淫羊藿苷联用三七总皂苷对AD模型鼠学习记忆的影响及其作用机制探讨
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摘要
目的在前期研究工作中,根据中药复方益智健脑颗粒的组方,从其主要组成药物中筛选出治疗阿尔茨海默病(Alzheimer's disease,AD)的有效成分组合—淫羊藿苷(Icariin, ICA)与三七总皂苷(Panax Notoginseng Saponins, PNS),本次研究以ICA联用PNS对AD模型小鼠—P8系快速老化小鼠(senescence-accelerated prone mice8, SAMP8)进行干预,检测干预后SAMP8的行为学改变,并应用从蛋白质组学技术分析ICA联用PNS治疗AD的潜在作用靶点,探讨其防治AD的作用机制。
方法将50只6月龄雄性SAMP8随机分为低剂量治疗组、中剂量治疗组、高剂量治疗组、模型组和西药对照组,每组10只；另设10只R1系抗快速老化小鼠(senescence accelerated resistant mouse1, SAMR1)为正常对照组。低、中、高剂量治疗组均以ICA+PNS灌胃(剂量依次为2.5+20mg/kg,5+40mg/kg,10+80mg/kg),西药对照组以多奈哌齐灌胃(剂量为1mg/kg),模型组和正常对照组以等剂量双蒸水灌胃。8周后,以Morris水迷宫对各组小鼠进行行为学测试,分析其学习记忆能力的变化；同时,从低、中、高剂量治疗组之中筛选出最佳剂量组,作为后续实验中的治疗组；行为学测试结束后,应用双向凝胶电泳技术分别分离治疗组和模型组SAMP8海马组织总蛋白,以胶体考马斯亮蓝染色,Image Scanner图像扫描仪及Image Master双向凝胶电泳软件对图像进行扫描分析,以模型组图像为参照对象,选取治疗组中部分差异蛋白质点进行基质辅助激光解吸电离飞行时间质谱分析,得到肽质量指纹图谱,经MSDB和NCBInr数据库查询,鉴定差异表达蛋白质；采用Western blot和逆转录-聚合酶链反应(Reverse transcription-Polymerase chain reaction, RT-PCR)技术对部分差异表达蛋白质进行验证,同时检测这些差异表达蛋白在正常对照组SAMR1海马组织中的表达水平。
结果1.行为学测试结果显示,模型组小鼠的逃避潜伏期较正常对照组明显延长(P<0.05),且停留在原平台象限的时间和跨平台象限次数较正常对照组明显减少(P<0.05)；与模型组小鼠相比,中剂量治疗组、高剂量治疗组及西药对照组小鼠的逃避潜伏期明显缩短(P<0.05),而停留在原平台象限的时间和跨平台象限次数明显增加(P<0.05)；中剂量治疗组、高剂量治疗组与西药对照组小鼠之间的逃避潜伏期及停留在原平台象限的时间和跨平台象限次数均无明显差异(P>0.05),据此认为中剂量组为最佳剂量组。2.以模型组的双向凝胶电泳图谱为参照,发现治疗组与模型组存在23个差异点,其中12个在治疗组表达上调,11个表达下调。选取变化较为明显、边界较为清晰、无明显拖尾现象的差异蛋白质点进行鉴定：最终得到鉴定的有12个点,其中有7个在治疗组表达上调,5个表达下调。根据蛋白质数据库中提供的信息,发现这些差异表达蛋白治疗的AD作用机制涉及调节Ap代谢、抑制tau蛋白异常磷酸化、抗氧化应激、减轻脑内炎症反应、改善线粒体能量代谢障碍、抑制神经细胞凋亡等方面。3.差异蛋白验证结果：(1) Western blot验证结果：本次实验采用western blot技术检测flotillin-1和HMGB1在治疗组、模型组、西药对照组SAMP8及正常对照组SAMR1海马组织中的表达水平。结果显示：与模型组相比,flotillin-1和HMGB1在治疗组、西药对照组、正常对照组的表达明显下降(P<0.05),而二者在治疗组与西药对照组之间的表达水平无明显差异(P>0.05)。上述结果与蛋白质组学实验结果相符。(2)RT-PCR验证结果：本次实验同时采用RT-PCR技术检钡HMGB1和Ngb在治疗组、模型组、西药对照组SAMP8及正常对照组SAMR1海马组织中的表达水平。结果显示：HMGB1在治疗组、西药对照组及正常对照组的表达较模型组明显下降(P<0.05)；Ngb在治疗组、西药对照组及正常对照组的表达较模型组明显增高(P<0.05)；而二者在治疗组与西药对照组之间的表达水平均无明显差异(P>0.05)。上述结果与western blot的结果一致,亦与蛋白质组学实验的结果相符。
结论1.ICA联用PNS能显著改善AD模型小鼠SAMP8的学习能力及记忆巩固、再现能力。2.ICA联用PNS可调节AD模型小鼠SAMP8海马组织的多种蛋白质表达,对AD的治疗是多靶点、多途径的。3.ICA联用PNS可能通过调节flotillin-1、HMGB1、Ngb等蛋白质的表达水平来发挥其治疗作用,而这些蛋白质可能是防治AD的潜在靶点蛋白。
OBJECTIVE To explore the effect of Icariin(ICA) combined with Panax notoginseng saponins (PNS), under the guideline of Kidney-reinforcen and Blood-activating therapy method, on the behavior of senescence-accelerated mice P8(SAMP8), which is considered as an generally accepted mouse model of Alzheimer's disease (AD), thus to elucidate the therapeutic effect of ICA combined with PNS on SAMP8and the practicability of this method in the prevention and treatment of AD; To probe the potential remedial protein targets of AD by analyzing the differential expression of hippocampus proteins in SAMP8with the intervention of ICA combined with PNS, thus to analyze the therapeutic mechanicsm of the relevant target proteins from the angle of Multi-target treatment strategies in complex disease.
METHODS50six-month-old male SAMP8were randomly divided into3groups, which are the follows:combination group (n=30), model group (n=10) and medicine control group (n=10). Another10six-month-old male SAMR1were prepared as normal control group (n=10). Mice in combination group were individually ig administrated with ICA combined with PNS [(2.5+20),(5+40), and (10+80) mg/kg], Mice in medicine control group were treated with Donepezil HCL, and mice in model group and normal control group were administered intragastrically with the same dose of Double-distilled water. After8weeks, using Morris water maze for mice in each group to analyze their behavior to detect changes in learning and memory ability. After behavioral experiments, the total proteins of hippocampus tissue of SAMP8in treatment group (optimal dose group in behavioral experiments), model group and medicine control group were separated by two-dimensional gel electrophoresis respectively. The gels of the three groups were stained by Coomassie brilliant blue, scanned by ImageScanner and analyzed in PDQuest software. Taking the gel of model group as reference object, part of differential expression protein spots in treatment group and medicine control group were identified by peptide mass fingerprint based on the technology of matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and MSDB or NCBInr database searching. Using Western blot and Reverse transcription-Polymerase chain reaction (RT-PCR.) techniques to testify the expression differences of some identified protein spots. In the meanwhile, we also detected the expression levels of these proteins in the hippocampus tissue of SAMR1in mormal control group.
RESULTS:1. In Morris water maze test, SAMP8in the model group had longer escape latency compared with SAMR1in the normal control group (P<0.05); For SAMP8in the model group, the stay time in the former platform quadrant and former platform crossing times were much less than SAMR1mice in the normal control group (P<0.05); With the intervention of ICA with PNS combined, we can significantly shorten the escape latency and increase the stay time in the former platform quadrant and former platform crossing times for SAMP8in the treatment group (P<0.05); There was no significant diffenrence between the combination group (ICA+PNS5+40mg/kg, ig) and the combination group (10+80mg/kg, ig)(P>0.05).2. Taking the2-DE map of model group as reference object, we compared the map of treatment group with it of model group to obtain the differentially expressed protein spots. We found that there were23diferentialy expressed protein spots in the treatment group, of which12proteins were up-regulated and11proteins were down-regulated; For identification, we selected12diferentialy expressed protein spots in the treatment group and finally identified7points were identified;15diferentialy expressed protein spots in the model group were selected and finally9protein points were identified. According to the information provided in the protein database, we made analysis of these proteins as potential remedial targets for its direct or indirect remedial effects in the treatment of AD and found that the therapeutic mechanism of these proteins in AD involved in regulating Aβ metabolism, regulating phosphorylation of tau protein, anti-oxidative stress, inhibiting neuroin-flammation, regulation of mitochondrial energy metabolism and decreasing the neuron apoptosis, etc.3. Validation of some differentially expressed proteins:(1) The results of western blot:we detected the expression levels of flotillin-1and HMGB1in western blot experiment, and found that the expression levels of flotillin-1and HMGB1significantly increased in SAMP8in the model group compared with SAMR1in the normal control group (P<0.05); both flotillin-1and HMGB1significantly decreased in SAMP8in treatment group and medicine control treatment group compared with SAMR1in model control group (P<0.05), which is in accordance with the results in the proteomic experiment.(2) The results of RT-PCR:we also detected HMGB1and Ngb in RT-PCR experiment, and found that the expression levels of HMGB1significantly increased in SAMP8in the model group compared with SAMR1in the normal control group(P<0.05), the results consistent with the research in the western blot experiment; the expression levels of Ngb significantly decreased in SAMP8in the model control group compared with SAMR1in the normal control group (P<0.05); and found that the expression levels of Ngb can be significantly enhanced with the intervention of ICA combined with PNS (P<0.05), which is consistent with the results in the proteomic experiment.
CONCLUSIONS:1. The intervention of ICA combined with PNS can significantly improve the learning and memory ability as well as the ability of memory consolidation and reproduction in AD model mice SAMP8.2. Hippocampus tissue protein expression profiles of SAMP8can be regulated by ICA combined with PNS, showing which has multitarget mechanism of AD.3. ICA combined with PNS may have therapeutial effect on AD via regulating the protein expression such as flotillin-1, HMGB1and Ngb, which may be the target proteins against AD.
方法将50只6月龄雄性SAMP8随机分为低剂量治疗组、中剂量治疗组、高剂量治疗组、模型组和西药对照组,每组10只；另设10只R1系抗快速老化小鼠(senescence accelerated resistant mouse1, SAMR1)为正常对照组。低、中、高剂量治疗组均以ICA+PNS灌胃(剂量依次为2.5+20mg/kg,5+40mg/kg,10+80mg/kg),西药对照组以多奈哌齐灌胃(剂量为1mg/kg),模型组和正常对照组以等剂量双蒸水灌胃。8周后,以Morris水迷宫对各组小鼠进行行为学测试,分析其学习记忆能力的变化；同时,从低、中、高剂量治疗组之中筛选出最佳剂量组,作为后续实验中的治疗组；行为学测试结束后,应用双向凝胶电泳技术分别分离治疗组和模型组SAMP8海马组织总蛋白,以胶体考马斯亮蓝染色,Image Scanner图像扫描仪及Image Master双向凝胶电泳软件对图像进行扫描分析,以模型组图像为参照对象,选取治疗组中部分差异蛋白质点进行基质辅助激光解吸电离飞行时间质谱分析,得到肽质量指纹图谱,经MSDB和NCBInr数据库查询,鉴定差异表达蛋白质；采用Western blot和逆转录-聚合酶链反应(Reverse transcription-Polymerase chain reaction, RT-PCR)技术对部分差异表达蛋白质进行验证,同时检测这些差异表达蛋白在正常对照组SAMR1海马组织中的表达水平。
结果1.行为学测试结果显示,模型组小鼠的逃避潜伏期较正常对照组明显延长(P<0.05),且停留在原平台象限的时间和跨平台象限次数较正常对照组明显减少(P<0.05)；与模型组小鼠相比,中剂量治疗组、高剂量治疗组及西药对照组小鼠的逃避潜伏期明显缩短(P<0.05),而停留在原平台象限的时间和跨平台象限次数明显增加(P<0.05)；中剂量治疗组、高剂量治疗组与西药对照组小鼠之间的逃避潜伏期及停留在原平台象限的时间和跨平台象限次数均无明显差异(P>0.05),据此认为中剂量组为最佳剂量组。2.以模型组的双向凝胶电泳图谱为参照,发现治疗组与模型组存在23个差异点,其中12个在治疗组表达上调,11个表达下调。选取变化较为明显、边界较为清晰、无明显拖尾现象的差异蛋白质点进行鉴定：最终得到鉴定的有12个点,其中有7个在治疗组表达上调,5个表达下调。根据蛋白质数据库中提供的信息,发现这些差异表达蛋白治疗的AD作用机制涉及调节Ap代谢、抑制tau蛋白异常磷酸化、抗氧化应激、减轻脑内炎症反应、改善线粒体能量代谢障碍、抑制神经细胞凋亡等方面。3.差异蛋白验证结果：(1) Western blot验证结果：本次实验采用western blot技术检测flotillin-1和HMGB1在治疗组、模型组、西药对照组SAMP8及正常对照组SAMR1海马组织中的表达水平。结果显示：与模型组相比,flotillin-1和HMGB1在治疗组、西药对照组、正常对照组的表达明显下降(P<0.05),而二者在治疗组与西药对照组之间的表达水平无明显差异(P>0.05)。上述结果与蛋白质组学实验结果相符。(2)RT-PCR验证结果：本次实验同时采用RT-PCR技术检钡HMGB1和Ngb在治疗组、模型组、西药对照组SAMP8及正常对照组SAMR1海马组织中的表达水平。结果显示：HMGB1在治疗组、西药对照组及正常对照组的表达较模型组明显下降(P<0.05)；Ngb在治疗组、西药对照组及正常对照组的表达较模型组明显增高(P<0.05)；而二者在治疗组与西药对照组之间的表达水平均无明显差异(P>0.05)。上述结果与western blot的结果一致,亦与蛋白质组学实验的结果相符。
结论1.ICA联用PNS能显著改善AD模型小鼠SAMP8的学习能力及记忆巩固、再现能力。2.ICA联用PNS可调节AD模型小鼠SAMP8海马组织的多种蛋白质表达,对AD的治疗是多靶点、多途径的。3.ICA联用PNS可能通过调节flotillin-1、HMGB1、Ngb等蛋白质的表达水平来发挥其治疗作用,而这些蛋白质可能是防治AD的潜在靶点蛋白。
OBJECTIVE To explore the effect of Icariin(ICA) combined with Panax notoginseng saponins (PNS), under the guideline of Kidney-reinforcen and Blood-activating therapy method, on the behavior of senescence-accelerated mice P8(SAMP8), which is considered as an generally accepted mouse model of Alzheimer's disease (AD), thus to elucidate the therapeutic effect of ICA combined with PNS on SAMP8and the practicability of this method in the prevention and treatment of AD; To probe the potential remedial protein targets of AD by analyzing the differential expression of hippocampus proteins in SAMP8with the intervention of ICA combined with PNS, thus to analyze the therapeutic mechanicsm of the relevant target proteins from the angle of Multi-target treatment strategies in complex disease.
METHODS50six-month-old male SAMP8were randomly divided into3groups, which are the follows:combination group (n=30), model group (n=10) and medicine control group (n=10). Another10six-month-old male SAMR1were prepared as normal control group (n=10). Mice in combination group were individually ig administrated with ICA combined with PNS [(2.5+20),(5+40), and (10+80) mg/kg], Mice in medicine control group were treated with Donepezil HCL, and mice in model group and normal control group were administered intragastrically with the same dose of Double-distilled water. After8weeks, using Morris water maze for mice in each group to analyze their behavior to detect changes in learning and memory ability. After behavioral experiments, the total proteins of hippocampus tissue of SAMP8in treatment group (optimal dose group in behavioral experiments), model group and medicine control group were separated by two-dimensional gel electrophoresis respectively. The gels of the three groups were stained by Coomassie brilliant blue, scanned by ImageScanner and analyzed in PDQuest software. Taking the gel of model group as reference object, part of differential expression protein spots in treatment group and medicine control group were identified by peptide mass fingerprint based on the technology of matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and MSDB or NCBInr database searching. Using Western blot and Reverse transcription-Polymerase chain reaction (RT-PCR.) techniques to testify the expression differences of some identified protein spots. In the meanwhile, we also detected the expression levels of these proteins in the hippocampus tissue of SAMR1in mormal control group.
RESULTS:1. In Morris water maze test, SAMP8in the model group had longer escape latency compared with SAMR1in the normal control group (P<0.05); For SAMP8in the model group, the stay time in the former platform quadrant and former platform crossing times were much less than SAMR1mice in the normal control group (P<0.05); With the intervention of ICA with PNS combined, we can significantly shorten the escape latency and increase the stay time in the former platform quadrant and former platform crossing times for SAMP8in the treatment group (P<0.05); There was no significant diffenrence between the combination group (ICA+PNS5+40mg/kg, ig) and the combination group (10+80mg/kg, ig)(P>0.05).2. Taking the2-DE map of model group as reference object, we compared the map of treatment group with it of model group to obtain the differentially expressed protein spots. We found that there were23diferentialy expressed protein spots in the treatment group, of which12proteins were up-regulated and11proteins were down-regulated; For identification, we selected12diferentialy expressed protein spots in the treatment group and finally identified7points were identified;15diferentialy expressed protein spots in the model group were selected and finally9protein points were identified. According to the information provided in the protein database, we made analysis of these proteins as potential remedial targets for its direct or indirect remedial effects in the treatment of AD and found that the therapeutic mechanism of these proteins in AD involved in regulating Aβ metabolism, regulating phosphorylation of tau protein, anti-oxidative stress, inhibiting neuroin-flammation, regulation of mitochondrial energy metabolism and decreasing the neuron apoptosis, etc.3. Validation of some differentially expressed proteins:(1) The results of western blot:we detected the expression levels of flotillin-1and HMGB1in western blot experiment, and found that the expression levels of flotillin-1and HMGB1significantly increased in SAMP8in the model group compared with SAMR1in the normal control group (P<0.05); both flotillin-1and HMGB1significantly decreased in SAMP8in treatment group and medicine control treatment group compared with SAMR1in model control group (P<0.05), which is in accordance with the results in the proteomic experiment.(2) The results of RT-PCR:we also detected HMGB1and Ngb in RT-PCR experiment, and found that the expression levels of HMGB1significantly increased in SAMP8in the model group compared with SAMR1in the normal control group(P<0.05), the results consistent with the research in the western blot experiment; the expression levels of Ngb significantly decreased in SAMP8in the model control group compared with SAMR1in the normal control group (P<0.05); and found that the expression levels of Ngb can be significantly enhanced with the intervention of ICA combined with PNS (P<0.05), which is consistent with the results in the proteomic experiment.
CONCLUSIONS:1. The intervention of ICA combined with PNS can significantly improve the learning and memory ability as well as the ability of memory consolidation and reproduction in AD model mice SAMP8.2. Hippocampus tissue protein expression profiles of SAMP8can be regulated by ICA combined with PNS, showing which has multitarget mechanism of AD.3. ICA combined with PNS may have therapeutial effect on AD via regulating the protein expression such as flotillin-1, HMGB1and Ngb, which may be the target proteins against AD.
引文
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