the rats in variuos groups， and metabolomics technique was used to detect the metabolite levels in serum of the rats in various groups. Results Compared with sham operation group， the score of neurological deficit of the rats in model group was significantly increased （P<0.05）， the morphology of brain tissue was significantly changed and a small amount of glialcell hyperplasia was seen，the levels of 14 kinds of serum metabolites including 3，3'，4'，5-tetrahydroxysilbene and docosahexaenoic acid （DHA） and so on were significantly decreased （P<0.05）， and the levels of 12 kinds of serum metabolites including carnosine and so on were significantly increased （P<0.05）； compared with model group， the score of neurological deficit of the rats in arctigenin group was significantly decreased （P<0.05）， neuronal injury was improved， the levels of 14 kinds of serum metabolites including 3，3'，4'，5-tetrahydroxysilbene and DHA and so on were significantly increased （P<0.05）， and the levels of 12 kinds of serum metabolites including carnosine and so on were significantly decreased （P<0.05）. Conclusion Arctigenin may play an anti-cerebral ischemia-reperfusion role by regulating the metabolites such as DHA， 3，3'，4'，5-tetrahydroxysilbene and carnosine involved in the amino acid metabolism pathway such as histidine metabolism and arginine and proline metabolism.