电针调节血脑屏障通透性的P-糖蛋白调控机制探讨
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摘要
[目的]探讨电针对血脑屏障(blood brain barrier,BBB)通过P-糖蛋白(P-glycoporotein,P-gp)路径调控的可能性。[方法]根据BBB结构与功能特点,立足于电针对BBB的促透效应的现有研究报道,通过探讨P-gp相关调控路径及电针对此通路部分相关物质的影响,分析电针通过P-gp路径实现BBB促透效应的可能性。[结果]电针可以调节一氧化氮(nitric oxide,NO)、一氧化氮合酶(nitric oxide synthase,NOS)水平,降低促炎细胞因子肿瘤坏死因子(tumor necrosis factor-α,TNF-α)含量,抑制核转录因子κB(nuclear factor kappa B,NF-k B)水平;提高血管内皮生长因子(vascular endothelial growth factor,VEGF)水平,调节VEGF信使单链核糖核酸(messenger Ribonucleic Acid,m RNA)、质膜结合血管内皮生长因子受体(fetal Liver Kinase 1,flk-1)、磷酸化微囊蛋白1(caveolin-1)。[结论]电针可能通过调节促炎细胞因子肿瘤坏死因子/蛋白激酶Cβ1/1-磷酸鞘氨醇受体1(tumor necrosis factor-α/protein kinase cβ1/sphingosine 1-phosphatereceptor,TNF-α/PKCβ1/S1PR1)信号通路和血管内皮生长因子信号通路中的相关分子水平来调控P-gp来影响BBB通透性。
[Objective]Discuss the possibility of electroacupuncture influencing the permeability of BBB which was suspected by the regulation of P-glycoprotein.[Methods]According to the structure of BBB,the reports about electroacupuncture help permeate BBB through the material related with P-gp,analysing the possibility of electroacupuncture through the P-gp related methods influencing the permeability of BBB.[Results]Electroacupuncture can adjust the content of NO and NOS,reduce TNF-α,suppress NF-kb; In another way,it can increase the content of VEGF,influence VEGF m RNA,Flt-1,Flk-1,pcaveolin-1.[Conclusion]There is a great possibility of electroacupuncture influencing the permeability of BBB through two main signal pathways and regulating P-glycoprotein are TNF-α/PKCβ/S1PR1 signaling and vascular endothelial growth factor signaling.
[Objective]Discuss the possibility of electroacupuncture influencing the permeability of BBB which was suspected by the regulation of P-glycoprotein.[Methods]According to the structure of BBB,the reports about electroacupuncture help permeate BBB through the material related with P-gp,analysing the possibility of electroacupuncture through the P-gp related methods influencing the permeability of BBB.[Results]Electroacupuncture can adjust the content of NO and NOS,reduce TNF-α,suppress NF-kb; In another way,it can increase the content of VEGF,influence VEGF m RNA,Flt-1,Flk-1,pcaveolin-1.[Conclusion]There is a great possibility of electroacupuncture influencing the permeability of BBB through two main signal pathways and regulating P-glycoprotein are TNF-α/PKCβ/S1PR1 signaling and vascular endothelial growth factor signaling.
引文
[1]张珉,张俊钰,钟武.血脑屏障开放方法研究进展[J].国际药学研究杂志,2016,43(1):126-133.
[2]许兵,张俞,杜久林.血脑屏障的研究进展[J].生理学报,2016,68(3):306-322.
[3]Liebner S,Czupalla C J,Wolburg H.Current concepts of blood-brain barrier development[J].Int J Dev Biol,2011,55(4-5):467-476.
[4]Zhao Z,Nelson AR,Betsholtz C,etc.Establishment and dysfunction of the blood-brain barrier[J].Cell,2015,163(5):1064-1078.
[5]沈梅红,李忠仁,项晓人,等.电针对脑缺血再灌注大鼠大脑皮层超微结构的影响[J].针刺研究,2009,34(3):167-170.
[6]陈媛媛,周慧,张江松,等.从“通玄府”法与“醒脑开窍”针刺法的相关性探讨中风病的临床证治[J].针刺研究,2015,38(4):38-40.
[7]林咸明,谭克平,张爱军,等.电针诱导神经生长因子透血脑屏障效应及其机制分析[J].针刺研究,2009,34(2):110-113.
[8]喻斌,吕高红,孙永,等.电针配合冰片对小鼠血脑屏障通透性的影响[J].针刺研究,2011,36(5):335-340.
[9]喻斌,阮鸣,孙永,等.电针对抑郁大鼠大脑皮层ATP结合盒式蛋白表达的影响[J].针刺研究,2013,38(4):286-190.
[10]Zhong Y,Hennig B,and Michal Toborek.Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregulation of P-glycoprotein in brain endothelial cells[J].J Cereb Blood Flow Metab,2010,30(3):522-533.
[11]Dong XZ,Bi MG.Research progress on regulation of P-glycoprotein by reactive oxygen specices[J].Chin Pharmacol Bull,2010,26(10):1386-1390.
[12]Robey RW,Massey PR,Amiri-Kordestani L,et al.ABCTransporters:Unvalidated Therapeutic Targets in Cancer and the CNS[J].Anticancer Agents Med Chem,2010,10(8):625-633.
[13]Miller DS.Regulation of P-glycoprotein and other ABCdrug transporters at the blood-brain barrier[J].Trends Pharmacol Sci,2010,31:246-254.
[14]Miller DS.Regulation of ABC Transporters Blood-Brain Barrier:The Good,the Bad,and the Ugly[J].Adv Cancer Res,2015,125:43-70.
[15]Miller DS,Cannon RE.Signaling pathways that regulate basal ABC transporter activity at the blood-brain barrier.[J].Curr Pharm Des,2013,20(10):1463-1471.
[16]Miller DS.Regulation of ABC Transporters Blood-Brain张异,等:电针调节血脑屏障通透性的P-糖蛋白调控机制探讨Barrier:The Good,the Bad,and the Ugly[J].Adv Cancer Res,2015,125:43-70.
[17]Rigor RR,Hawkins BT,Miller DS.Activation of PKCisoformβI at the blood-brain barrier rapidly decreases P-glycoprotein activity and enhances drug delivery to the brain[J].J Cereb Blood Flow Metab,2010,30(7):1373-1383.
[18]Cannon RE,Peart JC,Hawkins BT,et al.Targeting bloodbrain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain[J].Proc Natl Acad Sci U S A,2012,109:15930-15935.
[19]Bauer B,Hartz AM,Miller DS.Tumor Necrosis Factor and Endothelin-1 Increase P-Glycoprotein Expression and Transport Activity at the Blood-Brain Barrier[J].Mol Pharmacol,2007,71(3):667-675.
[20]谢振伟,臧彦楠,赵立波.调控血脑屏障ABC转运体信号转导通路的研究现状[J].中国临床药理学杂志,2014,30(11):1057-1059.
[21]Miller DS,Cannon RE.Signaling pathways that regulate basal ABC transporter activity at the blood-brain barrier.[J].Curr Pharm Des,2013,20(10):1463-1471.
[22]Hawkins BT,Sykes DB,Miller DS.Rapid,reversible modulation of blood-brain barrier P-glycoprotein transport activity by vascular endothelial growth factor[J].J Neurosci,2010,30(4):1417-1425.
[23]姜元辉,石岚,姚远,等.针刺百会、腰奇穴对癫痫大鼠惊厥潜伏期及海马区NO、NOS、SOD影响的实验研究[J].慢性病学杂志,2016,17(3):259-266.
[24]孔素平,谭奇纹,于慧娟,等.电针夹脊穴对急性心肌缺血大鼠血清NO、ET及IL-1β的影响[J].世界中西医结合杂志,2011,6(4):333-334.
[25]胥虹贝,罗勇,朱艳含,等.电针通过e NOS促进局灶脑缺血/再灌注大鼠脑缺血皮质区血管再生[J].中国组织化学与细胞化学杂志,2015,24(5):381-387.
[26]朱艳含,罗勇,胥虹贝,等.电针介导e NOS动员内源性EPCs促MCAO/R大鼠脑内皮血管再生[J].中国实验动物学报,2015,23(3):291-296.
[27]王吉锡,张宏男,张玉瑶,等.针刺“百会”、“大椎”、“足三里”穴对AD模型大鼠学习记忆能力及脑组织内MAO、NOS表达的影响[J].中医药信息,2012,29(3):94-96.
[28]刘红,宋修涛,卢岩,等.电针对MCAO模型大鼠海马CA1区P-GP表达的影响[J].山东中医药大学学报,2010,34(3):260-262.
[29]俞坤强,李晓洁,彭洪卫,等.电针百会、神庭穴对MCAO大鼠学习记忆能力及IL-1β、TNF-α表达的影响[J].中国中医急症,2015,24(11):1891-1894.
[30]王鲜,黄佳,柳维林,等.电针对缺血再灌注损伤大鼠缺血周围区皮质小胶质细胞活化的影响[J].中国康复理论与实践,2015,21(11):1251-1255.
[31]孔立红,刘胜洪,毛娟娟,等.电针对脑缺血大鼠NF-κB及TNF-α表达的影响[J].中国康复医学杂志,2009,24(8):711-714.
[32]洪银珠,任秀君,施昱丞,等.电针干预对高血脂合并脑缺血大鼠血脂四项及TNF-α含量的影响[J].针灸临床杂志,2007,23(4):51-55.
[33]刑东.针刺预处理通过MMP9调节TJP诱导大鼠脑缺血耐受的研究[D].第四军医大学硕士学位论文,2015:12.
[34]乔云英,吴富东,王健,等.电针对佐剂性关节炎大鼠下丘脑中NF-KB表达的影响[J].中华中医药学刊,2011,29(6):1260-1262.
[35]尤艳利,徐晓明,舒适,等.电针水沟穴对MCAO模型大鼠缺血半暗带VEGF及arresten表达的影响[J].上海中医药大学学报,2014,28(6):80-84.
[36]林咸明,陈丽萍,姚旭.不同时程电针预处理对脑缺血再灌注大鼠血脑屏障基质金属蛋白酶-9、血管内皮生长因子的影响[J].针刺研究,2015,40(1):40-44.
[37]王储蓄.电针督脉组穴对血管性痴呆大鼠学习记忆与海马VEGF及其受体Flt-1、Flk-1m RNA表达的影响[D].安徽中医药大学硕士学位论文,2015:45.
[38]蔡荣林,程红亮,周婷,等.电针对血管性认知障碍大鼠学习记忆与海马内血管内皮生长因子及其受体1、2 m RNA表达的影响[J].针刺研究,2015,40(1):25-29.
[39]毛庆菊,陈邦国.电针对局灶性脑缺血再灌注大鼠大脑皮层微血管超微结构及血管内皮生长因子表达的影响[J].针刺研究,2012,37(6):476-481.
[40]张彤,林涛,王秀志,等.电针预处理对脑缺血再灌注大鼠骨髓和血浆中EPCs及VEGF的影响[J].中国康复医学杂志,2009,24(5):428-432.
[41]邹蓉.电针预处理对脑缺血再灌注大鼠脑内小窝蛋白-1以及血脑屏障通透性的影响[D].南京中医药大学,2014:33.
[2]许兵,张俞,杜久林.血脑屏障的研究进展[J].生理学报,2016,68(3):306-322.
[3]Liebner S,Czupalla C J,Wolburg H.Current concepts of blood-brain barrier development[J].Int J Dev Biol,2011,55(4-5):467-476.
[4]Zhao Z,Nelson AR,Betsholtz C,etc.Establishment and dysfunction of the blood-brain barrier[J].Cell,2015,163(5):1064-1078.
[5]沈梅红,李忠仁,项晓人,等.电针对脑缺血再灌注大鼠大脑皮层超微结构的影响[J].针刺研究,2009,34(3):167-170.
[6]陈媛媛,周慧,张江松,等.从“通玄府”法与“醒脑开窍”针刺法的相关性探讨中风病的临床证治[J].针刺研究,2015,38(4):38-40.
[7]林咸明,谭克平,张爱军,等.电针诱导神经生长因子透血脑屏障效应及其机制分析[J].针刺研究,2009,34(2):110-113.
[8]喻斌,吕高红,孙永,等.电针配合冰片对小鼠血脑屏障通透性的影响[J].针刺研究,2011,36(5):335-340.
[9]喻斌,阮鸣,孙永,等.电针对抑郁大鼠大脑皮层ATP结合盒式蛋白表达的影响[J].针刺研究,2013,38(4):286-190.
[10]Zhong Y,Hennig B,and Michal Toborek.Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregulation of P-glycoprotein in brain endothelial cells[J].J Cereb Blood Flow Metab,2010,30(3):522-533.
[11]Dong XZ,Bi MG.Research progress on regulation of P-glycoprotein by reactive oxygen specices[J].Chin Pharmacol Bull,2010,26(10):1386-1390.
[12]Robey RW,Massey PR,Amiri-Kordestani L,et al.ABCTransporters:Unvalidated Therapeutic Targets in Cancer and the CNS[J].Anticancer Agents Med Chem,2010,10(8):625-633.
[13]Miller DS.Regulation of P-glycoprotein and other ABCdrug transporters at the blood-brain barrier[J].Trends Pharmacol Sci,2010,31:246-254.
[14]Miller DS.Regulation of ABC Transporters Blood-Brain Barrier:The Good,the Bad,and the Ugly[J].Adv Cancer Res,2015,125:43-70.
[15]Miller DS,Cannon RE.Signaling pathways that regulate basal ABC transporter activity at the blood-brain barrier.[J].Curr Pharm Des,2013,20(10):1463-1471.
[16]Miller DS.Regulation of ABC Transporters Blood-Brain张异,等:电针调节血脑屏障通透性的P-糖蛋白调控机制探讨Barrier:The Good,the Bad,and the Ugly[J].Adv Cancer Res,2015,125:43-70.
[17]Rigor RR,Hawkins BT,Miller DS.Activation of PKCisoformβI at the blood-brain barrier rapidly decreases P-glycoprotein activity and enhances drug delivery to the brain[J].J Cereb Blood Flow Metab,2010,30(7):1373-1383.
[18]Cannon RE,Peart JC,Hawkins BT,et al.Targeting bloodbrain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain[J].Proc Natl Acad Sci U S A,2012,109:15930-15935.
[19]Bauer B,Hartz AM,Miller DS.Tumor Necrosis Factor and Endothelin-1 Increase P-Glycoprotein Expression and Transport Activity at the Blood-Brain Barrier[J].Mol Pharmacol,2007,71(3):667-675.
[20]谢振伟,臧彦楠,赵立波.调控血脑屏障ABC转运体信号转导通路的研究现状[J].中国临床药理学杂志,2014,30(11):1057-1059.
[21]Miller DS,Cannon RE.Signaling pathways that regulate basal ABC transporter activity at the blood-brain barrier.[J].Curr Pharm Des,2013,20(10):1463-1471.
[22]Hawkins BT,Sykes DB,Miller DS.Rapid,reversible modulation of blood-brain barrier P-glycoprotein transport activity by vascular endothelial growth factor[J].J Neurosci,2010,30(4):1417-1425.
[23]姜元辉,石岚,姚远,等.针刺百会、腰奇穴对癫痫大鼠惊厥潜伏期及海马区NO、NOS、SOD影响的实验研究[J].慢性病学杂志,2016,17(3):259-266.
[24]孔素平,谭奇纹,于慧娟,等.电针夹脊穴对急性心肌缺血大鼠血清NO、ET及IL-1β的影响[J].世界中西医结合杂志,2011,6(4):333-334.
[25]胥虹贝,罗勇,朱艳含,等.电针通过e NOS促进局灶脑缺血/再灌注大鼠脑缺血皮质区血管再生[J].中国组织化学与细胞化学杂志,2015,24(5):381-387.
[26]朱艳含,罗勇,胥虹贝,等.电针介导e NOS动员内源性EPCs促MCAO/R大鼠脑内皮血管再生[J].中国实验动物学报,2015,23(3):291-296.
[27]王吉锡,张宏男,张玉瑶,等.针刺“百会”、“大椎”、“足三里”穴对AD模型大鼠学习记忆能力及脑组织内MAO、NOS表达的影响[J].中医药信息,2012,29(3):94-96.
[28]刘红,宋修涛,卢岩,等.电针对MCAO模型大鼠海马CA1区P-GP表达的影响[J].山东中医药大学学报,2010,34(3):260-262.
[29]俞坤强,李晓洁,彭洪卫,等.电针百会、神庭穴对MCAO大鼠学习记忆能力及IL-1β、TNF-α表达的影响[J].中国中医急症,2015,24(11):1891-1894.
[30]王鲜,黄佳,柳维林,等.电针对缺血再灌注损伤大鼠缺血周围区皮质小胶质细胞活化的影响[J].中国康复理论与实践,2015,21(11):1251-1255.
[31]孔立红,刘胜洪,毛娟娟,等.电针对脑缺血大鼠NF-κB及TNF-α表达的影响[J].中国康复医学杂志,2009,24(8):711-714.
[32]洪银珠,任秀君,施昱丞,等.电针干预对高血脂合并脑缺血大鼠血脂四项及TNF-α含量的影响[J].针灸临床杂志,2007,23(4):51-55.
[33]刑东.针刺预处理通过MMP9调节TJP诱导大鼠脑缺血耐受的研究[D].第四军医大学硕士学位论文,2015:12.
[34]乔云英,吴富东,王健,等.电针对佐剂性关节炎大鼠下丘脑中NF-KB表达的影响[J].中华中医药学刊,2011,29(6):1260-1262.
[35]尤艳利,徐晓明,舒适,等.电针水沟穴对MCAO模型大鼠缺血半暗带VEGF及arresten表达的影响[J].上海中医药大学学报,2014,28(6):80-84.
[36]林咸明,陈丽萍,姚旭.不同时程电针预处理对脑缺血再灌注大鼠血脑屏障基质金属蛋白酶-9、血管内皮生长因子的影响[J].针刺研究,2015,40(1):40-44.
[37]王储蓄.电针督脉组穴对血管性痴呆大鼠学习记忆与海马VEGF及其受体Flt-1、Flk-1m RNA表达的影响[D].安徽中医药大学硕士学位论文,2015:45.
[38]蔡荣林,程红亮,周婷,等.电针对血管性认知障碍大鼠学习记忆与海马内血管内皮生长因子及其受体1、2 m RNA表达的影响[J].针刺研究,2015,40(1):25-29.
[39]毛庆菊,陈邦国.电针对局灶性脑缺血再灌注大鼠大脑皮层微血管超微结构及血管内皮生长因子表达的影响[J].针刺研究,2012,37(6):476-481.
[40]张彤,林涛,王秀志,等.电针预处理对脑缺血再灌注大鼠骨髓和血浆中EPCs及VEGF的影响[J].中国康复医学杂志,2009,24(5):428-432.
[41]邹蓉.电针预处理对脑缺血再灌注大鼠脑内小窝蛋白-1以及血脑屏障通透性的影响[D].南京中医药大学,2014:33.