冰片对黄芪甲苷和三七总皂苷配伍有效成分在脑缺血/再灌注模型大鼠脑组织分布的影响
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摘要
目的探讨冰片是否具有促进黄芪甲苷(AST IV)和三七总皂苷(PNS)配伍时主要有效成分透过大脑中动脉栓塞(MCAO)再灌注模型大鼠血脑屏障的作用。方法大鼠随机分为假手术组、模型组、冰片组、AST IV组、PNS组、AST IV+PNS组、冰片+AST IV+PNS组,制备MCAO再灌注大鼠模型,以液相色谱-质谱联用法(LC-MS/MS)测定大鼠患侧与健侧大脑皮层、小脑中AST IV和PNS有效成分(人参皂苷Rg1、Rb1和三七皂苷R1)的含量。结果 AST IV无论是单用还是与PNS、冰片配伍,其口服后主要分布在大脑皮层,尤其是患侧大脑皮层。冰片+AST IV+PNS能使患侧与健侧大脑皮层中AST IV含量显著增加。PNS单用,其有效成分人参皂苷Rg1、Rb1和三七皂苷R1主要分布在患侧小脑。冰片+AST IV+PNS能使患侧大脑皮层中人参皂苷Rb1含量显著增加,使健侧和患侧大脑皮层中人参皂苷Rg1含量增加,使大脑皮层尤其是患侧大脑皮层及小脑中三七皂苷R1含量增加。结论大鼠脑缺血再灌注后,AST IV与PNS的有效成分人参皂苷Rb1、Rg1及三七皂苷R1在大脑皮层和小脑均有一定的分布。AST IV单用时,AST IV主要分布在大脑皮层;PNS单用时,人参皂苷Rb1、Rg1及三七皂苷R1主要分布在小脑。冰片与AST IV、PNS合用后,能促进AST IV及人参皂苷Rb1、Rg1及三七皂苷R1向大脑皮层富集,尤其是向缺血再灌注侧大脑皮层富集;而且能不同程度地促进AST IV,人参皂苷Rb1、Rg1及三七皂苷R1在大脑皮层的吸收,尤其是在患侧大脑皮层的吸收。
Objective To investigate whether borneol can promote the bioactive components of the combination of astragaloside IV(AST IV) and Panax notoginseng saponins(PNS) into the blood-brain barrier of rats with middle cerebral artery occlusion(MCAO)/reperfusion. Methods Using the model of MCAO/reperfusion, rats were randomly divided into sham-operation group, model group, borneol group, AST IV group, PNS group, AST IV + PNS group and borneol + AST IV + PNS group, and the content of AST IV and the bioactive components of PNS(ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1) in the cerebral cortex and the cerebellum of the affected side and the healthy side were determined by liquid chromatography-mass spectrometry(LC-MS/MS). Results AST IV, whether used alone or combined with PNS and borneol, was mainly distributed in the cerebral cortex after oral administration, especially in the affected cerebral cortex. Borneol combined with AST IV and PNS significantly increased the content of AST IV in the affected and the healthy cerebral cortex. The bioactive components of PNS such as ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 was mainly distributed in the affected side of the cerebellum when PNS was used alone. Borneol combined with AST IV + PNS significantly increased the content of ginsenoside Rb1 in the cerebral cortex, especially in the affected cortex, increased the content of Rg1 in the healthy and the affected cortex, and increased the content of notoginsenoside R1 in the cerebral cortex, especially in the affected cortex, as well as in the cerebellum. Conclusion AST IV and the bioactive components of PNS such as ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 have a certain distribution in the cerebral cortex and the cerebellum after cerebral ischemia-reperfusion in rats. AST IV was mainly distributed in the cerebral cortex when it was used alone, ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 were mainly distributed in the cerebellum when PNS was used alone. The combination of borneol combined with AST IV and PNS can promote the gather of AST IV, ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 to the cerebral cortex, especially to the cortex of the ischemia-reperfusion side; Moreover, it can promote the absorption of AST IV, ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 in the cerebral cortex to varying degrees, especially in the affected cortex.
Objective To investigate whether borneol can promote the bioactive components of the combination of astragaloside IV(AST IV) and Panax notoginseng saponins(PNS) into the blood-brain barrier of rats with middle cerebral artery occlusion(MCAO)/reperfusion. Methods Using the model of MCAO/reperfusion, rats were randomly divided into sham-operation group, model group, borneol group, AST IV group, PNS group, AST IV + PNS group and borneol + AST IV + PNS group, and the content of AST IV and the bioactive components of PNS(ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1) in the cerebral cortex and the cerebellum of the affected side and the healthy side were determined by liquid chromatography-mass spectrometry(LC-MS/MS). Results AST IV, whether used alone or combined with PNS and borneol, was mainly distributed in the cerebral cortex after oral administration, especially in the affected cerebral cortex. Borneol combined with AST IV and PNS significantly increased the content of AST IV in the affected and the healthy cerebral cortex. The bioactive components of PNS such as ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 was mainly distributed in the affected side of the cerebellum when PNS was used alone. Borneol combined with AST IV + PNS significantly increased the content of ginsenoside Rb1 in the cerebral cortex, especially in the affected cortex, increased the content of Rg1 in the healthy and the affected cortex, and increased the content of notoginsenoside R1 in the cerebral cortex, especially in the affected cortex, as well as in the cerebellum. Conclusion AST IV and the bioactive components of PNS such as ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 have a certain distribution in the cerebral cortex and the cerebellum after cerebral ischemia-reperfusion in rats. AST IV was mainly distributed in the cerebral cortex when it was used alone, ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 were mainly distributed in the cerebellum when PNS was used alone. The combination of borneol combined with AST IV and PNS can promote the gather of AST IV, ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 to the cerebral cortex, especially to the cortex of the ischemia-reperfusion side; Moreover, it can promote the absorption of AST IV, ginsenoside Rg1, ginsenoside Rb1, and notoginsenoside R1 in the cerebral cortex to varying degrees, especially in the affected cortex.
引文
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[7]汪宏锦,吴俊杰,薛强,等.冰片对血脑屏障通透性的双向调节作用影响因素及机制探讨[J].中国中药杂志,2017,42(11):2200-2205.
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[17]吴雪,欧阳丽娜,向大位,等.冰片及石菖蒲促进羟基红花黄色素A透过BBB的实验研究[J].中草药,2011,42(4):734-737.
[18]Lai X J,Zhang L,Li J S,et al.Comparative pharmacokinetics and bioavailability studies of three salvianolic acids after the administration of Salviae miltiorrhizae alone or with synthetical borneol in rats[J].Fitoterapia,2011,82(6):883-888.
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[20]Chen Z Z,Lu Y,Du S Y,et al.Influence of borneol and muscone on geniposide transport through MDCK and MDCK-MDR1 cells as blood-barrier in vitro model[J].Int J Pharm,2013,456(1):73-79.
[21]Zhang Q,Wu D,Wu J,et al.Improved blood-brain barrier distribution:Effect of borneol on the brain pharmacokinetics of kaempferol in rats by in vivo microdialysis sampling[J].J Ethnopharmacol,2015,doi:10.1016/j.jep.2015.01.003.
[22]Ren J G,Zou M J,Gao P,et al.Tissue distribution of borneolmodified ganciclovir-loaded solid lipid nanoparticles in mice after intravenous administration[J].Eur J Pharm Biopharm,2013,83(2):141-148.
[23]Zhang L,Han L M,Qin J,et al.The use of borneol as an enhancer for targeting aprotinin-conjugated PEG-PLGA nanoparticles to the brain[J].Pharm Res,2013,30(10):2560-2572.
[2]Huang X P,Tan H,Chen B Y,et al.Combination between total Astragalus extract and total Panax notoginseng saponins strengthened the protective effects on brain damage through improving energy metabolism and inhibiting apoptosis after cerebral ischemiareperfusion in mice[J].Chin J Integr Med,2017,23(6):445-452.
[3]Huang X P,Ding H,Lu J D,et al.Effects of the combination of the main active components of Astragalusand Panax notoginseng on inflammation and apoptosis of nerve cell after cerebral ischemia-reperfusion[J].Am JChin Med,2015,43(7):1419-1438.
[4]Chang Y X,Sun Y G,Li J,et al.The experimental study of Astragalus membranaceus on meridian tropsim:The distribution study of astragaloside IV in rat tissues[J].JChromatogr Aphy B,2012,doi:10.1016/j.jchromb.2012.10.024.
[5]Zhang W D,Zhang C,Liu R H,et al.Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs[J].Life Sci,2006,79(8):808-815.
[6]Liu H,Yang J,Du F,et al.Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats[J].Drug Metab Dispos,2009,37(12):2290-2298.
[7]汪宏锦,吴俊杰,薛强,等.冰片对血脑屏障通透性的双向调节作用影响因素及机制探讨[J].中国中药杂志,2017,42(11):2200-2205.
[8]顾振,韩群颖,苏殿三,等.大鼠短暂性局灶性脑缺血模型改进的制作方法[J].南京医科大学学报:自然科学版,2001,21(6):513-514.
[9]杨筱倩,陈仙蕾,杨仁义,等.冰片配伍黄芪甲苷与三七总皂苷抗脑缺血再灌注损伤有效剂量的研究[J].湖南中医药大学学报,2019,39(4):39-44.
[10]Meairs S,Wahlgren N,Dirnagl U,et al.Stroke research priorities for the next decade-a representative view of the European scientific community[J].Cerebrovasc Dis,2006,22(2/3):75-82.
[11]中国药典[S].一部.2015.
[12]李伟荣,陈瑞玉,黄天来,等.天然冰片对小鼠脑内氨基酸类神经递质含量的影响[J].中药新药与临床药理,2011,22(2):164-167.
[13]Li W R,Chen R Y,Yang L,et al.Pharmacokinetics of natural borneol after oral administration in mice brain and its effect on excitation ratio[J].Eur J Drug MetabPharmacokinet,2012,37(1):39-44.
[14]王利苹,奉建芳,胡凯莉.芳香开窍中药对血脑屏障通透性的调节作用及其机制研究进展[J].中国中药杂志,2014,39(6):949-955.
[15]魏宇宁,刘萍,何新荣,等.微透析法研究冰片对头孢曲松在大鼠脑纹状体中含量的影响[J].中国中药杂志,2010,35(19):2605-2608.
[16]Wu C,Liao Q F,Yao M C,et al.Effect of natural borneol on the pharmacokinetics and distribution of nimodipine in mice[J].Eur J Drug Metab Pharmacokinet,2013,39(1):17-24.
[17]吴雪,欧阳丽娜,向大位,等.冰片及石菖蒲促进羟基红花黄色素A透过BBB的实验研究[J].中草药,2011,42(4):734-737.
[18]Lai X J,Zhang L,Li J S,et al.Comparative pharmacokinetics and bioavailability studies of three salvianolic acids after the administration of Salviae miltiorrhizae alone or with synthetical borneol in rats[J].Fitoterapia,2011,82(6):883-888.
[19]Yu B,Ruan M,Cui X B,et al.Effects of borneol on the pharmacokinetics of geniposide in cortex,hippocampus,hypothalamus and striatum of conscious rat by simultaneous brain microdialysis coupled with UPLC-MS[J].J Pharm Biomed,2013,doi:10.1016/j.jpba.2013.01.017.
[20]Chen Z Z,Lu Y,Du S Y,et al.Influence of borneol and muscone on geniposide transport through MDCK and MDCK-MDR1 cells as blood-barrier in vitro model[J].Int J Pharm,2013,456(1):73-79.
[21]Zhang Q,Wu D,Wu J,et al.Improved blood-brain barrier distribution:Effect of borneol on the brain pharmacokinetics of kaempferol in rats by in vivo microdialysis sampling[J].J Ethnopharmacol,2015,doi:10.1016/j.jep.2015.01.003.
[22]Ren J G,Zou M J,Gao P,et al.Tissue distribution of borneolmodified ganciclovir-loaded solid lipid nanoparticles in mice after intravenous administration[J].Eur J Pharm Biopharm,2013,83(2):141-148.
[23]Zhang L,Han L M,Qin J,et al.The use of borneol as an enhancer for targeting aprotinin-conjugated PEG-PLGA nanoparticles to the brain[J].Pharm Res,2013,30(10):2560-2572.