固本健脑法对MCI大鼠学习记忆功能及海马Aβ表达的影响
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摘要
老年性痴呆,即阿尔茨海默病(Alzheimer’s disease,AD),是一种以记忆和认知损害为主要临床特征的慢性进行性神经系统退行性疾病。AD目前尚无真正有效的治疗方法,尤其是中晚期AD,其脑功能损害已进入不可逆的阶段,故而治疗效果明显不佳。轻度认知障碍(Mild cognitive impairment,MCI)是目前公认的前痴呆状态(尤其意味着前阿尔茨海默病状态),对其进行深入研究可望提供最佳治疗时间窗,预防或推迟AD的发生。
β-淀粉样蛋白(β-amyloid,Aβ)在AD发病机制中的核心作用已经得到广泛接受, Aβ异常释放与沉积是AD老年斑形成的始动因子和老年斑核中的重要成分,在AD的神经细胞损伤级联反应中,淀粉样沉淀等典型病理生理学改变出现于tau蛋白异常磷酸化之前;Aβ代谢异常是MCI向AD转化的可靠生物学指标之一。脂代谢异常会导致脑动脉硬化,从而改变脑微环境、降低脑血流、使脑代谢受损,致使老年认知功能减退;血清胆固醇升高是MCI的重要危险因素,已有发现高胆固醇血症引起脑中Aβ沉积的证据。Aβ的聚集可以经补体途径产生炎症反应,研究提示,中枢炎症是AD病理变化的早期特征;严格回归分析发现血浆中白介素-6(IL-6)水平升高同认知功能损害有密切的关系,是导致认知障碍的危险因素。因此,减少脑内Aβ的生成和集聚,降低血脂水平以改善脑微环境、增加脑血流、保持脑代谢正常,降低血浆中IL-6水平、阻断Aβ的炎症级联效应等治疗措施,在MCI的早期干预治疗中应具有尤其重要的意义。
导师袁德培教授等根据多年临床经验提出以固本健脑立法论治MCI,并依此创制了固本健脑液及相应加减方,临床应用证明确有佳效,能显著改善学习记忆能力和中医辨证之衰老见证积分值,且无任何毒副作用;前期的实验研究也证实,固本健脑液能平和降低老年大鼠血粘度、提高老龄鼠红细胞SOD活力,有提高细胞免疫功能和对抗脾脏、胸腺萎缩的作用;固本健脑方可明显提高实验动物脑中去甲肾上腺素(NA)和多巴胺(DA)的含量,并显著抑制脑内单胺氧化酶(MAO)和乙酰胆碱酯酶(AchE)活力,促进实验动物学习记忆能力。
目的:以固本健脑法的前期研究为基础,建立符合MCI行为学、病理学特征的实验性动物模型,更深入的揭示固本健脑法增强学习记忆能力的机制,为本法在临床更好地化裁应用提供更丰富的依据。
方法:①采用系统回顾性的文献研究方法,分析探讨以固本健脑立法论治MCI的理论基础。②以腹腔注射D-半乳糖和NaNO2的方法建立MCI大鼠模型,予固本健脑液(高、中、低剂量)于模型动物,并设立正常对照组、吡拉西坦(脑复康)对照组比较观察,观察固本健脑液对MCI模型大鼠行为学(水迷宫实验)、海马结构Aβ表达(免疫组化染色法)、血清胆固醇水平(常规酶法等)、血清IL-6含量(ELISA法)的影响。
结果:①记忆能力减退的病变广泛涉及五脏、六腑、奇恒之府、气血津液精、经络等各个环节,但其中最为关键的是脾肾的亏虚。②行为学变化:模型大鼠出现明显的记忆功能障碍,水迷宫实验中其逃避潜伏期、搜索路径长度和跨过平台相同次数所需时间均较正常对照组明显延长(P<0.05),固本健脑液(高、中、低剂量)和吡拉西坦治疗均能使上述指标明显改善(P<0.05),且以固本健脑液高、中剂量组效果更为显著(P<0.05)。③Aβ免疫组化染色结果:模型组海马区Aβ表达较正常组明显增多,各个治疗组均能减少Aβ在海马区的表达,但固本健脑液低剂量组和吡拉西坦组效果相对不突出。④血清胆固醇水平和血清IL-6含量变化:模型组血清胆固醇水平和血清IL-6含量升高,明显高于正常组(P<0.05),固本健脑液各剂量组都能降低血脂水平和血清中IL-6水平,且以高、中剂量组效果更佳;吡拉西坦组可有效降低血清胆固醇水平(P<0.05),但降低血清中IL-6水平的效果不佳。
结论:以上结果提示:按照固本健脑法组方(本课题使用固本健脑液),能显著改善MCI模型大鼠学习记忆功能,可减少实验动物脑内Aβ的生成和聚集、降低血脂水平和血清中IL-6水平、改善脑微环境,从而可以有效防止MCI向AD的转化。以方(法)测证,说明导师袁德培教授等关于脾肾(后、先天之本)亏虚、脑髓失养、兼夹痰瘀导致认知障碍的认识是合理的,依此提出的固本健脑法是MCI的有效治则。
Senile dementia,that is Alzheimer's disease (AD),is a chronic, neurodegenerative disease, which is characterized by the impairment of memory and cognition as the main clinical features. So far there is no completely effective method to treat AD, especially the advanced AD, in that at this time the brain damage has entered an irreversible phase and led to poor treatment. Mild cognitive impairment (MCI) is widely recognized as the pre-dementia state, also the former state of the Alzheimer's disease, thus in-depth study to MCI is expected to provide the best treatment time to prevent and delay AD.
As been widely accepted,β-amyloid protein (Aβ) plays a central role in AD pathogenesis. The abnormal release and deposition of Aβis the initiating factor to form senile plaque and the important components of its core. In the injury cascade reaction of AD's nerve cell, typical changes of the pathophysiology, such as amyloid precipitation,have occurred before the abnormal phosphorylation of tau protein. Be-sides,abnormal metabolism of Aβis one of the reliable biological indicators to show the conversion of MCI to AD.Lipid metabolism may lead to cerebral arteriosclerosis,which will be able to change the brain microenvironment, reduce cerebral blood flow and damage to brain metabolism, resulting in the cognition of the aged declines. So the increase of serum cholesterol is an important and harzardous factor for MCI, and the evidence that high blood cholesterol disease could cause Aβdepositing had been found. Aβaggregating can generate the inflammatory reaction by the pathway of complement, and there have been researches to suggest that central inflammation is the early feature of AD's pathological changes. Moreover, rigorous regression analy-sis showed that the level of the interleukin-6 (IL-6) in the plasma increasing had related to the damage of the cognitive function closely, thus it is a risk factor leading to cognitive impairment.Therefore, the therapeutic measures, decreasing the generation and aggregation of cerebral Aβ, lowering the level of blood fat to improve the brain microenvironment, increasing cerebral blood flow to maintaine normal brain metabolism and lowering the level of IL-6 in plasma to block the inflammation cascade effects of Aβ, have particular significance in the early treatment to MCI.
Tutor Professor Yuan Depei, according to his clinical experience in many years, has proposed a method that strengthening our foundation and brain to treat the MCI, and created this physic liquor and the corresponding plus and minus prescription, whose clinical application has been proven quite effective to improve learning and memory ability significantly and raise the aging integral value of the TCM testimony, moreover, without any side effects. And preliminary experimental study had also confirmed that the physic liquid can be reduce blood viscosity in aged rats and increase the activity of their erythrocyte SOD with a placid way to improve the cellular immune function and against the atrophy of spleen and thymus. Furthermore, this physic liquor could obviously increase the content of noradrenaline (NA) and dopamine (DA) in the brains of experimental animals, and significantly inhibit monoamine oxidase (MAO) and the vitality of acetylcholinesterase (AchE) to pro-mote the learning and memonic ability of laboratory animals.
Objective: This topic was based on the early research of the consolidating foundation and strengthening brain method. To establish experimental animal model in accord with the praxiological and pathological characteristics of MCI;thereby, the mechanism of the consolidating foundation and strengthening brain method to enhancing the learning and memonic ability had been more in-depth revealed, which provided a more extensive basis to the clinical application of this method. Methods:①With systematic review of the literature research methods, analyze the theoretical basis of consolidating foundation and strengthening brain method in treating MCI.②To built MCI model of rats by the way of intra-peritoneal injection of D-galactose and NaNO2.Then,divided into high, medium and low dose, injected into the model animals, and set up the normal control group, and piracetam control group to observe the impact on the Rat Behavior by water maze test, Aβexpression of hippocampus with immunohistochemical staining-method,the level of the serum cholesterol, using routine methods, etc. and the content of serum IL-6 with ELISA.
Results:①The subside of learning and memonic ability, related to five internal organs, six hollow organs, house of Qi Heng, Qi, blood, body fluid, Jing, meridian, and so on. But the most important is the deficiency of spleen and kidney.②Behavior change: the model rats,whose escape latency in the water maze and the time of searching path length and crossing the platform with the same number, was significantly longer than the normal control group (P<0.05). But the treatment of both the consolidating foundation and strengthening brain liquor and piracetam could make the index above improved significantly (P<0.05), even the high and medium dose group of our liquor appeared better treatment (P <0.05).③Aβimmunohistochemistry results:The expression of model group in hippocampus of Aβincreased significantly compared with the normal group, and all the treatment group could reduce the expression of Aβin the hippocampus, but the effect of both the low dose group of our liquor and Piracetam group is not obvious.④The level of serum cholesterol and the content of serum IL-6 changes: The level of serum cholesterol and the content of serum IL-6 of model group increased, significantly higher than the normal group (P<0.05).And our liquor, in spite of any dose, could reduce the level of blood fat and serum IL-6, besides, the effect of high and medium dose group was better. Piracetam group could reduce the level of serum cholesterol effectively (P<0.05), but with a poor effect to lower the level of serum IL-6.
Conclusion: These results suggest that:According to the method of our consolidating foun-dation and strengthening brain to prescribe,can not only promote the learning and memonic ability of the rats with MIC significantly, but also reduce the generation and accumulation of Aβin brain of experimental animals and decrease the levels both the blood fat and Serum IL-6 to improve the brain microenvironment, which can prevent the conversion of MCI to AD effectively. From tests above, a conclusion can be drawn that tutor Professor Yuan Depei's realization that the spleen and kidney deficiency, brain dystrophy, and stagnant phlegm led to cognitive impairment is reasonable, and the consolidating foundation and strengthening brain method is an effective treatment to MCI.
β-淀粉样蛋白(β-amyloid,Aβ)在AD发病机制中的核心作用已经得到广泛接受, Aβ异常释放与沉积是AD老年斑形成的始动因子和老年斑核中的重要成分,在AD的神经细胞损伤级联反应中,淀粉样沉淀等典型病理生理学改变出现于tau蛋白异常磷酸化之前;Aβ代谢异常是MCI向AD转化的可靠生物学指标之一。脂代谢异常会导致脑动脉硬化,从而改变脑微环境、降低脑血流、使脑代谢受损,致使老年认知功能减退;血清胆固醇升高是MCI的重要危险因素,已有发现高胆固醇血症引起脑中Aβ沉积的证据。Aβ的聚集可以经补体途径产生炎症反应,研究提示,中枢炎症是AD病理变化的早期特征;严格回归分析发现血浆中白介素-6(IL-6)水平升高同认知功能损害有密切的关系,是导致认知障碍的危险因素。因此,减少脑内Aβ的生成和集聚,降低血脂水平以改善脑微环境、增加脑血流、保持脑代谢正常,降低血浆中IL-6水平、阻断Aβ的炎症级联效应等治疗措施,在MCI的早期干预治疗中应具有尤其重要的意义。
导师袁德培教授等根据多年临床经验提出以固本健脑立法论治MCI,并依此创制了固本健脑液及相应加减方,临床应用证明确有佳效,能显著改善学习记忆能力和中医辨证之衰老见证积分值,且无任何毒副作用;前期的实验研究也证实,固本健脑液能平和降低老年大鼠血粘度、提高老龄鼠红细胞SOD活力,有提高细胞免疫功能和对抗脾脏、胸腺萎缩的作用;固本健脑方可明显提高实验动物脑中去甲肾上腺素(NA)和多巴胺(DA)的含量,并显著抑制脑内单胺氧化酶(MAO)和乙酰胆碱酯酶(AchE)活力,促进实验动物学习记忆能力。
目的:以固本健脑法的前期研究为基础,建立符合MCI行为学、病理学特征的实验性动物模型,更深入的揭示固本健脑法增强学习记忆能力的机制,为本法在临床更好地化裁应用提供更丰富的依据。
方法:①采用系统回顾性的文献研究方法,分析探讨以固本健脑立法论治MCI的理论基础。②以腹腔注射D-半乳糖和NaNO2的方法建立MCI大鼠模型,予固本健脑液(高、中、低剂量)于模型动物,并设立正常对照组、吡拉西坦(脑复康)对照组比较观察,观察固本健脑液对MCI模型大鼠行为学(水迷宫实验)、海马结构Aβ表达(免疫组化染色法)、血清胆固醇水平(常规酶法等)、血清IL-6含量(ELISA法)的影响。
结果:①记忆能力减退的病变广泛涉及五脏、六腑、奇恒之府、气血津液精、经络等各个环节,但其中最为关键的是脾肾的亏虚。②行为学变化:模型大鼠出现明显的记忆功能障碍,水迷宫实验中其逃避潜伏期、搜索路径长度和跨过平台相同次数所需时间均较正常对照组明显延长(P<0.05),固本健脑液(高、中、低剂量)和吡拉西坦治疗均能使上述指标明显改善(P<0.05),且以固本健脑液高、中剂量组效果更为显著(P<0.05)。③Aβ免疫组化染色结果:模型组海马区Aβ表达较正常组明显增多,各个治疗组均能减少Aβ在海马区的表达,但固本健脑液低剂量组和吡拉西坦组效果相对不突出。④血清胆固醇水平和血清IL-6含量变化:模型组血清胆固醇水平和血清IL-6含量升高,明显高于正常组(P<0.05),固本健脑液各剂量组都能降低血脂水平和血清中IL-6水平,且以高、中剂量组效果更佳;吡拉西坦组可有效降低血清胆固醇水平(P<0.05),但降低血清中IL-6水平的效果不佳。
结论:以上结果提示:按照固本健脑法组方(本课题使用固本健脑液),能显著改善MCI模型大鼠学习记忆功能,可减少实验动物脑内Aβ的生成和聚集、降低血脂水平和血清中IL-6水平、改善脑微环境,从而可以有效防止MCI向AD的转化。以方(法)测证,说明导师袁德培教授等关于脾肾(后、先天之本)亏虚、脑髓失养、兼夹痰瘀导致认知障碍的认识是合理的,依此提出的固本健脑法是MCI的有效治则。
Senile dementia,that is Alzheimer's disease (AD),is a chronic, neurodegenerative disease, which is characterized by the impairment of memory and cognition as the main clinical features. So far there is no completely effective method to treat AD, especially the advanced AD, in that at this time the brain damage has entered an irreversible phase and led to poor treatment. Mild cognitive impairment (MCI) is widely recognized as the pre-dementia state, also the former state of the Alzheimer's disease, thus in-depth study to MCI is expected to provide the best treatment time to prevent and delay AD.
As been widely accepted,β-amyloid protein (Aβ) plays a central role in AD pathogenesis. The abnormal release and deposition of Aβis the initiating factor to form senile plaque and the important components of its core. In the injury cascade reaction of AD's nerve cell, typical changes of the pathophysiology, such as amyloid precipitation,have occurred before the abnormal phosphorylation of tau protein. Be-sides,abnormal metabolism of Aβis one of the reliable biological indicators to show the conversion of MCI to AD.Lipid metabolism may lead to cerebral arteriosclerosis,which will be able to change the brain microenvironment, reduce cerebral blood flow and damage to brain metabolism, resulting in the cognition of the aged declines. So the increase of serum cholesterol is an important and harzardous factor for MCI, and the evidence that high blood cholesterol disease could cause Aβdepositing had been found. Aβaggregating can generate the inflammatory reaction by the pathway of complement, and there have been researches to suggest that central inflammation is the early feature of AD's pathological changes. Moreover, rigorous regression analy-sis showed that the level of the interleukin-6 (IL-6) in the plasma increasing had related to the damage of the cognitive function closely, thus it is a risk factor leading to cognitive impairment.Therefore, the therapeutic measures, decreasing the generation and aggregation of cerebral Aβ, lowering the level of blood fat to improve the brain microenvironment, increasing cerebral blood flow to maintaine normal brain metabolism and lowering the level of IL-6 in plasma to block the inflammation cascade effects of Aβ, have particular significance in the early treatment to MCI.
Tutor Professor Yuan Depei, according to his clinical experience in many years, has proposed a method that strengthening our foundation and brain to treat the MCI, and created this physic liquor and the corresponding plus and minus prescription, whose clinical application has been proven quite effective to improve learning and memory ability significantly and raise the aging integral value of the TCM testimony, moreover, without any side effects. And preliminary experimental study had also confirmed that the physic liquid can be reduce blood viscosity in aged rats and increase the activity of their erythrocyte SOD with a placid way to improve the cellular immune function and against the atrophy of spleen and thymus. Furthermore, this physic liquor could obviously increase the content of noradrenaline (NA) and dopamine (DA) in the brains of experimental animals, and significantly inhibit monoamine oxidase (MAO) and the vitality of acetylcholinesterase (AchE) to pro-mote the learning and memonic ability of laboratory animals.
Objective: This topic was based on the early research of the consolidating foundation and strengthening brain method. To establish experimental animal model in accord with the praxiological and pathological characteristics of MCI;thereby, the mechanism of the consolidating foundation and strengthening brain method to enhancing the learning and memonic ability had been more in-depth revealed, which provided a more extensive basis to the clinical application of this method. Methods:①With systematic review of the literature research methods, analyze the theoretical basis of consolidating foundation and strengthening brain method in treating MCI.②To built MCI model of rats by the way of intra-peritoneal injection of D-galactose and NaNO2.Then,divided into high, medium and low dose, injected into the model animals, and set up the normal control group, and piracetam control group to observe the impact on the Rat Behavior by water maze test, Aβexpression of hippocampus with immunohistochemical staining-method,the level of the serum cholesterol, using routine methods, etc. and the content of serum IL-6 with ELISA.
Results:①The subside of learning and memonic ability, related to five internal organs, six hollow organs, house of Qi Heng, Qi, blood, body fluid, Jing, meridian, and so on. But the most important is the deficiency of spleen and kidney.②Behavior change: the model rats,whose escape latency in the water maze and the time of searching path length and crossing the platform with the same number, was significantly longer than the normal control group (P<0.05). But the treatment of both the consolidating foundation and strengthening brain liquor and piracetam could make the index above improved significantly (P<0.05), even the high and medium dose group of our liquor appeared better treatment (P <0.05).③Aβimmunohistochemistry results:The expression of model group in hippocampus of Aβincreased significantly compared with the normal group, and all the treatment group could reduce the expression of Aβin the hippocampus, but the effect of both the low dose group of our liquor and Piracetam group is not obvious.④The level of serum cholesterol and the content of serum IL-6 changes: The level of serum cholesterol and the content of serum IL-6 of model group increased, significantly higher than the normal group (P<0.05).And our liquor, in spite of any dose, could reduce the level of blood fat and serum IL-6, besides, the effect of high and medium dose group was better. Piracetam group could reduce the level of serum cholesterol effectively (P<0.05), but with a poor effect to lower the level of serum IL-6.
Conclusion: These results suggest that:According to the method of our consolidating foun-dation and strengthening brain to prescribe,can not only promote the learning and memonic ability of the rats with MIC significantly, but also reduce the generation and accumulation of Aβin brain of experimental animals and decrease the levels both the blood fat and Serum IL-6 to improve the brain microenvironment, which can prevent the conversion of MCI to AD effectively. From tests above, a conclusion can be drawn that tutor Professor Yuan Depei's realization that the spleen and kidney deficiency, brain dystrophy, and stagnant phlegm led to cognitive impairment is reasonable, and the consolidating foundation and strengthening brain method is an effective treatment to MCI.
引文
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