涤痰汤对Alzheimer病模型大鼠行为学及中枢胆碱能系统的影响
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摘要
目的
本实验通过在老年大鼠前脑基底核注射Aβ_(25-35)和IBO混合液诱导复合AD动物模型，观察涤痰汤对AD模型大鼠行为学及中枢胆碱能系统的影响，探讨涤痰汤治疗AD的机制，为涤痰汤治疗AD提供科学依据。
方法
15月龄Wistar大鼠50只，雌雄各半，随机分为5组，即正常组、假手术组、模型组、哈伯因组、涤痰汤组，每组10只。采用大鼠前脑基底核注射Aβ_(25-35)和IBO混合液诱导复合AD动物模型。动物经涤痰汤和哈伯因干预28天后，各组大鼠用Morris水迷宫行为学实验(包括定位航行实验和空间搜索实验两部分)检测大鼠学习记忆能力，并用放射免疫法检测大鼠海马和皮质区Ach、AchE和ChAT活性变化。
结果
1．大鼠定位航行实验前4天平均潜伏期和后2天平均潜伏期表明：模型组潜伏期较其他组明显延长，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较有显著差异(P＜0.01)。哈伯因组与涤痰汤组前4天潜伏期比较有显著差异(P＜0.01)，涤痰汤组少于哈伯因组，后2天潜伏期无差异(P＞0.05)。正常组与假手术组比较无差异(P＞0.05)。
2．大鼠定位航行实验表明：模型组象限百分比明显减少，20％区域和40％区域明显增加，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较有显著差异(P＜0.01)。哈伯因组与涤痰汤组比较40％区域有显著差异(P＜0.01)，涤痰汤组短于哈伯因组，象限百分比和20％区域无差异(P＞0.05)。正常组与假手术组比较无差异(P＞0.05)。
3．大鼠空间搜索实验表明：模型组象限百分与其他组比较明显减少，而20％区域和40％区域则明显增加，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较有显著差异(P＜0.01)。哈伯因组与涤痰汤组比较20％区域有明显差异(P＜0.01)，涤痰汤组少于哈伯因组，象限百分比和40％区域无差异(P＞0.05)。正常组与假手术组无差异(P＞0.05)。
4．大鼠穿过原平台位置次数的实验表明：模型组穿过原平台位置次数明显比其它各组少，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较有显著差异(P＜0.01)。哈伯因组与涤痰汤组比较无显著差异(P＞0.05)，正常组与假手术组比较无显著差异(P＞0.05)。
5．大鼠中枢胆碱能系统的实验表明：模型组脑组织Ach和ChAT活性明显减少，AchE活性明显升高，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较Ach、ChAT活性明显减少，AchE活性明显增加，统计有显著差异(P＜0.01)。涤痰汤组Ach、ChAT活性与哈伯因组比较增加，统计有差异(P＜0.05)，AchE活性两组比较无差异(P＞0.05)。正常组与假手术组比较无差异(P＞0.05)。
结论
1．老年大鼠前脑基底核区注射Aβ_(25-35)和IBO混合液诱导复合老年性痴呆大鼠模型，表现为学习记忆能力明显降低，Ach、ChAT活性明显降低，AchE活性明显升高，该模型体现了AD的部分特点，是一种较可靠的AD动物模型。
2．涤痰汤可显著改善AD模型大鼠的学习记忆障碍。
3．涤痰汤可提高脑组织中Ach和ChAT的表达，降低AchE的活性，对中枢胆碱能系统损害具有保护作用。
4．中医痰与AD的发生、发展有密切关系，涤痰开窍法是防治AD的基本治法，涤痰汤治疗AD疗效肯定。
Objective
This experiment in old rats forebrain nuclear injection IBO and Aβ_(25-35)mixture of compound-induced animal model of AD observed Ditan decoction ratmodel of AD behavior and the central cholinergic system, Discussion Ditan treatingAD mechanism for the treatment ofAD Ditan decoction provide a scientific basis.
Method
5-month-old Wistar rats 50, half male and half female, were divided into fivegroups: normal, sham-operated group, model group, Huperzine A group and Ditandecoction groups, each 10. Rat forebrain nuclear injection and IBO Aβ_(25-35) mixtureof compound-induced animal model of AD. Animal Ditan decoction and Haberintervention by 28 days, the rats with Morris water maze behavioral experiments(including positioning navigation experiments and experimental search space of twoparts) Frederick Measuring learning and memory in rats and usedassayed.Meanwhile rat hippocampus and cortex Ach, AchE and ChAT activity.
Results
1. Experimental rats navigation positioning before the average incubation periodis four clays after two days and the average incubation period showed : model grouplatency than other groups significantly prolonged compared with the normal grouphad significantly (P＜0.01) Huperzine A Group and the group Ditan decoctionsignificant differences (P＜0.01). Huperzine A group Ditan Decoction four daysbefore the incubation period more significant difference (P＜0.01) Ditan Decoctionless than Huperzine group, after two days of incubation period (P＞0.05). Normalgroup and sham surgery group (P＞0.05).
2. Rats positioning navigation experiments show: the model group quadrantpercentage reduction, 20% and 40% of the regional regional significantly increasedCompared with the normal group had significantly (P＜0.01) Huperzine A and Group and the group Ditan decoction significant differences (P＜0.01). Huperzine A groupDitan decoction regional group 40% significant differences (P＜0.01) DitanDecoction short of Huperzine A group quadrant% and 20% no regional difference(P＞0.05). Normal group and sham surgery group (P＞0.05).
3. Spatial search results show: the model group quadrant% compared with theother groups decreased, and 20% and 40% of the region there is a marked increasefrom the region, compared with the normal group had significantly (P＜0.01)Huperzine A and Group and the group Ditan decoction significant differences(P＜0.01). Huperzine A group Ditan decoction regional group is 20% (P＜0.01) DitanDecoction less than Huperzine A group quadrant% and 40% no regional difference(P＞0.05). Normal group and sham surgery group (P＞0.05).
4. In the original platform location through the number of experiments show:the original model through the platform location other than the obvious number ofthe small group, Compared with the normal group had significantly (P＜0.01).Huperzine group and Ditan decoction with model group compared with a significantdifference (P＜0.01) normal group and sham group showed no significant difference(P＞0.05), Huperzine A group Ditan Decoction group was no significant difference(P＞0.05).
5. Rats central cholinergic system experiments show: model Ach brain tissueand reduce the activity of CHAT, AchE activity was significantly higher, comparedwith the normal group had significantly (P＜0.01) Huperzine A and Group decoctionand Ditan group Ach, CHAT activity was significantly reduced, AchE activityincreased significantly, statistical significant difference (P＜0.01). Ditan DecoctionAch, ChAT activity and Huperzine group, a statistical difference (P＜0.05) AchEactivity of the two groups showed no difference (P＞0.05). Normal group and shamsurgery group (P＞0.05).
Conclusion
1. Aged rat basal forebrain nuclei injection IBO and Aβ_(25-35) mixture ofcompound-induced Alzheimer's disease rats, performance of the learning andmemory abilities significantly lower Ach, ChAT activity decreased significantlyincreased activity of AchE, The model embodies the characteristics of the AD is amore reliable animal model of AD.
2. Ditan decoction can be significantly improved AD rat model of learning andmemory impairment.
3. Ditan decoction can enhance brain tissue Ach and the expression of CHAT,reducing the activity of AchE. the cholinergic nervous system damage protectiverole.
4. Chinese AD incidence of sputum and development is closely related to DitanResuscitation control is the basic rule AD, Ditan decoction Treatment AD efficacy.
本实验通过在老年大鼠前脑基底核注射Aβ_(25-35)和IBO混合液诱导复合AD动物模型，观察涤痰汤对AD模型大鼠行为学及中枢胆碱能系统的影响，探讨涤痰汤治疗AD的机制，为涤痰汤治疗AD提供科学依据。
方法
15月龄Wistar大鼠50只，雌雄各半，随机分为5组，即正常组、假手术组、模型组、哈伯因组、涤痰汤组，每组10只。采用大鼠前脑基底核注射Aβ_(25-35)和IBO混合液诱导复合AD动物模型。动物经涤痰汤和哈伯因干预28天后，各组大鼠用Morris水迷宫行为学实验(包括定位航行实验和空间搜索实验两部分)检测大鼠学习记忆能力，并用放射免疫法检测大鼠海马和皮质区Ach、AchE和ChAT活性变化。
结果
1．大鼠定位航行实验前4天平均潜伏期和后2天平均潜伏期表明：模型组潜伏期较其他组明显延长，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较有显著差异(P＜0.01)。哈伯因组与涤痰汤组前4天潜伏期比较有显著差异(P＜0.01)，涤痰汤组少于哈伯因组，后2天潜伏期无差异(P＞0.05)。正常组与假手术组比较无差异(P＞0.05)。
2．大鼠定位航行实验表明：模型组象限百分比明显减少，20％区域和40％区域明显增加，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较有显著差异(P＜0.01)。哈伯因组与涤痰汤组比较40％区域有显著差异(P＜0.01)，涤痰汤组短于哈伯因组，象限百分比和20％区域无差异(P＞0.05)。正常组与假手术组比较无差异(P＞0.05)。
3．大鼠空间搜索实验表明：模型组象限百分与其他组比较明显减少，而20％区域和40％区域则明显增加，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较有显著差异(P＜0.01)。哈伯因组与涤痰汤组比较20％区域有明显差异(P＜0.01)，涤痰汤组少于哈伯因组，象限百分比和40％区域无差异(P＞0.05)。正常组与假手术组无差异(P＞0.05)。
4．大鼠穿过原平台位置次数的实验表明：模型组穿过原平台位置次数明显比其它各组少，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较有显著差异(P＜0.01)。哈伯因组与涤痰汤组比较无显著差异(P＞0.05)，正常组与假手术组比较无显著差异(P＞0.05)。
5．大鼠中枢胆碱能系统的实验表明：模型组脑组织Ach和ChAT活性明显减少，AchE活性明显升高，与正常组比较有显著差异(P＜0.01)，与哈伯因组和涤痰汤组比较Ach、ChAT活性明显减少，AchE活性明显增加，统计有显著差异(P＜0.01)。涤痰汤组Ach、ChAT活性与哈伯因组比较增加，统计有差异(P＜0.05)，AchE活性两组比较无差异(P＞0.05)。正常组与假手术组比较无差异(P＞0.05)。
结论
1．老年大鼠前脑基底核区注射Aβ_(25-35)和IBO混合液诱导复合老年性痴呆大鼠模型，表现为学习记忆能力明显降低，Ach、ChAT活性明显降低，AchE活性明显升高，该模型体现了AD的部分特点，是一种较可靠的AD动物模型。
2．涤痰汤可显著改善AD模型大鼠的学习记忆障碍。
3．涤痰汤可提高脑组织中Ach和ChAT的表达，降低AchE的活性，对中枢胆碱能系统损害具有保护作用。
4．中医痰与AD的发生、发展有密切关系，涤痰开窍法是防治AD的基本治法，涤痰汤治疗AD疗效肯定。
Objective
This experiment in old rats forebrain nuclear injection IBO and Aβ_(25-35)mixture of compound-induced animal model of AD observed Ditan decoction ratmodel of AD behavior and the central cholinergic system, Discussion Ditan treatingAD mechanism for the treatment ofAD Ditan decoction provide a scientific basis.
Method
5-month-old Wistar rats 50, half male and half female, were divided into fivegroups: normal, sham-operated group, model group, Huperzine A group and Ditandecoction groups, each 10. Rat forebrain nuclear injection and IBO Aβ_(25-35) mixtureof compound-induced animal model of AD. Animal Ditan decoction and Haberintervention by 28 days, the rats with Morris water maze behavioral experiments(including positioning navigation experiments and experimental search space of twoparts) Frederick Measuring learning and memory in rats and usedassayed.Meanwhile rat hippocampus and cortex Ach, AchE and ChAT activity.
Results
1. Experimental rats navigation positioning before the average incubation periodis four clays after two days and the average incubation period showed : model grouplatency than other groups significantly prolonged compared with the normal grouphad significantly (P＜0.01) Huperzine A Group and the group Ditan decoctionsignificant differences (P＜0.01). Huperzine A group Ditan Decoction four daysbefore the incubation period more significant difference (P＜0.01) Ditan Decoctionless than Huperzine group, after two days of incubation period (P＞0.05). Normalgroup and sham surgery group (P＞0.05).
2. Rats positioning navigation experiments show: the model group quadrantpercentage reduction, 20% and 40% of the regional regional significantly increasedCompared with the normal group had significantly (P＜0.01) Huperzine A and Group and the group Ditan decoction significant differences (P＜0.01). Huperzine A groupDitan decoction regional group 40% significant differences (P＜0.01) DitanDecoction short of Huperzine A group quadrant% and 20% no regional difference(P＞0.05). Normal group and sham surgery group (P＞0.05).
3. Spatial search results show: the model group quadrant% compared with theother groups decreased, and 20% and 40% of the region there is a marked increasefrom the region, compared with the normal group had significantly (P＜0.01)Huperzine A and Group and the group Ditan decoction significant differences(P＜0.01). Huperzine A group Ditan decoction regional group is 20% (P＜0.01) DitanDecoction less than Huperzine A group quadrant% and 40% no regional difference(P＞0.05). Normal group and sham surgery group (P＞0.05).
4. In the original platform location through the number of experiments show:the original model through the platform location other than the obvious number ofthe small group, Compared with the normal group had significantly (P＜0.01).Huperzine group and Ditan decoction with model group compared with a significantdifference (P＜0.01) normal group and sham group showed no significant difference(P＞0.05), Huperzine A group Ditan Decoction group was no significant difference(P＞0.05).
5. Rats central cholinergic system experiments show: model Ach brain tissueand reduce the activity of CHAT, AchE activity was significantly higher, comparedwith the normal group had significantly (P＜0.01) Huperzine A and Group decoctionand Ditan group Ach, CHAT activity was significantly reduced, AchE activityincreased significantly, statistical significant difference (P＜0.01). Ditan DecoctionAch, ChAT activity and Huperzine group, a statistical difference (P＜0.05) AchEactivity of the two groups showed no difference (P＞0.05). Normal group and shamsurgery group (P＞0.05).
Conclusion
1. Aged rat basal forebrain nuclei injection IBO and Aβ_(25-35) mixture ofcompound-induced Alzheimer's disease rats, performance of the learning andmemory abilities significantly lower Ach, ChAT activity decreased significantlyincreased activity of AchE, The model embodies the characteristics of the AD is amore reliable animal model of AD.
2. Ditan decoction can be significantly improved AD rat model of learning andmemory impairment.
3. Ditan decoction can enhance brain tissue Ach and the expression of CHAT,reducing the activity of AchE. the cholinergic nervous system damage protectiverole.
4. Chinese AD incidence of sputum and development is closely related to DitanResuscitation control is the basic rule AD, Ditan decoction Treatment AD efficacy.
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37. Li Y, Qin HQ, Chen QS, et al.Neurochemical and behavioral effects of the intrahippocampal co-injection of beta-amyloid proteinl-40 and ibotenic acid in rats.Life Sci. 2005,76(11): 1189-97.
38. Doody RS Stevens JC, Beck C, et al Practice Paran elerc Standants Subeunm ittee of the American Academy Neurology, Neurology 2001, 56 1154
39．黄天俊．应用层析—酶抑制技术确定若干结构类型的中药活性成分 华西药学杂志，1988，3(1)：19
40. Van Leeuwen F W, de Kleijn D P V, van den Hurk H H, et al. Frameshift mutants of beta amyloid precursor protein and ubiquitin in Alzheimer's disease and Down patients. Science. 1998, 279 (5348): 242-247.
41. xiao XQ,wangR,HanYF, et al Protective effects of HUperzine A on betamy loid(25-35) induced oxidative injury in ran pheochromocy tom a cells Neurocisc lett 2000(286)(3): 155
42．闵知人．近几年来中医药治疗老年性痴呆的概况[M]中药研究与开发综述一香港科技大学生物技术研究所访问学者文集，北京：科学出版社2000
43．魏翠柏，田金洲，贾建平．老年痴呆中医病因病机理论的认识与思考 中华中医药杂志(原中国医药学报)，2005，20(8)：496-498
1．王平．脑衰老与老年痴呆的中医病机探析．湖北中医杂志 2002，9：4-5
2．任振华、李光武．中药有效成分治疗老年性痴呆的研究进展中成药 2004，26(12)：76-78
3．杨济民．老年性痴呆的中医论治．中医药研究，2001，17(2)：61-62
4．刘胜坚．中医对老年痴呆研究．光明中医，2006，21(1)：18-19
5．李雅根．．浅析从痰瘀互结论治老年性痴呆．江西中药，2002，33，(2)：19
6．吴烈钊．从中医理论谈老年痴呆的诊治和预防．汕头医学院学报，1998，11：44-45
7．王平．脑衰老与老年痴呆的中医病机探析．湖北中医杂志2002，9：4-5
8．闵知人．近几年来中医药治疗老年性痴呆的概况．中药研究与开发综述一香港科技大学生物技术研究所访问学者文集，北京：科学出版社 2000
9．杨济民．老年性痴呆的中医论治．中医药研究2001，17(2)：58—59
10．金虹．试论从中草药活性成分开发新型治疗阿尔茨海默病的酶抑制剂时珍国医国药2006，17(1)：19-20
11．杜怀棠、周丽珍．近十年中医衰老学说研究述评．北京中医报，1996，18(12)：2
12．魏翠柏、田金洲、贾建平．老年痴呆中医病因病机理论的认识与思考．中华中医药杂志(原中国医药学报) 2005，20(8)：496-498．
1．李谷才、尹端沚、夏姣云、汪勇先．阿尔茨海默病研究进展．脑与神经疾病杂志．2005，13(40)73-74．
2．陈新平、陈彪．阿尔茨海默病病因学及发病机制研究进展．中国现代神经疾病杂志．2005，5(3)20-23．
3．赖红、叶和珏、赵海花．新型胆碱酯酶抑制剂对AD大鼠空间记忆和海马结构胆碱能纤维的影响．中国药理学通报．2005，21(7)841-844
4. Mufson EJ,IkonomovicMD,StyrenSD,etal。Preservation of brain nerve growth factorinmild cognitive impairment and Alzheimer's disease[J]. Arch Neurol,2003,60(8):1143-1148
5. M orimoto K, Yoshimi K,Tonohiro T et al. co-injection of beta-amyloid with ibotenic acid induces synergistic loss of rat hippo-campal neurons.Neuroscience, 1998, 84(2)479-487.
6．刘佳福综述．刘振国审校阿尔茨海默病炎症发病机制的研究进展．中风与神经疾病杂志2004，21(5)87-88．
7．丁新生．阿尔茨海默病的生物学标志和影像学检查．中国现代神经疾病杂志．2005，5(3)：9-14．
8．赵树民，李长龄．阿尔茨海默病发生机制研究的新方向——胆固醇代谢．中国新药杂志．2005，14(11)19-24．
9．耿佃盛．神经生长因子与老年性痴呆．国外经病学神经外科学分册，2000，7(3)153-156
10．韩济生．神经科学纲要．北京：北京医科大学中国协和医科大学联合出版社．1993：765-773
11. Abe E,Casamenti F, Giovannelli L.et al.Administration of arnyloid β-peptides into the medical septum of rats decrease acetylcho-line release from hippocampus in vivo.Brain Res,1994, 633(1-2) 162-164.
12. Li Y, Qin HQ, Chen QS, et al.Neurochemical and behavioral effects of the intrahippocampal co-injection of beta-amyloid pro tein1-40 and ibotenic acid in rats.Life Sci. 2005,76(11) 1189-119.
13. Ito Y, Ito M, Takagi N, et al. Neurotoxicity induced by amyloid beta-peptide and ibotenic acid in organotypic hippocampal cul- tures: protection by S-allyl-L-cysteine, a garlic compound. Brain Res. 2003, 985(1): 98-107
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4．张均田，石成璋，梅保幸，等．“水迷宫”自动控制仪的研制及在神经药理研究中的应用 药物分析杂志，1991，11：23-26．
5．包新民，舒斯云．人鼠脑立体定位图谱．北京人民卫生出版社，1991．31-32．
6．陈新平，陈彪．阿尔茨海默病因学及发病机制研究进展．中国现代神经疾病杂志，2005，5(3)：152-154．
7．丁新生．阿尔茨海默病的生物学标志和影像学检查．中国现代神经疾病杂志．2005，5(3)：141-146．
8．黑爱莲，蔡剑平．阿尔茨海默病的概况综述．中国神经免疫学和神经病学杂志，2005，12(4)：42-44．
9. Dunnett SB, Everitt BJ, Robin Tw The basal forebrain—cortical cholinergic system: Interpreting function consequences of excitotoxic lesions. Trends in Neuroscience, 1991, 14:494—501
10. Abe E,Casamenti F, Giovannelli L.et al.Administration of amyloid β-peptides into the medical septum of rats decrease acetylcho- line release from hippocampus in vivo.Brain Res, 1994, 633 (1-2): 162-164.
11．陈可冀主编．跨世纪脑科学：老年性痴呆发病机理与诊治．北京：北京医科大学中国协和医科大学联合出版社，1998：309-314，174-181
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13. xiao XQ,wangR,HanYF, et al Protective effects of HUperzine A on betamy loid(25-35) induced oxidative injury in ran pheochromocy tom a cells
14．王彩霞，李德新．滋脾益智方对三种智力障碍模型小鼠益智作用的比较．中医药学刊，2002，20(4)：438-439
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20．周礼，梁平．阿尔茨海默病分子病理机制研究进展．中华老年医学杂志，2001，20(2)：151-153．
21．岳建平．涤痰化瘀法治疗老年脑血管性痴呆症20例[J]湖北中医杂志，1996，(03)．28-29．
22．李雅根．浅析从痰瘀互结论治老年性痴呆．江西中药，2002，33，(2)：19．
23．吴烈钊．从中医理论谈老年痴呆的诊治和预防．汕头医学院学报，1998，11：44-45．
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25. Ghanevati M, Miller CA.Phospho-beta-catenin accumulation in Alzheimer's disease and in aggresomes attributable to proteasome dysfunction. J Mol Neurosci. 2005,25(1):79-94.
26．任振华、李光武．中药有效成分治疗老年性痴呆的研究进展．中成药2004，26(12)：76-78．
27．彭国平、牛贺明、徐丽华．枳实活性成分的研究．南京中医药大学学报(自然科学版)2001，17，(2)：26-27．
28．刘雪松．益智药物对老年智能改变作用的探讨．上海中医药杂志，1987，(10)：30．
29．杜怀棠，周丽珍．近十年中医衰老学说研究述评．北京中医药大学报，1996，18(12)：2．
30．王平．脑衰老与老年痴呆的中医病机探析．湖北中医杂志，2002，9：4-5
31．张均田，石成璋，梅保幸，等．“水迷宫”自动控制仪的研制及在神经药理研究中的应用[J]药物分析杂志，1991，11：23-26
32. Pappolla MA,ChyanYJ,Poeggeler B.An assessment of the antioxi- dant and the antiamyloidugenip roperties of melatonin: implcations for Alzheimer's disease. Neural Transm,2000, 107(1): 23-31
33. Lee C, Yu MH.. Protein folding and diseases. J Biochem Mol Biol. 2005,38(3):275-280.
34. Ohda C. Tamara T, Komatsu K.Repair of amyloid beta (25-35) induced memory impairment and synaptic lose by a Kampo formula. Zokumei-to. Brain Res, 2003,990(1-2): 141-147
35. Wilkinson,K.D. Ubiquifinafion and deubiquitination:targeting of proteins for degradation by the proteasome.Semin Cell Dev Bid,2000 (11): 141-148.
36. M orimoto K, Yoshimi K,Tonohiro T et al.co-injection of beta- amyloid with ibotenic acid induces synergistic loss of rat hippo- campal neurons.Neuroscience, 1998, 84(2): 479-487.
37. Li Y, Qin HQ, Chen QS, et al.Neurochemical and behavioral effects of the intrahippocampal co-injection of beta-amyloid proteinl-40 and ibotenic acid in rats.Life Sci. 2005,76(11): 1189-97.
38. Doody RS Stevens JC, Beck C, et al Practice Paran elerc Standants Subeunm ittee of the American Academy Neurology, Neurology 2001, 56 1154
39．黄天俊．应用层析—酶抑制技术确定若干结构类型的中药活性成分 华西药学杂志，1988，3(1)：19
40. Van Leeuwen F W, de Kleijn D P V, van den Hurk H H, et al. Frameshift mutants of beta amyloid precursor protein and ubiquitin in Alzheimer's disease and Down patients. Science. 1998, 279 (5348): 242-247.
41. xiao XQ,wangR,HanYF, et al Protective effects of HUperzine A on betamy loid(25-35) induced oxidative injury in ran pheochromocy tom a cells Neurocisc lett 2000(286)(3): 155
42．闵知人．近几年来中医药治疗老年性痴呆的概况[M]中药研究与开发综述一香港科技大学生物技术研究所访问学者文集，北京：科学出版社2000
43．魏翠柏，田金洲，贾建平．老年痴呆中医病因病机理论的认识与思考 中华中医药杂志(原中国医药学报)，2005，20(8)：496-498
1．王平．脑衰老与老年痴呆的中医病机探析．湖北中医杂志 2002，9：4-5
2．任振华、李光武．中药有效成分治疗老年性痴呆的研究进展中成药 2004，26(12)：76-78
3．杨济民．老年性痴呆的中医论治．中医药研究，2001，17(2)：61-62
4．刘胜坚．中医对老年痴呆研究．光明中医，2006，21(1)：18-19
5．李雅根．．浅析从痰瘀互结论治老年性痴呆．江西中药，2002，33，(2)：19
6．吴烈钊．从中医理论谈老年痴呆的诊治和预防．汕头医学院学报，1998，11：44-45
7．王平．脑衰老与老年痴呆的中医病机探析．湖北中医杂志2002，9：4-5
8．闵知人．近几年来中医药治疗老年性痴呆的概况．中药研究与开发综述一香港科技大学生物技术研究所访问学者文集，北京：科学出版社 2000
9．杨济民．老年性痴呆的中医论治．中医药研究2001，17(2)：58—59
10．金虹．试论从中草药活性成分开发新型治疗阿尔茨海默病的酶抑制剂时珍国医国药2006，17(1)：19-20
11．杜怀棠、周丽珍．近十年中医衰老学说研究述评．北京中医报，1996，18(12)：2
12．魏翠柏、田金洲、贾建平．老年痴呆中医病因病机理论的认识与思考．中华中医药杂志(原中国医药学报) 2005，20(8)：496-498．
1．李谷才、尹端沚、夏姣云、汪勇先．阿尔茨海默病研究进展．脑与神经疾病杂志．2005，13(40)73-74．
2．陈新平、陈彪．阿尔茨海默病病因学及发病机制研究进展．中国现代神经疾病杂志．2005，5(3)20-23．
3．赖红、叶和珏、赵海花．新型胆碱酯酶抑制剂对AD大鼠空间记忆和海马结构胆碱能纤维的影响．中国药理学通报．2005，21(7)841-844
4. Mufson EJ,IkonomovicMD,StyrenSD,etal。Preservation of brain nerve growth factorinmild cognitive impairment and Alzheimer's disease[J]. Arch Neurol,2003,60(8):1143-1148
5. M orimoto K, Yoshimi K,Tonohiro T et al. co-injection of beta-amyloid with ibotenic acid induces synergistic loss of rat hippo-campal neurons.Neuroscience, 1998, 84(2)479-487.
6．刘佳福综述．刘振国审校阿尔茨海默病炎症发病机制的研究进展．中风与神经疾病杂志2004，21(5)87-88．
7．丁新生．阿尔茨海默病的生物学标志和影像学检查．中国现代神经疾病杂志．2005，5(3)：9-14．
8．赵树民，李长龄．阿尔茨海默病发生机制研究的新方向——胆固醇代谢．中国新药杂志．2005，14(11)19-24．
9．耿佃盛．神经生长因子与老年性痴呆．国外经病学神经外科学分册，2000，7(3)153-156
10．韩济生．神经科学纲要．北京：北京医科大学中国协和医科大学联合出版社．1993：765-773
11. Abe E,Casamenti F, Giovannelli L.et al.Administration of arnyloid β-peptides into the medical septum of rats decrease acetylcho-line release from hippocampus in vivo.Brain Res,1994, 633(1-2) 162-164.
12. Li Y, Qin HQ, Chen QS, et al.Neurochemical and behavioral effects of the intrahippocampal co-injection of beta-amyloid pro tein1-40 and ibotenic acid in rats.Life Sci. 2005,76(11) 1189-119.
13. Ito Y, Ito M, Takagi N, et al. Neurotoxicity induced by amyloid beta-peptide and ibotenic acid in organotypic hippocampal cul- tures: protection by S-allyl-L-cysteine, a garlic compound. Brain Res. 2003, 985(1): 98-107