灯盏细辛脑靶向神经保护药效物质基础研究
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摘要
脑缺血,中医称为“中风”或“脑卒中”,是一个复杂的病理级联反应机制,其核心问题是神经元损害引起的神经功能障碍,因此,对脑缺血脑神经保护的治疗就很必要。中医的整体观、中药的复杂性和作用机制的多样性,使其在脑缺血损伤的神经保护治疗上独具优势。很多治疗脑缺血中药制剂在临床上疗效肯定,但由于缺乏更深入研究,药效物质基础尚未明确。目前在中药及天然药脑神经保护药物研究中,由于筛选的活性成分生物利用度低,尤其难透过血脑屏障,所以难以应用于临床。因此本文从现有制剂入手,提出了“中药及其制剂→脑神经保护+透过血脑屏障→中药脑靶向神经保护药效物质基础”的研究思路。
灯盏细辛来源于菊科飞蓬属植物短葶飞蓬(Erigeron breviscapus(Vant.)Hand.-Mazz.),始载于《滇南本草》,其记载有:“左瘫右痪,水煎点水酒服。”灯盏细辛药材、灯盏细辛注射液现已收载于《中华人民共和国药典》(2005年版·一部)。由于灯盏细辛对心脑血管疾病临床治疗上的优势,灯盏细辛注射液、灯盏花素注射液、灯盏花素片等制剂已广泛应用于临床。灯盏细辛治疗脑缺血、中风后遗症等缺血性脑血管病的研究,主要是从改善血液流变性、缺血再灌注损伤的保护、抗脑血栓等方面进行,而其脑神经保护与及透血脑屏障药效物质基础尚不明确。
目的:本文从临床制剂有效性出发,从药物成分透血脑屏障与脑神经保护作用入手,研究灯盏细辛治疗脑缺血脑靶向神经保护药效物质基础。
方法:
1.采用HPLC法建立了灯盏细辛不同制剂的HPLC指纹图谱研究;采用毛细管电泳-间接化学发光联用(CE-CL)方法,进行了灯盏细辛注射液抗氧化作用有效组分的指纹图谱研究。
2.采用正反相硅胶、聚酰胺柱色谱和制备HPLC等现代提取分离方法对灯盏细辛进行了系统的提取分离,采用~1H-NMR、~(13)C-NMR、MS等波谱技术进行结构鉴定。同时采用酯化和酰化对咖啡酸和野黄芩苷进行了结构修饰。
3.采用体外培养大鼠大脑皮层神经细胞,MTT法测定细胞存活率,评价灯盏细辛制剂脑神经保护活性,并筛选灯盏细辛脑神经保护有效成分。
4.采用体外共培养原代大鼠脑微血管内皮细胞(BMVEC)和星型胶质细胞(AC),建立体外血脑屏障模型(BBBM),采用HPLC检测透血脑屏障有效成分。
结果:
1.灯盏细辛制剂主要化学组分为野黄芩苷、咖啡酸、二咖啡酰奎宁酸等黄酮和咖啡酰类成分,灯盏细辛注射液中有野黄芩苷等四个抗氧化作用有效组分。
2.分离出12个化合物,鉴定了其中9个化合物的结构,分别是:野黄芩苷、野黄芩素、芹菜素、芹菜素-7-O-葡萄糖醛酸、1,5-咖啡酰奎宁酸、3,4-咖啡酰奎宁酸、木栓酮、豆甾醇、正十四脂肪酸。结构修饰,得到咖啡酸甲酯、咖啡酸乙酯、3,4-二乙酰基咖啡酸、野黄芩素、野黄芩苷乙酯五种衍生物。
3.灯盏细辛注射液、灯盏花素注射液等制剂具有促进大脑皮层神经细胞存活的作用;灯盏细辛中主要化学成分野黄芩苷、芹菜素-7-O-葡萄糖醛酸等黄酮类成分,以及咖啡酸、二咖啡酰奎宁酸类成分也促进大脑皮层神经细胞存活的作用。咖啡酸和野黄芩苷的结构修饰后衍生物均有一定的脑神经保护作用。
4.1,5-DCQ、3,5-DCQ、3,4-DCQ、芹菜素-7-O-葡萄糖醛酸,均可不同程度透过BBBM。咖啡酸和野黄芩苷的结构修饰后产物中,咖啡酸甲酯、3,4-二乙酰基咖啡酸、野黄芩苷乙酯可透过BBBM。
结论:
1.灯盏细辛及其制剂中主要含有黄酮和咖啡酰类成分,灯盏细辛注射液、灯盏花素注射液等制剂具有脑神经保护作用;灯盏细辛中主要脑神经保护的有效成分为野黄芩苷、芹菜素-7-O-葡萄糖醛酸等黄酮类成分,以及咖啡酸、二咖啡酰奎宁酸类成分。灯盏细辛中野黄芩苷的神经保护作用可能与其清除氧自由基有关。
2.1,5-DCQ、3,5-DCQ、3,4-DCQ、芹菜素-7-O-葡萄糖醛酸,均可不同程度透过BBBM,它们为灯盏细辛脑靶向神经保护药效物质基础。
3.咖啡酸和野黄芩苷结构修饰后产物,均由亲水性变为亲脂性,油水分配系数提高了约10~3-10~5倍,其中咖啡酸甲酯、3,4-二乙酰基咖啡酸、野黄芩苷乙酯均为脑靶向神经保护有效成分。
创新点:
1.本文基本建立从现有临床确有疗效中药制剂出发,进行“中药及其制剂→脑神经保护+透过血脑屏障→中药脑靶向神经保护药效物质基础”的新模式。
2.采用体外共培养BBBM和大脑皮层神经细胞培养,基本阐明灯盏细辛透血脑屏障神经保护有效成分。
Cerebral ischemia,known as the "stroke" in Chinese medicine,is a complex mechanism of cascade of pathological,and its core problem is nerval dysfunction caused by neural damage.Therefore,the neuroprotection is of great necessity to the treatment.Because of the overall concept,the complexity,and the diversity of the mechanism,Chinese medicine has great advantages in the therapy of cerebral ischemic on the neuroprotection.But the active components from Chinese medicine and natural medicine have low bioavailability and are difficult through the blood-brain barrier,so they are difficult to clinical application.In this paper,regarding exist preparation as the breakthrough point,the research idea is "traditional Chinese medicine→the blood-brain barrier+neuroprotection→brain-targeting effective components of neuroprotective"
Erigeron breviscapus(Vant.) Hand.-Mazz.was firstly recorded in Yunnan Materia Medica.Erigeron breviscapus and Erigeron injection are contained in "People's Republic of China Pharmacopoeia"(2005).Erigeron injection,erigeron injection,tablets,et al.have been widely used in clinical.At present,the improved blood rheology,ischemia-reperfusion injury protection and anti-cerebral thrombosis are mainly studied on Erigeron breviscapus,however,the effective components of cerebral neuroprotective and the blood-brain barrier permeability are not yet clear.
Objective:To study on the clinic efficacy of preparations,based on the blood-brain barrier permeability and nerve protection mechanism,the effective substance of the treatment of cerebral ischemia,of E.breviscapus has been studied.
Methods:
1.To establish HPLC fingerprints of the different preparations of erigeron was analyzed the effective components of antioxidant activity of erigeron injection by CE-CL.
2.To extract and isolate the compounds of E.breviscapus by silica gel,ODS, polyamide column chromatography and HPLC,their structures were characterized by ~1H-NMR,~(13)C-NMR and MS.With the method of esterifying and acetyling, derivatives were synthesized.
3.To cultivate rat cerebral conical neurons cell in vitro and determine the survival rate by MTT,the neuroprotection activity of erigeron preparations and E. breviscapus was evaluated,with neuroprotection active ingredients screened.
4.To co-culture BMVEC and AC in vitro,blood-brain barrier model(BBBM) was established with the active components analysized by HPLC.
Result:
1.The main chemical group of Erigeron preparation are contain with scutellarin, caffeic acid,double caffeoyl quinic acid such as flavonoids and caffeoyl-constituents. And erigeron injections had four effective ingredients.
2.12 compounds were isolated,with 9 identified,as follows:scutellarin, scutellarein,apigenin,apigenin-7-O-glucuronic acid,1,5-di-O-caffeoyl quinic acid, 3,4-di-O-caffeoyl quinic acid,friedelin,stigmasterol,fourteen acids.At the same time,after structurally modified,synthesis caffeoyl methyl ester,caffeoyl ethyl ester, 3,4-diacetyl-caffeic,scutellarin and glycolamide were gained.
3.The preparations,such as erigeron injection,scutellarin injection,and so on, could promote the survival of nerve cell in vitro,so did the flavonoids of scutellarin, apigenin-7-O-glucuronic acid,the caffeoyl constituents of caffeic acid,double caffeoyl quinic acid and the derivatives of caffeic acid and scutellarin.
4.The blood-brain barrier model in vitro was successful.1,5-DCQ,3,5-DCQ, 3,4-DCQ,apigenin-7-O-glucuronic,could pass through BBBM,so did coffee methyl ester,3,4-diacetyl-caffeic acid,glycolamide ester of scutellarin.
Conclusion:
1.Erigeron preparation and E.breviscapus mainly contain flavonoids and double caffeoyl quinic acids.The neuroprotective compounds are scutellarin,caffeic acid, 1,5-DCQ,3,5-DCQ,3,4-DCQ and so on.The neuroprotection of scutellarin are related on the antioxidant activity.
2.The brain-targeting effective components of neuroprotective from Erigeron are 1,5-DCQ,3,5-DCQ,3,4-DCQ,apigenin-7-O-glucuronic.
3.The products of the structural modification of caffeic acid and scutellarin have changed from hydrophilicity to lipophilicify,which the oil-water partition coefficient increases about 10~3～10~5.Coffee methyl ester,3,4-diacetyl-caffeic acid,glycolamide ester of scutellarin are also the brain-targeting effective components of neuroprotective.
Innovation:
1.The research idea is "Traditional Chinese medicine→through the blood-brain barrier+neuroprotection→brain-targeting effective components of neuroprotective"
2.The effective components of neuroprotective of E.breviscapus has essentially evaluated by co-cultured in vitro rat brain microvascular endothelial cells and brain microvascular endothelial cells.
灯盏细辛来源于菊科飞蓬属植物短葶飞蓬(Erigeron breviscapus(Vant.)Hand.-Mazz.),始载于《滇南本草》,其记载有:“左瘫右痪,水煎点水酒服。”灯盏细辛药材、灯盏细辛注射液现已收载于《中华人民共和国药典》(2005年版·一部)。由于灯盏细辛对心脑血管疾病临床治疗上的优势,灯盏细辛注射液、灯盏花素注射液、灯盏花素片等制剂已广泛应用于临床。灯盏细辛治疗脑缺血、中风后遗症等缺血性脑血管病的研究,主要是从改善血液流变性、缺血再灌注损伤的保护、抗脑血栓等方面进行,而其脑神经保护与及透血脑屏障药效物质基础尚不明确。
目的:本文从临床制剂有效性出发,从药物成分透血脑屏障与脑神经保护作用入手,研究灯盏细辛治疗脑缺血脑靶向神经保护药效物质基础。
方法:
1.采用HPLC法建立了灯盏细辛不同制剂的HPLC指纹图谱研究;采用毛细管电泳-间接化学发光联用(CE-CL)方法,进行了灯盏细辛注射液抗氧化作用有效组分的指纹图谱研究。
2.采用正反相硅胶、聚酰胺柱色谱和制备HPLC等现代提取分离方法对灯盏细辛进行了系统的提取分离,采用~1H-NMR、~(13)C-NMR、MS等波谱技术进行结构鉴定。同时采用酯化和酰化对咖啡酸和野黄芩苷进行了结构修饰。
3.采用体外培养大鼠大脑皮层神经细胞,MTT法测定细胞存活率,评价灯盏细辛制剂脑神经保护活性,并筛选灯盏细辛脑神经保护有效成分。
4.采用体外共培养原代大鼠脑微血管内皮细胞(BMVEC)和星型胶质细胞(AC),建立体外血脑屏障模型(BBBM),采用HPLC检测透血脑屏障有效成分。
结果:
1.灯盏细辛制剂主要化学组分为野黄芩苷、咖啡酸、二咖啡酰奎宁酸等黄酮和咖啡酰类成分,灯盏细辛注射液中有野黄芩苷等四个抗氧化作用有效组分。
2.分离出12个化合物,鉴定了其中9个化合物的结构,分别是:野黄芩苷、野黄芩素、芹菜素、芹菜素-7-O-葡萄糖醛酸、1,5-咖啡酰奎宁酸、3,4-咖啡酰奎宁酸、木栓酮、豆甾醇、正十四脂肪酸。结构修饰,得到咖啡酸甲酯、咖啡酸乙酯、3,4-二乙酰基咖啡酸、野黄芩素、野黄芩苷乙酯五种衍生物。
3.灯盏细辛注射液、灯盏花素注射液等制剂具有促进大脑皮层神经细胞存活的作用;灯盏细辛中主要化学成分野黄芩苷、芹菜素-7-O-葡萄糖醛酸等黄酮类成分,以及咖啡酸、二咖啡酰奎宁酸类成分也促进大脑皮层神经细胞存活的作用。咖啡酸和野黄芩苷的结构修饰后衍生物均有一定的脑神经保护作用。
4.1,5-DCQ、3,5-DCQ、3,4-DCQ、芹菜素-7-O-葡萄糖醛酸,均可不同程度透过BBBM。咖啡酸和野黄芩苷的结构修饰后产物中,咖啡酸甲酯、3,4-二乙酰基咖啡酸、野黄芩苷乙酯可透过BBBM。
结论:
1.灯盏细辛及其制剂中主要含有黄酮和咖啡酰类成分,灯盏细辛注射液、灯盏花素注射液等制剂具有脑神经保护作用;灯盏细辛中主要脑神经保护的有效成分为野黄芩苷、芹菜素-7-O-葡萄糖醛酸等黄酮类成分,以及咖啡酸、二咖啡酰奎宁酸类成分。灯盏细辛中野黄芩苷的神经保护作用可能与其清除氧自由基有关。
2.1,5-DCQ、3,5-DCQ、3,4-DCQ、芹菜素-7-O-葡萄糖醛酸,均可不同程度透过BBBM,它们为灯盏细辛脑靶向神经保护药效物质基础。
3.咖啡酸和野黄芩苷结构修饰后产物,均由亲水性变为亲脂性,油水分配系数提高了约10~3-10~5倍,其中咖啡酸甲酯、3,4-二乙酰基咖啡酸、野黄芩苷乙酯均为脑靶向神经保护有效成分。
创新点:
1.本文基本建立从现有临床确有疗效中药制剂出发,进行“中药及其制剂→脑神经保护+透过血脑屏障→中药脑靶向神经保护药效物质基础”的新模式。
2.采用体外共培养BBBM和大脑皮层神经细胞培养,基本阐明灯盏细辛透血脑屏障神经保护有效成分。
Cerebral ischemia,known as the "stroke" in Chinese medicine,is a complex mechanism of cascade of pathological,and its core problem is nerval dysfunction caused by neural damage.Therefore,the neuroprotection is of great necessity to the treatment.Because of the overall concept,the complexity,and the diversity of the mechanism,Chinese medicine has great advantages in the therapy of cerebral ischemic on the neuroprotection.But the active components from Chinese medicine and natural medicine have low bioavailability and are difficult through the blood-brain barrier,so they are difficult to clinical application.In this paper,regarding exist preparation as the breakthrough point,the research idea is "traditional Chinese medicine→the blood-brain barrier+neuroprotection→brain-targeting effective components of neuroprotective"
Erigeron breviscapus(Vant.) Hand.-Mazz.was firstly recorded in Yunnan Materia Medica.Erigeron breviscapus and Erigeron injection are contained in "People's Republic of China Pharmacopoeia"(2005).Erigeron injection,erigeron injection,tablets,et al.have been widely used in clinical.At present,the improved blood rheology,ischemia-reperfusion injury protection and anti-cerebral thrombosis are mainly studied on Erigeron breviscapus,however,the effective components of cerebral neuroprotective and the blood-brain barrier permeability are not yet clear.
Objective:To study on the clinic efficacy of preparations,based on the blood-brain barrier permeability and nerve protection mechanism,the effective substance of the treatment of cerebral ischemia,of E.breviscapus has been studied.
Methods:
1.To establish HPLC fingerprints of the different preparations of erigeron was analyzed the effective components of antioxidant activity of erigeron injection by CE-CL.
2.To extract and isolate the compounds of E.breviscapus by silica gel,ODS, polyamide column chromatography and HPLC,their structures were characterized by ~1H-NMR,~(13)C-NMR and MS.With the method of esterifying and acetyling, derivatives were synthesized.
3.To cultivate rat cerebral conical neurons cell in vitro and determine the survival rate by MTT,the neuroprotection activity of erigeron preparations and E. breviscapus was evaluated,with neuroprotection active ingredients screened.
4.To co-culture BMVEC and AC in vitro,blood-brain barrier model(BBBM) was established with the active components analysized by HPLC.
Result:
1.The main chemical group of Erigeron preparation are contain with scutellarin, caffeic acid,double caffeoyl quinic acid such as flavonoids and caffeoyl-constituents. And erigeron injections had four effective ingredients.
2.12 compounds were isolated,with 9 identified,as follows:scutellarin, scutellarein,apigenin,apigenin-7-O-glucuronic acid,1,5-di-O-caffeoyl quinic acid, 3,4-di-O-caffeoyl quinic acid,friedelin,stigmasterol,fourteen acids.At the same time,after structurally modified,synthesis caffeoyl methyl ester,caffeoyl ethyl ester, 3,4-diacetyl-caffeic,scutellarin and glycolamide were gained.
3.The preparations,such as erigeron injection,scutellarin injection,and so on, could promote the survival of nerve cell in vitro,so did the flavonoids of scutellarin, apigenin-7-O-glucuronic acid,the caffeoyl constituents of caffeic acid,double caffeoyl quinic acid and the derivatives of caffeic acid and scutellarin.
4.The blood-brain barrier model in vitro was successful.1,5-DCQ,3,5-DCQ, 3,4-DCQ,apigenin-7-O-glucuronic,could pass through BBBM,so did coffee methyl ester,3,4-diacetyl-caffeic acid,glycolamide ester of scutellarin.
Conclusion:
1.Erigeron preparation and E.breviscapus mainly contain flavonoids and double caffeoyl quinic acids.The neuroprotective compounds are scutellarin,caffeic acid, 1,5-DCQ,3,5-DCQ,3,4-DCQ and so on.The neuroprotection of scutellarin are related on the antioxidant activity.
2.The brain-targeting effective components of neuroprotective from Erigeron are 1,5-DCQ,3,5-DCQ,3,4-DCQ,apigenin-7-O-glucuronic.
3.The products of the structural modification of caffeic acid and scutellarin have changed from hydrophilicity to lipophilicify,which the oil-water partition coefficient increases about 10~3～10~5.Coffee methyl ester,3,4-diacetyl-caffeic acid,glycolamide ester of scutellarin are also the brain-targeting effective components of neuroprotective.
Innovation:
1.The research idea is "Traditional Chinese medicine→through the blood-brain barrier+neuroprotection→brain-targeting effective components of neuroprotective"
2.The effective components of neuroprotective of E.breviscapus has essentially evaluated by co-cultured in vitro rat brain microvascular endothelial cells and brain microvascular endothelial cells.
引文
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