中国药理学通报2024，Vol.40Issue(1)：83-90,8.DOI:10.12360/CPB202305018
泽泻醇A保护血脑屏障改善脑缺血/再灌注损伤的作用和机制研究
Effect of alisol A on cerebral ischemia reperfusion injury by protecting blood brain barrier and its mechanism
摘要
Abstract
Aim To investigate whether alisol A(AA)could improve the blood brain barrier(BBB)mediated cortex cerebral ischemia-reperfusion injury(CIRI)by inhibiting matrix metalloproteinase 9(MMP-9).Methods The global cerebral ischemia-reperfusion(GCI/R)model in mice was established,and the AA was intragastric injected subsequently for seven days.The modified neurological severity scores(mNSS),open field test and Y-maze test were applied to detect neurological function.Magnetic resonance spectroscopy(MRS)was used to detect relevant neu-rosubstance metabolism in cortex of mice.Transmission electron microscope(TEM)was employed to observe the ultrastructure of BBB in cortex.Western blot and immunohistochemistry were used to detect the MMP-9 level in cortex.The binding possibility of AA and MMP-9 was determined by molecular docking.Results Compared with Sham group,mice in GCI/R group have an increased mNSS score but decreased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test(P＜0.01).While mice in GCI/R+AA group have a decreased mNSS score but increased at total distance and center distance to total distance ratio in open field test as well as alternation rate in Y-maze test(P＜0.01)compared with GCI/R group.MRS results found that in cortex of GCI/R group mice,the level of GABA and NAA significantly decreased while the Cho,mI and Tau level increased(P＜0.01).Whereas in GCI/R+AA group mice,the GABA and NAA level increased and the Cho,mI and Tau decreased signifi-cantly(P＜0.01).By TEM we observed that the basilemma of cerebral microvessels collapsed,the lu-men narrowed,the endothelial cells were active and plasma membranes ruffled,gaps between cells were enlarged and tight junctions were damaged and the end feet of astrocytes were swollen in GCI/R group mice.While in GCI/R+AA group mice,the lumen was filled,plasma membranes of endothelial cells were smooth,tight junctions were complete and end feet of astrocytes were in normal condition.Western blot and immunohistochemistry both found that the MMP-9 level increased in GCI/R group mice(P＜0.01)and de-creased in GCI/R+AA group mice(P＜0.05).Mo-lecular docking proved the binding between aliso A and MMP9 through TYR-50 and ARG-106,and the bind-ing energy was calculated as-6.24 kcal·mol-1.Conclusions The AA could improve CIRI in cortex of mice,and the potential mechanism might be inhibiting the BBB damage caused by increasing MMP-9 level.关键词
脑缺血/再灌注损伤/基质金属蛋白酶9/泽泻醇A/血脑屏障/神经保护/分子对接Key words
cerebral ischemia reperfusion injury/ma-trix metalloproteinase 9/alisol A/blood brain barrier/neuroprotection/molecular docking引用本文复制引用
邓云飞,李惠红,魏伟,周阳杰,薛偕华..泽泻醇A保护血脑屏障改善脑缺血/再灌注损伤的作用和机制研究[J].中国药理学通报,2024,40(1):83-90,8.基金项目
国家自然科学基金资助项目(No 82274620) （No 82274620）
福建省卫健委科技计划项目(No 2021zyyj69) （No 2021zyyj69）
福建省自然科学基金资助项目(No 2021J01957) （No 2021J01957）
