精制清开灵对阿尔茨海默病模型鼠的治疗作用及机制研究
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摘要
背景：阿尔茨海默病(Alzheimer's disease, AD)是老年人中患病率高、危害性大的中枢神经系统退行性疾病之一,也是最常见的一种老年期痴呆。随着人口老龄化现象加剧,该疾病已居于老年人死亡原因的前几位。目前,AD的病因及发病机制未完全阐明,尚缺乏有效的治疗途径。清开灵是临床常用中药制剂之一,对中风急性期为主的中医脑病临床疗效显著。一系列药学及药效学研究已证实清开灵含有超过60种复合物,并发现黄芩苷、栀子苷和胆酸是其最主要的活性成分。前期研究提取黄芩苷、栀子苷和胆酸制成精制清开灵,发现精制清开灵可替代清开灵在中风患者中的治疗作用,并基于“毒损脑络”理论,在中风后血管性痴呆的临床治疗中亦显示出良好的治疗功效。由于AD和血管性痴呆具有共同的危险因素,病理改变也相互重叠,并且随着中医对AD发病机理更深入的认识,发现“毒损脑络”同时是AD发生发展的核心,提示基于“解毒通络”治法,精制清开灵可能对AD亦有治疗作用。
目的：本研究从行为学、组织病理学、神经影像学以及基因表达不同层面综合评价国家重点中药保护品种清开灵有效组份(精制清开灵)基于“解毒通络”法治疗AD的有效性和其作用机制,进一步探讨“毒损脑络”理论及“解毒通络”法在AD中医研究领域中的意义,为今后寻找有效治疗AD中药及提高中医药药物疗效方而提供新的思路。
方法：选择雄性SD大鼠(体重250-300克)用基底前脑注射鹅蒿蕈氨酸(IBO)法建立大鼠痴呆模型,并设立对照组、模型组和药物组。药物组大鼠在造模第三天起给予精制清开灵(1.25mg/ml黄芩苷,6.25mg/mL的栀子苷,和1.75mg/mL的胆酸)灌胃给药,给药剂量每十3ml/kg。对照组和模型组大鼠造模后灌服等量生理盐水。连续灌胃给药一个月后,开始Morris水迷宫行为学实验。选择隐蔽平台实验和反向平台试验评估造模是否成功并评价精制清开灵是否可以改善AD模型大鼠的空间学习记忆能力。完成Morris水迷宫行为学实验第二天进行FDG-PET检查,从神经影像学方而评估精制清开灵是否可以改善AD模型大鼠脑葡萄糖能量代谢水平。之后,三组各随机选择1只大鼠用于组织学检查,光镜下观察精制清开灵对海马神经元的结构变化的影响。其余大鼠进行DNA芯片和免疫印迹分析,从分子水平和蛋白质水平评价药物疗效和作用机制。
结果：精制清开灵可显著改善基底前脑注射鹅蒿蕈氨酸引起的认知、脑功能影像和脑组织学形态的异常。
Morris水迷宫行为学实验结果显示,隐藏平台实验中,逃避潜伏期的时间效应(F4,108=18.178,P<0.001)和组效应(F2,27=41.426,P<0.001)显著。模型组潜伏期和游泳距离明显长于(P<0.001)对照组和药物组。反向平台实验中,逃避潜伏期的时间效应和组效应均显著(F2,54=12.607,P<0.001；F2,27=23.013,P<0.001,模型组、药物组与对照组比较P<0.001)。游泳速度各组之间没有统计学差异。
FDG-PET检查结果显示,与对照组相比模型组众多的大脑区域的FDG-PET信号显著下降。受影响的区域包括前核、海马、中脑、双侧初级皮质、嗅球和下丘脑的左侧,伏隔核右侧皮质(P<0.05)。与模型组相比,药物组左侧嗅球和左前核的FDG-PET信号下降程度相对减小,此外,左海马FDG-PET信号显著增加(P<0.05)
光镜下观察海马组织结构变化发现,对照组海马CA1区的神经元呈有序排列,没有明显的细胞形态异常。模型组的神经元排列异常,细胞质发生变性、细胞坏死(核固缩和核溶解等),细胞数量减少等,另外有胶质细胞增多表明有炎症反应的产生。药物组细胞形态和组织结构基本恢复正常,胶质细胞减少。
DNA微阵列分析与免疫印迹分析结果显示,与模型组相比,药物组19个基因的表达显著改变(P<0.05或P<0.01)。其中11个基因与神经保护作用和神经发生相关,8个基因与抗氧化、蛋白降解、胆固醇的代谢、血管生成、应激反应、和凋亡等相关。除了与细胞凋亡相关的基因下调,其它基因表达上调。此外我们选择在预防AD有着重要的作用的5个基因TRH, EGF, CRBP1, CBR1, ACE进行蛋白质印迹技术验证结果表明,与模型组相比药物组的5个基因蛋白表达水平显着增加(P<0.05或P<0.01),结果与DNA微阵列的结果一致。
结论：精制清开灵可改善由基底前脑注射鹅膏蕈氨酸引起痴呆,这种改善的作用机制可能通过精制清开灵可以调节多种涉及保护神经元、促进神经再生方面起关键作用的通路作用实现,此外,也与精制清开灵的抗氧化作用、抗蛋白质降解等作用相关。
Background:Alzheimer's disease (Alzheimer's disease, AD) has a high incidence rate in the elderly, which is one of the most harmful degenerative diseases in central nervous system and it is also the most common form of senile dementia. Due to the aggravation of population aging, this disease already ranks among the elderly cause of death in the first few. At present, the pathogenesis of the the disease has not been fully elucidated so that there is no satisfactory therapy for AD. Qingkailing (QKL) is one of the famous traditional Chinese medicines which have significant clinical effect on cerebral illness of TCM, the acute cerebral ischemic stroke. A series of pharmaceutical and pharmacodynamic studies have been conducted that identified more than60compounds in QKL and found3compounds, i.e.baicalin, jasminoidin, and cholic acid as the most active ones. Previous research has suggested that extracting baicalin, geniposide and acid as a combination of refined QKL(RQKL) can replace QKL in the treatment of stroke patients. Furthermore, based on the "toxic brain collateral damage" theory, RQKL also showed better therapeutic efficacy in the clinical treatment of post-stroke dementia. By the virtue of the common risk factors and overlapped pathologic change shared by AD and vascular dementia, and with the deeper understanding of AD pathogenesis, researchers found that "toxic brain collateral damage" is also the core of the development of AD. Hence, we proposed that on the basis of unblock collaterals and subcollaterals, the potential mechanism of RQKL, would increase the curative effect of AD.
Objective:This study applied a comprehensive method combined with behavioristics, histopathology, neuroimaging and gene expression to assess the effectiveness and mechanism of refined Qingkailing when based on "JieDuTongLuo " treatment, then to do a further exploration about the "toxic damaged brain collaterals" theory and the significance of "JieDuTongLuo" treatment in the AD field of Chinese medicine research in. Furthermore, the research may provide a new train of thought for finding effective Chinese medical ways in AD treatment.
Methods:To model dementia rats by injecting ibotenic acid (IBO) into the basal forebrain of male rats (weights between250g and300g), then devided modeling rats into contral group, model group and medicine group. Medicine group would be given gavage 3ml/kg each day with drug solution from the third day after operation,and the drug solution contained baicalin1.25mg/ml,geniposide6.25mg/ml, bile acids1.75mg/ml, while the contral group and IBO model group would be given gavage with normal saline after modeling. Within gavage for one month, rats would accept Morris water maze behavioral experiments in order to test whether the dementia model was successed and whether the RQKL could improve spatial learning and memory of Alzheimer's disease model rats by hidden platform experiments and reverse assays. To assess the improvement of energy metabolism of brain glucose in AD model rats with the usage of RQKL, rats would receive neuroimaging of FDG-PET test in the second day after Morris water maze behavioral experiments ended. And then, researchers picked three rats randomly from each group for a histological examination in order to abserve structural changes in hippocampal neurons after taking RQKL, while rest of rats would be tested within DNA microchips and western blot methods. The research might assess effects of AD Chinese medical treatment from molecular level and it also provided an import ant theoretical reference and basis for improving compatibility of modern Chinese medicines.
Result:RQKL treatment significantly attenuated IBO-induced abnormalities in cognition, brain functional images, and brain histological morphology. Morris water maze test results as follows:in the hidden platform test, the escape latency time was dependent on both the time effect (F4,108=18.178, P＜0.001) and the group effect (F2,27=41.426, P＜0.001); the control and durg groups escaped significantly faster than the IBO-model group (both P<0.001).A similar result was observed for the swim distance (F4,108=14.393and P＜0.001for the time effect; F2.27=8.784and P<0.001for the group difference; and P＜0.001and P＜0.05for the comparisons of the control group and the durg group to the IBO-model group). Swim speed was not significantly different between the groups. In the reverse hidden platform test, the time effect and differences between the groups were both significant factors in the escape latency time (F2,54=12.607, P＜0.001; F2,27=23.013, P＜0.001); compared with the IBO-model group, the escape latency times in the control group and the durg group were significantly shorter (both P<0.001). A similar result was observed for the swim distance (F2,54=12.886and P＜0.001for the time effect; F2,27=12.268and P<0.001for the group difference; and P＜0.001for the comparisons of the control group and the durg group to the IBO-model group). No significant differences in the swim speed were observed between groups.
FDG-PET examination showed that compared with the control group, significant decreases in FDG-PET signals were observed in the IBO-model group for numerous brain regions. The affected regions included the anterior nucleus, the hippocampus, the midbrain, the intragyral nuclei and the primary cortex on both sides, the olfactory bulb and the hypothalamus on the left side, and the nucleus accumbens and the primary barrel cortex on the right side (P<0.05). Compared with the IBO-model group, in the durg group, the decrease in the left olfactory bulb and the left anterior nucleus was significantly attenuated; additionally,a significant increase in the FDG-PET signal was observed in the left hippocampus (P<0.05).
Light microscope to observe the change of the structure of the hippocampus results showed in the control group, neurons in the hippocampal CA1region showed an orderly arrangement with no apparent abnormalities in cellular morphology. In the IBO-model group, neuron arrangement was disrupted with severe lesions in the nucleus and cytoplasm such as karyolysis and eosinophilia, and a neuronal cell loss was noted. In the durg group, these abnormalities were ameliorated.
DNA microarray analysis showed that compared with the IBO-model group, in the durg group, the expression of19genes was significantly changed (P<0.05or P<0.01). Of these19genes,11are related to neuroprotection and neurogenesis and the other8are related to anti-oxidation, protein degradation, cholesterol metabolism, angiogenesis, stress response, and apoptosis. Gene expression was increased in all cases except for the gene related to apoptosis.TRH, EGF, CRBP1, CBR1, and ACE were selected for verification by western blot because previous studies have shown that they are more important in preventing AD in comparison to the others in the19genes significantly regulated by RQKL.The results showed that the protein expression levels of these5genes were significantly increased in the durg group compared with the IBO-model group (P<0.05or P<0.01), which was consistent with the results of the DNA microarray. Conclusion:RQKL can ameliorate the IBO-induced dementia in rats and may show significant effects in the treatment of AD. The therapeutic mechanism may be related to RQKL's modulation of a number of processes, mainly through promotion of neuroprotection and neurogenesis, with additional promotion of anti-oxidation, protein degradation, etc.
目的：本研究从行为学、组织病理学、神经影像学以及基因表达不同层面综合评价国家重点中药保护品种清开灵有效组份(精制清开灵)基于“解毒通络”法治疗AD的有效性和其作用机制,进一步探讨“毒损脑络”理论及“解毒通络”法在AD中医研究领域中的意义,为今后寻找有效治疗AD中药及提高中医药药物疗效方而提供新的思路。
方法：选择雄性SD大鼠(体重250-300克)用基底前脑注射鹅蒿蕈氨酸(IBO)法建立大鼠痴呆模型,并设立对照组、模型组和药物组。药物组大鼠在造模第三天起给予精制清开灵(1.25mg/ml黄芩苷,6.25mg/mL的栀子苷,和1.75mg/mL的胆酸)灌胃给药,给药剂量每十3ml/kg。对照组和模型组大鼠造模后灌服等量生理盐水。连续灌胃给药一个月后,开始Morris水迷宫行为学实验。选择隐蔽平台实验和反向平台试验评估造模是否成功并评价精制清开灵是否可以改善AD模型大鼠的空间学习记忆能力。完成Morris水迷宫行为学实验第二天进行FDG-PET检查,从神经影像学方而评估精制清开灵是否可以改善AD模型大鼠脑葡萄糖能量代谢水平。之后,三组各随机选择1只大鼠用于组织学检查,光镜下观察精制清开灵对海马神经元的结构变化的影响。其余大鼠进行DNA芯片和免疫印迹分析,从分子水平和蛋白质水平评价药物疗效和作用机制。
结果：精制清开灵可显著改善基底前脑注射鹅蒿蕈氨酸引起的认知、脑功能影像和脑组织学形态的异常。
Morris水迷宫行为学实验结果显示,隐藏平台实验中,逃避潜伏期的时间效应(F4,108=18.178,P<0.001)和组效应(F2,27=41.426,P<0.001)显著。模型组潜伏期和游泳距离明显长于(P<0.001)对照组和药物组。反向平台实验中,逃避潜伏期的时间效应和组效应均显著(F2,54=12.607,P<0.001；F2,27=23.013,P<0.001,模型组、药物组与对照组比较P<0.001)。游泳速度各组之间没有统计学差异。
FDG-PET检查结果显示,与对照组相比模型组众多的大脑区域的FDG-PET信号显著下降。受影响的区域包括前核、海马、中脑、双侧初级皮质、嗅球和下丘脑的左侧,伏隔核右侧皮质(P<0.05)。与模型组相比,药物组左侧嗅球和左前核的FDG-PET信号下降程度相对减小,此外,左海马FDG-PET信号显著增加(P<0.05)
光镜下观察海马组织结构变化发现,对照组海马CA1区的神经元呈有序排列,没有明显的细胞形态异常。模型组的神经元排列异常,细胞质发生变性、细胞坏死(核固缩和核溶解等),细胞数量减少等,另外有胶质细胞增多表明有炎症反应的产生。药物组细胞形态和组织结构基本恢复正常,胶质细胞减少。
DNA微阵列分析与免疫印迹分析结果显示,与模型组相比,药物组19个基因的表达显著改变(P<0.05或P<0.01)。其中11个基因与神经保护作用和神经发生相关,8个基因与抗氧化、蛋白降解、胆固醇的代谢、血管生成、应激反应、和凋亡等相关。除了与细胞凋亡相关的基因下调,其它基因表达上调。此外我们选择在预防AD有着重要的作用的5个基因TRH, EGF, CRBP1, CBR1, ACE进行蛋白质印迹技术验证结果表明,与模型组相比药物组的5个基因蛋白表达水平显着增加(P<0.05或P<0.01),结果与DNA微阵列的结果一致。
结论：精制清开灵可改善由基底前脑注射鹅膏蕈氨酸引起痴呆,这种改善的作用机制可能通过精制清开灵可以调节多种涉及保护神经元、促进神经再生方面起关键作用的通路作用实现,此外,也与精制清开灵的抗氧化作用、抗蛋白质降解等作用相关。
Background:Alzheimer's disease (Alzheimer's disease, AD) has a high incidence rate in the elderly, which is one of the most harmful degenerative diseases in central nervous system and it is also the most common form of senile dementia. Due to the aggravation of population aging, this disease already ranks among the elderly cause of death in the first few. At present, the pathogenesis of the the disease has not been fully elucidated so that there is no satisfactory therapy for AD. Qingkailing (QKL) is one of the famous traditional Chinese medicines which have significant clinical effect on cerebral illness of TCM, the acute cerebral ischemic stroke. A series of pharmaceutical and pharmacodynamic studies have been conducted that identified more than60compounds in QKL and found3compounds, i.e.baicalin, jasminoidin, and cholic acid as the most active ones. Previous research has suggested that extracting baicalin, geniposide and acid as a combination of refined QKL(RQKL) can replace QKL in the treatment of stroke patients. Furthermore, based on the "toxic brain collateral damage" theory, RQKL also showed better therapeutic efficacy in the clinical treatment of post-stroke dementia. By the virtue of the common risk factors and overlapped pathologic change shared by AD and vascular dementia, and with the deeper understanding of AD pathogenesis, researchers found that "toxic brain collateral damage" is also the core of the development of AD. Hence, we proposed that on the basis of unblock collaterals and subcollaterals, the potential mechanism of RQKL, would increase the curative effect of AD.
Objective:This study applied a comprehensive method combined with behavioristics, histopathology, neuroimaging and gene expression to assess the effectiveness and mechanism of refined Qingkailing when based on "JieDuTongLuo " treatment, then to do a further exploration about the "toxic damaged brain collaterals" theory and the significance of "JieDuTongLuo" treatment in the AD field of Chinese medicine research in. Furthermore, the research may provide a new train of thought for finding effective Chinese medical ways in AD treatment.
Methods:To model dementia rats by injecting ibotenic acid (IBO) into the basal forebrain of male rats (weights between250g and300g), then devided modeling rats into contral group, model group and medicine group. Medicine group would be given gavage 3ml/kg each day with drug solution from the third day after operation,and the drug solution contained baicalin1.25mg/ml,geniposide6.25mg/ml, bile acids1.75mg/ml, while the contral group and IBO model group would be given gavage with normal saline after modeling. Within gavage for one month, rats would accept Morris water maze behavioral experiments in order to test whether the dementia model was successed and whether the RQKL could improve spatial learning and memory of Alzheimer's disease model rats by hidden platform experiments and reverse assays. To assess the improvement of energy metabolism of brain glucose in AD model rats with the usage of RQKL, rats would receive neuroimaging of FDG-PET test in the second day after Morris water maze behavioral experiments ended. And then, researchers picked three rats randomly from each group for a histological examination in order to abserve structural changes in hippocampal neurons after taking RQKL, while rest of rats would be tested within DNA microchips and western blot methods. The research might assess effects of AD Chinese medical treatment from molecular level and it also provided an import ant theoretical reference and basis for improving compatibility of modern Chinese medicines.
Result:RQKL treatment significantly attenuated IBO-induced abnormalities in cognition, brain functional images, and brain histological morphology. Morris water maze test results as follows:in the hidden platform test, the escape latency time was dependent on both the time effect (F4,108=18.178, P＜0.001) and the group effect (F2,27=41.426, P＜0.001); the control and durg groups escaped significantly faster than the IBO-model group (both P<0.001).A similar result was observed for the swim distance (F4,108=14.393and P＜0.001for the time effect; F2.27=8.784and P<0.001for the group difference; and P＜0.001and P＜0.05for the comparisons of the control group and the durg group to the IBO-model group). Swim speed was not significantly different between the groups. In the reverse hidden platform test, the time effect and differences between the groups were both significant factors in the escape latency time (F2,54=12.607, P＜0.001; F2,27=23.013, P＜0.001); compared with the IBO-model group, the escape latency times in the control group and the durg group were significantly shorter (both P<0.001). A similar result was observed for the swim distance (F2,54=12.886and P＜0.001for the time effect; F2,27=12.268and P<0.001for the group difference; and P＜0.001for the comparisons of the control group and the durg group to the IBO-model group). No significant differences in the swim speed were observed between groups.
FDG-PET examination showed that compared with the control group, significant decreases in FDG-PET signals were observed in the IBO-model group for numerous brain regions. The affected regions included the anterior nucleus, the hippocampus, the midbrain, the intragyral nuclei and the primary cortex on both sides, the olfactory bulb and the hypothalamus on the left side, and the nucleus accumbens and the primary barrel cortex on the right side (P<0.05). Compared with the IBO-model group, in the durg group, the decrease in the left olfactory bulb and the left anterior nucleus was significantly attenuated; additionally,a significant increase in the FDG-PET signal was observed in the left hippocampus (P<0.05).
Light microscope to observe the change of the structure of the hippocampus results showed in the control group, neurons in the hippocampal CA1region showed an orderly arrangement with no apparent abnormalities in cellular morphology. In the IBO-model group, neuron arrangement was disrupted with severe lesions in the nucleus and cytoplasm such as karyolysis and eosinophilia, and a neuronal cell loss was noted. In the durg group, these abnormalities were ameliorated.
DNA microarray analysis showed that compared with the IBO-model group, in the durg group, the expression of19genes was significantly changed (P<0.05or P<0.01). Of these19genes,11are related to neuroprotection and neurogenesis and the other8are related to anti-oxidation, protein degradation, cholesterol metabolism, angiogenesis, stress response, and apoptosis. Gene expression was increased in all cases except for the gene related to apoptosis.TRH, EGF, CRBP1, CBR1, and ACE were selected for verification by western blot because previous studies have shown that they are more important in preventing AD in comparison to the others in the19genes significantly regulated by RQKL.The results showed that the protein expression levels of these5genes were significantly increased in the durg group compared with the IBO-model group (P<0.05or P<0.01), which was consistent with the results of the DNA microarray. Conclusion:RQKL can ameliorate the IBO-induced dementia in rats and may show significant effects in the treatment of AD. The therapeutic mechanism may be related to RQKL's modulation of a number of processes, mainly through promotion of neuroprotection and neurogenesis, with additional promotion of anti-oxidation, protein degradation, etc.
引文
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