补阳还五精简方脑健片治疗脑缺血后脑损伤的谱效关系和药代动力学数学模型研究
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摘要
目的：从整体动物、分子生物学、谱效关系和药代动力学四个方面着手,探讨脑健片抗脑缺血损伤的作用规律。通过建立局灶性脑缺血大鼠模型,研究补阳还五汤精简方脑健片对脑缺血大鼠脑损伤的保护作用及对大鼠海马组织周期蛋白CyclinB1和CyclinB2表达的影响；结合Matlab软件编程分析脑健片药效成分与脑损伤保护作用之间的谱效关系和药代动力学变化,探讨补阳还五汤全方和脑健片的药效物质基础及作用规律,并建立了补阳还五汤全方和脑健片的药代动力学数学模型,为脑健片临床应用的有效性提供科学的实验依椐。
方法：采用大脑中动脉线栓法建立局灶性脑缺血大鼠模型,将动物随机分为假手术组、模型组、补阳还五汤组、脑健片高、中、低剂量组。称取各组大鼠1d到7d的体重,并将各组大鼠于7d做神经功能评分,处理后TTC计算其梗死面积；于1d、3d、7d、14d、28d取脑组织进行WB、RT-PCR实验,检测其海马组织周期蛋白Cyclin B1和CyclinB2表达。运用PCA和GRA法对实验结果进行分析,获得补阳还五汤和脑健片指纹图谱与神经功能评分、脑梗死面积、脑干湿比等药效指标和周期蛋白Cyclin B1和Cyclin B2之间关系,并基于曲线拟合法建立其药代动力学数学模型。
结果：
(1)结合卡方拟合优度检验和两组独立样本T检验法,运用matlab编程分析的结果：脑健片组与模型组相比较,大鼠体重、脑干湿重比值明显增加(P<0.05),脑梗死面积(P<0.05)明显降低,且脑健片中剂量组对脑缺血的治疗效果最佳,其疗效略优于补阳还五汤组(正常人体剂量)。
(2)WB和RT-PCR检测结果表明：脑健片组与模型组相比较,能有效降低周期蛋白Cyclin B1和Cyclin B2表达,差异具有统计学意义(P<0.05),脑健片组和补阳还五汤全方组间对Cyclin B1和CyclinB2表达的调控作用没有显著差异(P>0.05)。
(3)谱效关系研究结果显示：脑健片和补阳还五汤样品共有峰排名均大于其各自的特有峰,且保留时间为tR=20.649、6.474、26.404min的化学成分对神经功能评分、脑梗死面积、脑干湿比、周期蛋白CyclinB1和Cyclin B2的贡献度排在前五位。
(4)药代动力学模型评价的结果显示：脑健片和补阳全方对阿魏酸与槀本内酯的吸收分布和消除无明显差异(P>0.05),但补阳全方中的洋川芎内酯A更容易被体内吸收、分布和消除。
结论：
(1)脑健片能有效改善神经功能症状、缩小脑梗死面积、减轻脑水肿,显著降低脑缺血模型大鼠海马组织cyclins B1、cyclins B2的表达,且其作用与补阳还五汤全方相当。
(2)脑健片中指纹图谱保留时间为tR=20.649、6.474、26.404min的化学成分对调控脑缺血损伤和干预周期蛋白起到关键作用,推测是其主要药效物质基础,且其作用机制可能与海马组织神经细胞周期的调控作用有关。
(3)脑健片和补阳还五汤对阿魏酸与槀本内酯的吸收、分布和消除无明显差异,但洋川芎内酯A的吸收分布和消除具有显著性差异,此种差异是否会影响脑健片的药效,有待进一步研究。
(4) PCA-GRA方法能客观评价中药复方的谱效关系,是一种值得借鉴的好方法。
(5)基于曲线拟合的方法,结合matlab科学工具编程,建立了符合脑健片和补阳还五汤全方中阿魏酸、洋川芎内酯A、桑本内酯三种成分的药代动力学模型,能有效、客观的评价药物在体内的吸收、分布和消除过程,且数学模型的拟合结果优于传统二室模型,为中药复方药代动力学研究提供了新思路。
(6)脑健片在治疗脑缺血方面具有良好的优势,符合中风患者的需求,为指导临床合理用药提供了理论依据。
Objective:From four aspects of Animal, Molecular Biology, spectrum-effect relationship and pharmacokinetics, study on the protective effect of cerebral ischemic injury.On the basis of the establishment of focal cerebral ischemia in rats, to study the protective effect of Naojian Tablet (the thin recipe of Buyanghuanwu), which is based on the method of benefiting vital energy, removing stasis and producing new, on cerebral ischemia injury in rat and the effect on the expression of hippocampal tissue cyclin, CyclinB1and CyclinB2. On this basis, combined with matlab software programming to analyze the spectrum-effect relationship between the effective component of Naojian Tablet and the protective effect on cerebral injury, as well as the pharmacokinetics,and to investigate the the material basis for efficacy and law of action of Buyanghuanwu recipe and Naojian Tablet, and to establish mathematical model fitting the spectrum-effect relationship and pharmacokinetics of Buyanghuanwu recipe and Naojian Tablet, providing scientific experiments basis for the effectiveness of clinical applications of Naojian Tablet.
Methods:The rat model of focal cerebral ischemia was built using middle cerebral artery occlusion, and the animals were randomly divided into sham operation group, model group, Buyanghuanwu Decoction (BYHWD) group, the high, medium and low dose of Naojian Tablet groups. The rats of each group were weighed at1d to7d, and the neurological score of the rats of each group was evaluated at7d, which was used to calculate infarct size with TTC after processing. The brain tissue was taken at1d,3d,7d,14d,28d to run WB, RT-PCR experiments to test the expression of their hippocampus cyclin, Cyclin B1and Cyclin B2. The experimental results were analyzed with PCA and GRA method to obtain the relationship between the fingerprints of BYHWD and Naojian Tablet, the pharmacodynamic indexes such as neurological score, cerebral infarct size, and dry-wet ratio of brain, and the Cyclin B1and Cyclin B2, then the spectrum-effect relationship and pharmacokinetics mathematical model was established based on curve-fitting method.
Results:
(1) Compared with the model group, body weight of rats in Naojian Tablet group increased significantly (P<0.05), neurological score (P<0.05), infarct size (P<0.05) and brain dry-wet ratio (P<0.05) were significantly decreased, and the medium dose group of Naojian Tablet had the optimal therapeutic effect on cerebral ischemia, which efficacy is slightly better than BYHWD group (normal human dose).
(2) The test results of WB and RT-PCR showed that, compared with the model group, the expression of Cyclin B1and Cyclin B2can be reduced effectively in Naojian Tablet group, the difference was statistically significant (P<0.05), the regulation of Naojian Tablet on cyclin was most obvious at7d (P<0.05); the expression of Cyclin B1and Cyclin B2had no significant difference between Naojian Tablet group and BYHWD group (P>0.05).
(3) The study result of spectrum-effect relationship showed that, for the samples of Naojian Tablet and BYHWD, the ranking of common peaks was larger than their respective unique peaks, and the contributions of chemical components at the retention time tR=20.649,6.474and26.404min on neurological score, infarct size, brain dry-wet ratio as well as Cyclin B1and Cyclin B2were of the top five.
(4) The results of evaluation of pharmacokinetics model showed that there was no significant difference (P>0.05) between Naojian Tablet and BYHWD on the absorption, distribution and elimination of ferulic acid and ligustilide, but the senkyunolide in BYHWD was more easily absorbed、distributed and eliminated in body.
Conclusion:
(1) Naojian Tablet can improve neurological symptoms, reduce infarct size, relieve cerebral edema effectively, confirming that Naojian Tablet has protective effect on cerebral ischemia injury, and its effect is equivalent to the whole receipt of BYHWD. 40
(2) Naojian Tablet can significantly reduce the expression of hippocampus Cyclins B1and Cyclins B2in cerebral ischemia model rats, and its effect is equivalent to the whole receipt of BYHWD.
(3) The chemical compositions of tR=20.649,6.474and26.404min in the fingerprinting spectrum of Naojian Tablet may play a key role in regulation of cerebral ischemic injury and intervention of cyclin, which were speculated as its primary efficacy material basis.
(4) There is no significant difference between Naojian Tablet and BYHWD on the absorption, distribution and elimination of ferulic acid and ligustilide, but the absorption, distribution and elimination of senkyunolide A has significant difference, on which a follow-up in-depth investigation can be carried on.
(5) The spectrum-effect relationship of traditional Chinese medicine compound can be objectively evaluated based on PCA-GRA method, which is a good method worth learning.
(6) The pharmacokinetic mathematical model established based on curve fitting method combined with matlab programming can effectively and objectively evaluate the absorption, distribution and elimination of drug in body, providing a new thought for the follow-up study of pharmacokintrics.
(7) Naojian Tablet have a good advantage in the treatment of cerebral ischemia, according with the needs of stroke patients, which provides a theoretical basis for indicating theclinical rational medication.
方法：采用大脑中动脉线栓法建立局灶性脑缺血大鼠模型,将动物随机分为假手术组、模型组、补阳还五汤组、脑健片高、中、低剂量组。称取各组大鼠1d到7d的体重,并将各组大鼠于7d做神经功能评分,处理后TTC计算其梗死面积；于1d、3d、7d、14d、28d取脑组织进行WB、RT-PCR实验,检测其海马组织周期蛋白Cyclin B1和CyclinB2表达。运用PCA和GRA法对实验结果进行分析,获得补阳还五汤和脑健片指纹图谱与神经功能评分、脑梗死面积、脑干湿比等药效指标和周期蛋白Cyclin B1和Cyclin B2之间关系,并基于曲线拟合法建立其药代动力学数学模型。
结果：
(1)结合卡方拟合优度检验和两组独立样本T检验法,运用matlab编程分析的结果：脑健片组与模型组相比较,大鼠体重、脑干湿重比值明显增加(P<0.05),脑梗死面积(P<0.05)明显降低,且脑健片中剂量组对脑缺血的治疗效果最佳,其疗效略优于补阳还五汤组(正常人体剂量)。
(2)WB和RT-PCR检测结果表明：脑健片组与模型组相比较,能有效降低周期蛋白Cyclin B1和Cyclin B2表达,差异具有统计学意义(P<0.05),脑健片组和补阳还五汤全方组间对Cyclin B1和CyclinB2表达的调控作用没有显著差异(P>0.05)。
(3)谱效关系研究结果显示：脑健片和补阳还五汤样品共有峰排名均大于其各自的特有峰,且保留时间为tR=20.649、6.474、26.404min的化学成分对神经功能评分、脑梗死面积、脑干湿比、周期蛋白CyclinB1和Cyclin B2的贡献度排在前五位。
(4)药代动力学模型评价的结果显示：脑健片和补阳全方对阿魏酸与槀本内酯的吸收分布和消除无明显差异(P>0.05),但补阳全方中的洋川芎内酯A更容易被体内吸收、分布和消除。
结论：
(1)脑健片能有效改善神经功能症状、缩小脑梗死面积、减轻脑水肿,显著降低脑缺血模型大鼠海马组织cyclins B1、cyclins B2的表达,且其作用与补阳还五汤全方相当。
(2)脑健片中指纹图谱保留时间为tR=20.649、6.474、26.404min的化学成分对调控脑缺血损伤和干预周期蛋白起到关键作用,推测是其主要药效物质基础,且其作用机制可能与海马组织神经细胞周期的调控作用有关。
(3)脑健片和补阳还五汤对阿魏酸与槀本内酯的吸收、分布和消除无明显差异,但洋川芎内酯A的吸收分布和消除具有显著性差异,此种差异是否会影响脑健片的药效,有待进一步研究。
(4) PCA-GRA方法能客观评价中药复方的谱效关系,是一种值得借鉴的好方法。
(5)基于曲线拟合的方法,结合matlab科学工具编程,建立了符合脑健片和补阳还五汤全方中阿魏酸、洋川芎内酯A、桑本内酯三种成分的药代动力学模型,能有效、客观的评价药物在体内的吸收、分布和消除过程,且数学模型的拟合结果优于传统二室模型,为中药复方药代动力学研究提供了新思路。
(6)脑健片在治疗脑缺血方面具有良好的优势,符合中风患者的需求,为指导临床合理用药提供了理论依据。
Objective:From four aspects of Animal, Molecular Biology, spectrum-effect relationship and pharmacokinetics, study on the protective effect of cerebral ischemic injury.On the basis of the establishment of focal cerebral ischemia in rats, to study the protective effect of Naojian Tablet (the thin recipe of Buyanghuanwu), which is based on the method of benefiting vital energy, removing stasis and producing new, on cerebral ischemia injury in rat and the effect on the expression of hippocampal tissue cyclin, CyclinB1and CyclinB2. On this basis, combined with matlab software programming to analyze the spectrum-effect relationship between the effective component of Naojian Tablet and the protective effect on cerebral injury, as well as the pharmacokinetics,and to investigate the the material basis for efficacy and law of action of Buyanghuanwu recipe and Naojian Tablet, and to establish mathematical model fitting the spectrum-effect relationship and pharmacokinetics of Buyanghuanwu recipe and Naojian Tablet, providing scientific experiments basis for the effectiveness of clinical applications of Naojian Tablet.
Methods:The rat model of focal cerebral ischemia was built using middle cerebral artery occlusion, and the animals were randomly divided into sham operation group, model group, Buyanghuanwu Decoction (BYHWD) group, the high, medium and low dose of Naojian Tablet groups. The rats of each group were weighed at1d to7d, and the neurological score of the rats of each group was evaluated at7d, which was used to calculate infarct size with TTC after processing. The brain tissue was taken at1d,3d,7d,14d,28d to run WB, RT-PCR experiments to test the expression of their hippocampus cyclin, Cyclin B1and Cyclin B2. The experimental results were analyzed with PCA and GRA method to obtain the relationship between the fingerprints of BYHWD and Naojian Tablet, the pharmacodynamic indexes such as neurological score, cerebral infarct size, and dry-wet ratio of brain, and the Cyclin B1and Cyclin B2, then the spectrum-effect relationship and pharmacokinetics mathematical model was established based on curve-fitting method.
Results:
(1) Compared with the model group, body weight of rats in Naojian Tablet group increased significantly (P<0.05), neurological score (P<0.05), infarct size (P<0.05) and brain dry-wet ratio (P<0.05) were significantly decreased, and the medium dose group of Naojian Tablet had the optimal therapeutic effect on cerebral ischemia, which efficacy is slightly better than BYHWD group (normal human dose).
(2) The test results of WB and RT-PCR showed that, compared with the model group, the expression of Cyclin B1and Cyclin B2can be reduced effectively in Naojian Tablet group, the difference was statistically significant (P<0.05), the regulation of Naojian Tablet on cyclin was most obvious at7d (P<0.05); the expression of Cyclin B1and Cyclin B2had no significant difference between Naojian Tablet group and BYHWD group (P>0.05).
(3) The study result of spectrum-effect relationship showed that, for the samples of Naojian Tablet and BYHWD, the ranking of common peaks was larger than their respective unique peaks, and the contributions of chemical components at the retention time tR=20.649,6.474and26.404min on neurological score, infarct size, brain dry-wet ratio as well as Cyclin B1and Cyclin B2were of the top five.
(4) The results of evaluation of pharmacokinetics model showed that there was no significant difference (P>0.05) between Naojian Tablet and BYHWD on the absorption, distribution and elimination of ferulic acid and ligustilide, but the senkyunolide in BYHWD was more easily absorbed、distributed and eliminated in body.
Conclusion:
(1) Naojian Tablet can improve neurological symptoms, reduce infarct size, relieve cerebral edema effectively, confirming that Naojian Tablet has protective effect on cerebral ischemia injury, and its effect is equivalent to the whole receipt of BYHWD. 40
(2) Naojian Tablet can significantly reduce the expression of hippocampus Cyclins B1and Cyclins B2in cerebral ischemia model rats, and its effect is equivalent to the whole receipt of BYHWD.
(3) The chemical compositions of tR=20.649,6.474and26.404min in the fingerprinting spectrum of Naojian Tablet may play a key role in regulation of cerebral ischemic injury and intervention of cyclin, which were speculated as its primary efficacy material basis.
(4) There is no significant difference between Naojian Tablet and BYHWD on the absorption, distribution and elimination of ferulic acid and ligustilide, but the absorption, distribution and elimination of senkyunolide A has significant difference, on which a follow-up in-depth investigation can be carried on.
(5) The spectrum-effect relationship of traditional Chinese medicine compound can be objectively evaluated based on PCA-GRA method, which is a good method worth learning.
(6) The pharmacokinetic mathematical model established based on curve fitting method combined with matlab programming can effectively and objectively evaluate the absorption, distribution and elimination of drug in body, providing a new thought for the follow-up study of pharmacokintrics.
(7) Naojian Tablet have a good advantage in the treatment of cerebral ischemia, according with the needs of stroke patients, which provides a theoretical basis for indicating theclinical rational medication.
引文
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[1]武孔云,梁光义,靳凤云,等.中药复方药效物质基础研究的思路和方法[J].世界科学技术-中医药现代化,2003,5(6)：13-16.
[2]王秀兰.传统复方有效物质研究概况[J].中国民族医药杂志,2005,41(1)：41-42.
[3]薛燕.中药复方霰弹理论[M].北京：中国环境科学出版社,1996：218-220.
[4]谢鸣.中药复方新药研制的思路与问题探讨[J].北京中医药大学学报,1996,19(5)：15-18.
[5]黄熙,任平.防治高血压、冠心病难点与突破口：方剂的药物监测[J].中国中医结合杂 志,1997,17(9)：515-515.
[6]黄熙.方剂体内/血清成分谱与靶成分概念的提出及意义[J].第四军医大学学报,1999,20(4)：277-279.
[7]邱峰,姚新生.中药体内直接物质基础研究的新思路[J].中药药理与临床,1999,15(3)：1-2.
[8]吴凤锷,吴蔚,田军.中药现代化的理论和方法研究[J].天然产物研究与开发,1999,11(2)：93-97.
[9]罗国安,王义明.中药复方的化学研究体系[J].世界科学技术-中药现代化,1999,综述一、中药复方物质基础研究进展171：16-19.
[10]罗国安,王义明.中药复方物质基础和药效相关性研究[J].世界科学技术-中药现代化,1999.1：11-15.
[11]王本祥,周秋丽.关于中药活性成分的认识及其研究方法[J].中国中药杂志,2001,26(1)：10-13.
[12]杜冠华.中药复方有效成分组学研究[J].中成药,2002,24(11)：878-880.
[13]马春涛,雷燕.中药复方效应物质基础的研究进展及展望[J].中国实验方剂学杂志,2003,9(3)：46-49.
[14]刘建勋,任钧国.中药复方作用物质基础研究探讨[J].中药研究与信息,2004,6(12)：8-11.
[15]谢鸣.关于中医药研究及发展的思考.北京中医药大学学报[J].2000,23(2)：2-5.
[16]王胜春,胡咏武,王俊琴,等.五灵胶囊药效作用的有效成分[J].第四军医大学学报,2004,25(17)：1587-1591.
[17]Yang, Hong. Study on compatibility of traditional Chinese medicine active constituents with antioxidant activity. Zhongguo Zhong yao za zhi=Zhongguo zhongyao zazhi=China journal of Chinese materia medica.2012 Jun;37(12):1826-9.
[18]Georgiadou. Effects of the active constituents of Crocus Sativus L., crocins, in an animal model of obsessive-compulsive disorder. Phytomedicine:international journal of phytotherapy and phytopharmacology.2012 Oct 15;19(13):1185-90.
[19]Ghosh Soma. Evaluation of the wound healing activity of methanol extract of Pedilanthus tithymaloides (L.) Poit leaf and its isolated active constituents in topical formulation. Journal of ethnopharmacology.2012 Aug 1;142(3):714-22.
[20]孙慧兰,吴伟康.四逆汤有效成分不同组合抗心肌缺血再灌注损伤的作用研究[J].中草药,2002,33(4)：333-336.
[21]野村麻乃.半夏泻心汤对自身免疫性结肠炎模型大鼠的作用及其有效成分[J].国外医学中医中药分册,2005,27(3)：186-186.
[22]黄兆胜,危建安,吴利.当归补血汤益气功效及其物质基础研究[J].中药药理与临床,2003,19(1)：5-7.
[23]黄兆胜,危建安,吴利.当归补血汤补血功效及其物质基础研究(二)[J].中药药理与临床,2003,19(5)：10-11.
[24]熊玉霞,孟宪丽,张艺,等.泻心汤抗内毒素有效部位的初步筛选[J].中草药,2006,37(12)：1844-1847.
[25]梁乾德,路晓钦,马增春,等.四物汤促进造血功能成分的初步研究[J].中国中药杂志,2004,29(6)：546-549.
[26]尹莲,徐立,时乐,等.加味四妙丸有致部位群的筛选研究[J].世界科学技术-中医药现代化,2005,7(4)：29-33.
[27]宋宗华,冯东,许俊博,等.苓桂术甘汤配伍机制及药效物质基础研究[J].中成药,2003,25(2)：133-138.
[28]刘曼,刘惠平,梁茂新,等.骨疏丹指纹图谱分析及其活性相关性研究[J].沈阳药科大学学报,2007,24(12)：758-762.
[29]窦志华,罗琳,丁安伟,等.复方五仁醇胶囊含药血清指纹图谱与保肝作用的谱效关系[J].南第四军医大学学报,2008,29(2)：116-118.
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