摘要
目的:对脑卒中患者进行血管再通治疗不仅受时间窗的限制,还伴随着出血性转化的风险。本研究在小鼠大脑中动脉阻塞(MCAO)模型上观察了丹酚酸B和人参皂苷Rg1合用(Salb/Rg1)对脑缺血时间窗和出血性转化的影响。方法:通过脑梗死体积、神经行为障碍和组织形态学检查评估SalB/Rg1的保护作用和时间窗。对MCAO小鼠进行葡萄糖刺激和再灌注考察SalB/Rg1对出血性转化的抑制。SalB/Rg1对出血性转化的抑制作用是通过免疫荧光染色和原位明胶酶谱技术来确定的。结果:通过组织病理学染色根据细胞结构进一步确定SalB/Rg1以剂量依赖的方式显著减少了梗塞体积并改善了神经行为,且SalB/Rg1对卒中的保护时间窗长达9h。其次,SalB/Rg1下调了出血评分、梗死体积并改善异常神经行为。最后,发现SalB/Rg1对出血性转化的抑制与它对神经血管单元完整性的保护相伴随。在梗死的边缘区域,SalB/Rg1减少了星形胶质细胞的激活,保持了内皮细胞之间连接蛋白(Claudin-5)的丰度,大大降低了基质金属肽酶9(MMP-9)的活性。结论:SalB/Rg1是一种很有前景的抗卒中,尤其是抗出血性转化的新策略。
Objective Application of recanalization on stroke patients is not only limited with time window,but also accompanied with the risk of hemorrhagic transformation.In present study,the effects of salvianolic acid B and ginsenoside Rg1 combination(SalB/Rg1)on time window and hemorrhagic transformation against ischemic stroke was evaluated on middle cerebral artery occlusion(MCAO)mice.Methods The protection and time window of SalB/Rg1 were estimated through infarct volume,neurobehavioral deficits,and histomorphological examination.The prohibition of SalB/Rg1 against hemorrhagic transformation was detected on MCAO mice stimulated with dextrose and reperfusion.Hemorrhagic transformation was assessed by the Heidelberg Bleeding Classification.The mechanism of SalB/Rg1 against hemorrhagic transformation was identified by immunofluorescence staining and in situ gelatin zymography.Results First,SalB/Rg1 significantly reduced infarct volume and improved neurobehavior in a dose-dependent manner.Then,the protective time window up to 9 hours was detected for SalB/Rg1 against stroke.Both the dose-dependent efficiency and longtime protection of SalB/Rg1 were further identified based on cytoarchitecture through histopathological stain.Second,SalB/Rg1 downregulated hemorrhagic score,infarct volume,and abnormal neurobehavior.Finally,the inhibition of SalB/Rg1 against hemorrhagic transformation was found to accompany with its protection on the integrity of neurovascular unit.Around the edge area of infarction,SalB/Rg1 attenuated the astrocyte activation,maintained the abundance of junction protein(claudin-5)between endothelial cells,considerably decreased matrix metallopeptidase 9 activity through in situ gelatin zymography.Conclusion SalB/Rg1 is a promising strategy for further development against stroke,especially against hemorrhagic transformation.
作者
邢荣荣
王一宇
王琳琳
沈海生
Yi Jin
于海英
刘荣霞
姜宝红
Rongrong Xing;Yiyu Wang;Linlin Wang;Haishang Shen;Yi jin;Haoying Yu;Rongxia Liu;Baohong jiang(school of Pharmacy,Key Laboratory of Molecular Pharmacology and Drug Evaluation,Ministry of Education,Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong,Yantai University,Yantai,Shandong,China;Shanghai nstitute of Materia Medica,Chinese Academy of Sciences,Shanghai,China;shenzhen Institute for Drug Control,Shenzhen Testing center of medical devices,Shenzhen,China)
基金
supported by the Biological Resources Programme,Chinese Academy of Sciences (KFJ-BRP-008-005)
Shanghai Science and Technology Development Foundation (21S21901900)
the Lingang Laboratory Grant (LG-QS-202206-01)
Ministry of Science and Technology of China (2021YFE0111300)
National Natural Science Foundation of China (81973513,81573646).
关键词
卒中
丹酚酸B
人参皂苷RG1
出血性转化
神经血管单元
stroke
salvianolic acid B
ginsenoside Rg1
hemorrhagic transformation
neurovascular unit
