基于神经保护探讨豨莶通栓制剂抗脑缺血损伤的多靶点作用机制
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摘要
脑缺血再灌注是脑损伤和慢性神经病变的重要原因,过程主要涉及神经元损伤,包括酸中毒、谷氨酸兴奋性中毒、氧自由基释放和氧化应激反应以及细胞凋亡和炎症损伤过程,是一个快速级联反应过程,是多重机制共同参与的结果,仅针对某一靶点或某一环节进行干预具有局限性,因此应从多途径多环节进行预防与治疗。该文以豨莶通栓制剂为研究载体,收集方中13味中药的全部化学成分,通过反向找靶技术得到豨莶通栓制剂发挥神经保护药效的关键靶点,其中包含5个谷氨酸受体以及TGFR-1和VEGFR-2,利用分子对接技术筛选上述靶点的潜在活性成分并分析其作用机制,发现豨莶通栓制剂中新红花苷、新沙苑子苷等单一成分可同时作用于不同靶点,方中川芎、当归、红花、三七中的化学成分可同时作用于不同的与神经保护相关的靶点,体现了豨莶通栓制剂通过多成分作用于多靶点发挥保护神经元抗脑缺血损伤的作用,从分子层次阐释了豨莶通栓制剂在神经保护方面抗脑缺血损伤的多靶点作用机制,为豨莶通栓制剂的临床应用以及实验研究提供了一定的方向。
In this paper, Xixian Tongshuan Preparation was used as the research object, and all the chemical components of the 13 traditional Chinese medicines were collected. The target finding technique was used to obtain the key targets of the neuroprotective effect of Xixian Tongshuan Preparation, including 5 glutamate receptors, TGFR-1 and VEGFR-2. Molecular docking technology was used to screen out the potential active components of the above targets and to analyze their mechanism of action. It was found that single component, such as neo-complanatoside and neo-carthamin, in Xixian Tongshuan Preparation could simultaneously act on different targets. The chemical constituents in Ligusticum chuanxiong, Angelica sinensis, Carthamus tinctorius, and Panax pseudo-ginseng could simultaneously act on different neuroprotective-related targets, which reflected the application of multi-components to multi-targets. Point and multiple sites played a key role in protecting neurons against cerebral ischemic injury. This study explains the multi-target mechanism of anti-cerebral ischemic injury in neuroprotection at the molecular level, and provides a certain direction for the clinical application and experimental research of Xixian Tongshuan Preparation.
In this paper, Xixian Tongshuan Preparation was used as the research object, and all the chemical components of the 13 traditional Chinese medicines were collected. The target finding technique was used to obtain the key targets of the neuroprotective effect of Xixian Tongshuan Preparation, including 5 glutamate receptors, TGFR-1 and VEGFR-2. Molecular docking technology was used to screen out the potential active components of the above targets and to analyze their mechanism of action. It was found that single component, such as neo-complanatoside and neo-carthamin, in Xixian Tongshuan Preparation could simultaneously act on different targets. The chemical constituents in Ligusticum chuanxiong, Angelica sinensis, Carthamus tinctorius, and Panax pseudo-ginseng could simultaneously act on different neuroprotective-related targets, which reflected the application of multi-components to multi-targets. Point and multiple sites played a key role in protecting neurons against cerebral ischemic injury. This study explains the multi-target mechanism of anti-cerebral ischemic injury in neuroprotection at the molecular level, and provides a certain direction for the clinical application and experimental research of Xixian Tongshuan Preparation.
引文
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[2] 刘抒雯,杨丽华,马春,等.中医药保护脑缺血再灌注损伤后神经血管单元的作用[J].中国实验方剂学杂志,2018,24(23):225.
[3] 王华.滋肾通络方对局灶性脑缺血大鼠神经细胞保护作用的研究[D].济南:山东中医药大学,2009.
[4] Harukuni I,Bhardwaj A.Mechanism of brain injury after global cerebral ischemia[J].Neurol Clin,2006,24(1):1.
[5] Lewen A,Matz P,Chan P H.Free radical pathways in CNS injury[J].J Neurotraum,2000,17(10):871.
[6] Harms J E,Benveniste M,Maclean J K F,et al.Functional analysis of a novel positive allosteric modulator of AMPA receptors derived from a structure-based drug design strategy[J].Neuropharmacology,2013,64(1):45.
[7] 王华,刘慧敏,王贞.滋肾通络方对MCAO大鼠代谢性谷氨酸受体1α基因表达的影响[J].四川中医,2010(6):19.
[8] Jiang L,Zhang X,Chen X,et al.Virtual screening and molecular dynamics study of potential negative allosteric modulators of mGluR1 from Chinese herbs[J].Molecules,2015,20(7):12769.
[9] 路芳,蒋芦荻,陈艳昆,等.基于神经保护探讨补阳还五汤抗脑缺血损伤的多靶点作用机制[J].北京中医药大学学报,2016,39(9):744.
[10] 王真真.TGF-β1对溶栓后出血转换的预防作用[D].南京:南京医科大学,2012.
[11] 张东威,塔娜,呼布沁,等.VEGF及其受体表达与缺血性脑卒中的关系及研究进展[J].内蒙古民族大学学报:自然科学版,2017,32(6):547.
[12] 林国芳.当归多糖对脑缺血再灌注损伤大鼠海马神经元的保护作用[J].中草药,2015,46(4):558.
[13] 唐映红,黄小平,谭华,等.三七总皂苷对脑缺血再灌注后神经元凋亡及凋亡线粒体途径和c-Jun氨基末端激酶表达的影响[J].中国实验方剂学杂志,2010,16(16):129.
[14] 石进峰,张博爱,贾延劼,等.麝香提取物对大鼠皮层神经细胞炎性损伤的保护作用[J].中国中西医结合杂志,2010,30(6):625.
[15] 陈佳佳,刘金春,常磊,等.冰片及其类似物对谷氨酸诱导神经元细胞损伤的保护作用[J].南京医科大学学报:自然科学版,2013(5):630.
[16] 朱丽娟.补阳还五汤对全脑缺血再灌大鼠皮层神经元GluR2/NR1/NR2B的影响[D].广州:广州中医药大学,2012.
[17] 朱玲,夏军.豨莶通栓胶囊治疗痰瘀阻络型缺血性中风的临床观察[J].中医药导报,2015,21(9):82.
[18] 许荔新,李凤才,师海波,等.豨莶通栓胶囊药效学研究[J].中草药,1999(3):208.
[19] 陈志强,栾颖,王昌禄.大黄中大黄酚-8-O-β-D-吡喃葡萄糖苷的提取、纯化及含量测定方法的研究[J].中南药学,2008,6(2):153.
[20] 颜辉,边旭云.超声辅助提取红花总黄酮的研究[J].安徽农业科学,2008,36(31):13675.
[21] 王阿丽.红花红色苷的研究[D].重庆:重庆大学,2006.