芳香开窍药冰片及石菖蒲对脑得生主要活性成分透过血脑屏障影响的研究
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摘要
一、目的
建立大鼠血浆及脑组织中羟基红花黄色素A (HSYA)、葛根素(Puer)、川芎嗪(TMP)及人参皂苷Rg1(Rg1)的测定方法。考察配伍芳香开窍药冰片或石菖蒲提取液对脑得生主要活性成分在大鼠体内的吸收以及透过血脑屏障(BBB)的影响。为芳香开窍药引经入脑提供实验依据。
二、方法
1实验动物及给药方法
1.1实验动物分组选用清洁级健康成年雄性大鼠198只(220-260g),按体重随机分3组：脑得生组(Ⅰ)、脑得生配伍冰片组(Ⅱ)、脑得生配伍石菖蒲组(Ⅲ),每组6×11只。1.2给药剂量及制备方法按照《中国药典》2005版,冰片剂量取中等剂量日剂量28 mg·kg-1、石菖蒲日剂量3.0 g·kg-1。脑得生日剂量含HSYA 20 mg·kg-1、Puer 20 mg·kg-1、TMP 10 mg·kg-1、Rg120 mg·kg-1。石菖蒲提取液的制备：石菖蒲加蒸馏水浸泡30 min,加热蒸馏,收集挥发油水混合溶液,加入适量吐温80(终含量1%),蒸馏水定容使得到3.0 g生药/mL的石菖蒲溶液。各组均配置成0.8%羧甲基纤维素钠(CMC-Na)混悬液。
1.3样品采集大鼠适应性喂养一周后,试验前一天禁食12 h。灌胃给药后,分别于10,20,30,45 min,1,1.5,2,3,6,8,12 h摘除眼球采血,肝素抗凝,于-70℃冰箱保存。试验完成后在冰台上快速取大鼠脑组织,剥离软脑膜,生理盐水洗净,滤纸吸干表面水分,称重,装入冻存管中,于-70℃冰箱保存。
2生物样品的测定方法
2.1采用UPLC-MS/MS测定血浆及脑组织匀浆中脑得生主要活性成分Puer、TMP、Rg1的浓度。
2.2采用HPLC测定血浆及脑组织匀浆中脑得生活性成分HSYA的浓度。
3数据处理以SPSS 13.0统计软件分析处理,各组大鼠脑血比(AUCbrain/AUCblood)用单因素方差分析检验。
三、结果
1方法学
1.1Puer、TMP、Rgl的测定方法学
血浆及脑组织中Puer、TMP、Rgl均与内标和内源性物质分离良好。血浆内Puer、TMP、Rgl和内标各待测物保留时间分别为3.16、2.18、3.59、2.59 min,脑匀浆中各待测物的保留时间分别为3.14、2.17、3.59、2.65 min。在12.50-5000.00 ng·mL-1线性范围内各待测物在血浆及脑组织中的线性良好,最低定量限分别为10 ng·mL-1 12.5 ng·mL-1、1Ong·mL-1。血浆中萃取回收率各待测物>80.77%,脑匀浆中各待测物>78.13%,日间和日内精密度在血浆中各待测物<10.27%,脑匀浆中各待测物低浓度<16.12%,中、高浓度<11.88%。
1.2 HSYA的测定方法学
血浆及脑组织内HSYA均与内标和内源性物质很好的分离。HSYA和内标的出峰时间分别为6.2 min和11.9 min。在40.00-2000.00 ng·mL-1线性范围内HSYA血浆及脑组织中线性良好,最低定量限均为40.00 ng-mL-1。血浆及脑组织内HSYA的萃取回收率分别>85.07%、>83.49%；日内精密度RSD分别<11.20%、<5.13%；日间精密度RSD分别<8.15%、<9.14%。
2动物实验
Ⅰ、Ⅱ、Ⅲ组中HSYA的AUC brain/AUC blood分别为0.69±0.044、0.98±0.054及1.64±0.082；Puer的AUC brain/AUC blood分别为0.58±0.11、0.61±0.04及0.78±0.04；TMP的AUC brain/AUC blood分别为0.0069±0.00085、0.0072±0.0010、0.014±0.0022。Rgl在血浆中的AUC0→12分别为9289.98±1750.48、13792.73±2065.88、15620.05±2936.68,在脑组织中未被检测到。
四、结论
1方法学
本实验方法可准确、快速测定大鼠血浆及脑匀浆中HSYA、Puer、TMP、Rgl浓度,用以芳香开窍药对脑得生主要活性成分透过BBB影响的考察。
2动物实验
冰片促进HSYA、Puer、TMP、Rgl吸收入血并增加HSYA、Puer、TMP脑组织内浓度,可有效增加BBB的通透性；石菖蒲提取液抑制HSYA、Puer吸收入血而提高TMP、Rg1的生物利用度,同时促进HSYA、Puer、TMP进入脑组织内,有效地提高BBB的通透性。由冰片及石菖蒲两种芳香开窍药类引经药促进脑得生主要活性成分透过BBB的作用得出结论：芳香开窍药可以作为脑引经药开启BBB,促进药物透过BBB进入脑部。
OBJECTIVES
To estabolish the methods for determination hydroxysafflor yellow A, puerarin, tetramethylpyrazine, ginsenosides Rg1 in rat plasma and brain; to inspect the effect of Broneolum syntheticum or Rhizoma acori talarinowii on the pharmacokinetics and the acrossing the blood-brain barrier of Naodesheng’s main active constituent; to study the mechanism of drugs of causing resuscitation by administering aromatic drugs opening the blood-brain barrier.
METHODS
1. Dose and sample collection
1.1 Male Sprague-Dawley rats (220-260g) were equally divided into three groups by randomized design according to their body weight: Naodesheng group (Ⅰ), Naodesheng compatibility Borneolum group (Ⅱ) and Naodesheng compatibility Rhizoma acori talarinowii group (III).
1.2 According to the“Chinese Pharmacopeia”of 2005 edition, the daily dose of Borneolum and extrat of Rhizoma acori talarinowii was 28 mg·kg-1,3.0 g·kg-1, respectively. Each rat was intragastric administration Naodesheng which included HSYA 20 mg·kg-1, Puer 20 mg·kg-1, TMP 10 mg·kg-1, Rg120 mg·kg-1. The extract of Rhizoma acori talarinowii: Rhizoma acori talarinowii had been soaked for 30 min and destiled. Collection the mixed solution of volatile oil and water, adding tween 80 (content 1%). At last, metered volume to 3.0 g·mL-1 with water.
1.3 Animals were fasted for 12h before experiments but had free access to water. Overnight-fasted rats were orally administered medicine suspended in 0.8%sodium carboxymethylcellulose solution. After oral administration of medicine, the rats were sacrificed by picking off eyeballs of rats at the time intervals of 10,20,30,45 min,1,1.5,2, 3,6,8,12 h, and the cerebra were collected and weighted. At each time point, six rats were sacrificed and sampled.
2. Sample analysis
2.1 Puerarin, tetramethylpyrazine, and ginsenosides Rg1 in rat plasma and brain were simultaneous determined by UPLC-MS/MS.
2.2 The HSYA in rat plasma and brain was determined by HPLC.
3. Data processing
The dates were analysised by SPSS 13.0 software. And then the of each group was tested by one-factor analysis of variance.
RESULTS
1 Simultaneous determination of puerarin, tetramethylpyrazine, and ginsenosides Rg1
The interference of endogenous compounds were assessed by analyzing standard puerarin, tetramethylpyrazine and Rg1 with the retention times of 3.16,2.18,3.59,2.59 min for plasma and 3.14,2.17, 3.59,2.65 min for brain homogenate samples. Standard curves exhibited good linearity. The limits of quantitations in plasma and brain both were 10 ng-mL"1,12.5 ng-mL-1,10 ng-mL-1, respectively. The extraction in plasma and brain recovery both were more than 80.77%.The intra-and inter-day precisions of analysis were less than 10.27%in plasma, and the lower concentration were less than 16.12%, center and higher concentration were less than 11.88%in brain.
2 Determination of HSYA
Under the optimized chromatographic conditions, HSYA and IS were separated well in rat plasma and brain homogenate with the retention times of 6.2 min and 11.9 min, respectively. Standard curves exhibited good linearity. The limits of quantitation in plasma and brain both were 40 ng·mL-1. The extraction in plasma and brain recovery were more than 85.07%,83.49%.The intra-day precisions of analysis were less than 11.2%,5.13% and the inter-day were less than 8.15%,9.14%, respectively.
3 Animal experiment
For theⅠ,Ⅱ,Ⅲgroups, the AUC brain/AUC blood of HSYA were 0.69±0.044,0.98±0.054 and I.64±0.082; the AUC bmin/AUC blood of puerarin were 0.58±0.11,0.61±0.04 and 0.78±0.04; the AUC brain/AUC blood of tetramethylpyrazine were 0.0069±0.00085,0.0072±0.0010 and 0.014±0.0022. The AUC0→12 of Rg1 was 9289.98±1750.48, 13792.73±2065.88 and 15620.05±2936.68 in plasma, respectively, but could not be determinated in brain.
CONCLUSIONS
1 Methods
The methods are rapid, sensitive, reproducible, accurate and suitable for analysis of the HSYA, Puer, TMP and Rg1 in rat plasma and brain to inspect the permeability of BBB.
2 Animal experiment
The Borneolum enhance the HSYA, Puer, TMP penetrating BBB; Rhizoma acori talarinowii inhibit the absorption of HSYA and Puer, but enhance the absorptiong of TMP and Rg1. The Rhizoma acori talarinowii enhance the permeability of BBB, efficiently. The drugs of causing resuscitation by administering aromatic drugs can be messenger drug to aim the medicine to the brain.
建立大鼠血浆及脑组织中羟基红花黄色素A (HSYA)、葛根素(Puer)、川芎嗪(TMP)及人参皂苷Rg1(Rg1)的测定方法。考察配伍芳香开窍药冰片或石菖蒲提取液对脑得生主要活性成分在大鼠体内的吸收以及透过血脑屏障(BBB)的影响。为芳香开窍药引经入脑提供实验依据。
二、方法
1实验动物及给药方法
1.1实验动物分组选用清洁级健康成年雄性大鼠198只(220-260g),按体重随机分3组：脑得生组(Ⅰ)、脑得生配伍冰片组(Ⅱ)、脑得生配伍石菖蒲组(Ⅲ),每组6×11只。1.2给药剂量及制备方法按照《中国药典》2005版,冰片剂量取中等剂量日剂量28 mg·kg-1、石菖蒲日剂量3.0 g·kg-1。脑得生日剂量含HSYA 20 mg·kg-1、Puer 20 mg·kg-1、TMP 10 mg·kg-1、Rg120 mg·kg-1。石菖蒲提取液的制备：石菖蒲加蒸馏水浸泡30 min,加热蒸馏,收集挥发油水混合溶液,加入适量吐温80(终含量1%),蒸馏水定容使得到3.0 g生药/mL的石菖蒲溶液。各组均配置成0.8%羧甲基纤维素钠(CMC-Na)混悬液。
1.3样品采集大鼠适应性喂养一周后,试验前一天禁食12 h。灌胃给药后,分别于10,20,30,45 min,1,1.5,2,3,6,8,12 h摘除眼球采血,肝素抗凝,于-70℃冰箱保存。试验完成后在冰台上快速取大鼠脑组织,剥离软脑膜,生理盐水洗净,滤纸吸干表面水分,称重,装入冻存管中,于-70℃冰箱保存。
2生物样品的测定方法
2.1采用UPLC-MS/MS测定血浆及脑组织匀浆中脑得生主要活性成分Puer、TMP、Rg1的浓度。
2.2采用HPLC测定血浆及脑组织匀浆中脑得生活性成分HSYA的浓度。
3数据处理以SPSS 13.0统计软件分析处理,各组大鼠脑血比(AUCbrain/AUCblood)用单因素方差分析检验。
三、结果
1方法学
1.1Puer、TMP、Rgl的测定方法学
血浆及脑组织中Puer、TMP、Rgl均与内标和内源性物质分离良好。血浆内Puer、TMP、Rgl和内标各待测物保留时间分别为3.16、2.18、3.59、2.59 min,脑匀浆中各待测物的保留时间分别为3.14、2.17、3.59、2.65 min。在12.50-5000.00 ng·mL-1线性范围内各待测物在血浆及脑组织中的线性良好,最低定量限分别为10 ng·mL-1 12.5 ng·mL-1、1Ong·mL-1。血浆中萃取回收率各待测物>80.77%,脑匀浆中各待测物>78.13%,日间和日内精密度在血浆中各待测物<10.27%,脑匀浆中各待测物低浓度<16.12%,中、高浓度<11.88%。
1.2 HSYA的测定方法学
血浆及脑组织内HSYA均与内标和内源性物质很好的分离。HSYA和内标的出峰时间分别为6.2 min和11.9 min。在40.00-2000.00 ng·mL-1线性范围内HSYA血浆及脑组织中线性良好,最低定量限均为40.00 ng-mL-1。血浆及脑组织内HSYA的萃取回收率分别>85.07%、>83.49%；日内精密度RSD分别<11.20%、<5.13%；日间精密度RSD分别<8.15%、<9.14%。
2动物实验
Ⅰ、Ⅱ、Ⅲ组中HSYA的AUC brain/AUC blood分别为0.69±0.044、0.98±0.054及1.64±0.082；Puer的AUC brain/AUC blood分别为0.58±0.11、0.61±0.04及0.78±0.04；TMP的AUC brain/AUC blood分别为0.0069±0.00085、0.0072±0.0010、0.014±0.0022。Rgl在血浆中的AUC0→12分别为9289.98±1750.48、13792.73±2065.88、15620.05±2936.68,在脑组织中未被检测到。
四、结论
1方法学
本实验方法可准确、快速测定大鼠血浆及脑匀浆中HSYA、Puer、TMP、Rgl浓度,用以芳香开窍药对脑得生主要活性成分透过BBB影响的考察。
2动物实验
冰片促进HSYA、Puer、TMP、Rgl吸收入血并增加HSYA、Puer、TMP脑组织内浓度,可有效增加BBB的通透性；石菖蒲提取液抑制HSYA、Puer吸收入血而提高TMP、Rg1的生物利用度,同时促进HSYA、Puer、TMP进入脑组织内,有效地提高BBB的通透性。由冰片及石菖蒲两种芳香开窍药类引经药促进脑得生主要活性成分透过BBB的作用得出结论：芳香开窍药可以作为脑引经药开启BBB,促进药物透过BBB进入脑部。
OBJECTIVES
To estabolish the methods for determination hydroxysafflor yellow A, puerarin, tetramethylpyrazine, ginsenosides Rg1 in rat plasma and brain; to inspect the effect of Broneolum syntheticum or Rhizoma acori talarinowii on the pharmacokinetics and the acrossing the blood-brain barrier of Naodesheng’s main active constituent; to study the mechanism of drugs of causing resuscitation by administering aromatic drugs opening the blood-brain barrier.
METHODS
1. Dose and sample collection
1.1 Male Sprague-Dawley rats (220-260g) were equally divided into three groups by randomized design according to their body weight: Naodesheng group (Ⅰ), Naodesheng compatibility Borneolum group (Ⅱ) and Naodesheng compatibility Rhizoma acori talarinowii group (III).
1.2 According to the“Chinese Pharmacopeia”of 2005 edition, the daily dose of Borneolum and extrat of Rhizoma acori talarinowii was 28 mg·kg-1,3.0 g·kg-1, respectively. Each rat was intragastric administration Naodesheng which included HSYA 20 mg·kg-1, Puer 20 mg·kg-1, TMP 10 mg·kg-1, Rg120 mg·kg-1. The extract of Rhizoma acori talarinowii: Rhizoma acori talarinowii had been soaked for 30 min and destiled. Collection the mixed solution of volatile oil and water, adding tween 80 (content 1%). At last, metered volume to 3.0 g·mL-1 with water.
1.3 Animals were fasted for 12h before experiments but had free access to water. Overnight-fasted rats were orally administered medicine suspended in 0.8%sodium carboxymethylcellulose solution. After oral administration of medicine, the rats were sacrificed by picking off eyeballs of rats at the time intervals of 10,20,30,45 min,1,1.5,2, 3,6,8,12 h, and the cerebra were collected and weighted. At each time point, six rats were sacrificed and sampled.
2. Sample analysis
2.1 Puerarin, tetramethylpyrazine, and ginsenosides Rg1 in rat plasma and brain were simultaneous determined by UPLC-MS/MS.
2.2 The HSYA in rat plasma and brain was determined by HPLC.
3. Data processing
The dates were analysised by SPSS 13.0 software. And then the of each group was tested by one-factor analysis of variance.
RESULTS
1 Simultaneous determination of puerarin, tetramethylpyrazine, and ginsenosides Rg1
The interference of endogenous compounds were assessed by analyzing standard puerarin, tetramethylpyrazine and Rg1 with the retention times of 3.16,2.18,3.59,2.59 min for plasma and 3.14,2.17, 3.59,2.65 min for brain homogenate samples. Standard curves exhibited good linearity. The limits of quantitations in plasma and brain both were 10 ng-mL"1,12.5 ng-mL-1,10 ng-mL-1, respectively. The extraction in plasma and brain recovery both were more than 80.77%.The intra-and inter-day precisions of analysis were less than 10.27%in plasma, and the lower concentration were less than 16.12%, center and higher concentration were less than 11.88%in brain.
2 Determination of HSYA
Under the optimized chromatographic conditions, HSYA and IS were separated well in rat plasma and brain homogenate with the retention times of 6.2 min and 11.9 min, respectively. Standard curves exhibited good linearity. The limits of quantitation in plasma and brain both were 40 ng·mL-1. The extraction in plasma and brain recovery were more than 85.07%,83.49%.The intra-day precisions of analysis were less than 11.2%,5.13% and the inter-day were less than 8.15%,9.14%, respectively.
3 Animal experiment
For theⅠ,Ⅱ,Ⅲgroups, the AUC brain/AUC blood of HSYA were 0.69±0.044,0.98±0.054 and I.64±0.082; the AUC bmin/AUC blood of puerarin were 0.58±0.11,0.61±0.04 and 0.78±0.04; the AUC brain/AUC blood of tetramethylpyrazine were 0.0069±0.00085,0.0072±0.0010 and 0.014±0.0022. The AUC0→12 of Rg1 was 9289.98±1750.48, 13792.73±2065.88 and 15620.05±2936.68 in plasma, respectively, but could not be determinated in brain.
CONCLUSIONS
1 Methods
The methods are rapid, sensitive, reproducible, accurate and suitable for analysis of the HSYA, Puer, TMP and Rg1 in rat plasma and brain to inspect the permeability of BBB.
2 Animal experiment
The Borneolum enhance the HSYA, Puer, TMP penetrating BBB; Rhizoma acori talarinowii inhibit the absorption of HSYA and Puer, but enhance the absorptiong of TMP and Rg1. The Rhizoma acori talarinowii enhance the permeability of BBB, efficiently. The drugs of causing resuscitation by administering aromatic drugs can be messenger drug to aim the medicine to the brain.
引文
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