通天草提取物对β-淀粉样蛋白诱导的AD大鼠的保护作用及分子机制研究
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摘要
目的：研究通天草提取物对老年痴呆(AD)大鼠的保护作用及机制。
方法：通天草提取物由本实验室提取并制成水提物和醇提物。将初筛后的大鼠随机分成以下8组：阴性对照组、假手术组、AD模型组、西药治疗组、通天草醇提物低剂量组和高剂量组、水提物低剂量组和高剂量组。采用脑内注射Aβ1-40(10μg/鼠),建立大鼠老年痴呆模型,然后给予通天草提取物治疗28d。采用Morris水迷宫实验检测大鼠的学习记忆等行为学能力；采用HE染色和透射电镜对海马组织进行病理学检测；血清中GSH-Px和T-SOD的活力以及MDA含量采用分光光度法进行测定；采用ELISA法检测血清中IL-1、IL-6、TNF-α的水平；采用免疫组织化学方法检测nNOS、iNOS、bcl-2、bax、GFAP蛋白的表达；采用RT-PCR法检测海马组织中NF-κB、IκB、H SP70、APP和BACE1mRNA的表达。
结果
1、通过Morris水迷宫实验和病理学检测结果,可以肯定本实验成功建立了Aβ诱导的AD大鼠模型。主要表现为逃避潜伏期明显延长AD模型组为(45.5±6.25)s,明显高于阴性对照组(24.5±5.75)s。AD模型组的穿越跳台次数(1.7±0.89)明显低于阴性对照组(3.2±1.27)。透射电镜结果显示,AD模型组海马神经元细胞间隔增大,突触明显减少,突触小泡融合,肿胀明显；神经元细胞皱缩明显,核膜皱缩并出现阶段性融合,核形异常,异染色质聚集,细胞器如线粒体、核糖体、溶酶体损伤明显,脂褐素异常增多
2、通天草提取物能明显改善AD大鼠的学习记忆能力。低、高剂量的醇提物投予动物后,能以剂量依赖方式明显缩短大鼠的逃避潜伏期,分别为(34.5±7.25)s和(24.0±6.5)s,与AD模型组(45.5±7.3)比较,差异有统计学意义；高剂量醇提物的降低作用与西药治疗组相似。同时通天草提取物各组均在不同程度上增加了大鼠穿越跳台的次数,高剂量醇提物的作用尤为明显
3、病理学HE染色结果可见,高剂量醇提物作用组大鼠海马区神经元细胞数量较AD模型组明显增多,神经元细胞核形态及排列紧密度上均明显改善,类似于西药治疗组。透射电镜可见,与AD模型组大鼠海马神经元细胞(细胞膜、细胞器等)的明显损伤相比,西药治疗组神经元细胞间界限清晰,连接较紧密,核形基本正常,核糖体、线粒体结构基本正常,脂褐素增多不明显,但仍可见毛细血管及星形胶质细胞肿胀；高剂量的通天草水提物和醇提物组海马神经元细胞皱缩不明显,突触数量有一定的增加,神经元细胞核尚欠规则,低剂量醇提物组可见大量的自噬体存在。
4、血清学检测结果发现,通天草提取物各组能明显抑制血清中Aβ1-40水平,与AD模型组(316.8±28.2pg/mL)相比,差异有显著性(p<0.05,p<0.01),醇提物的作用更明显。通天草醇提物(高、低剂量)和水提物高剂量组能明显降低MDA水平,同时增加GSH-Px的活性；通天草提取物各组均能增加T-SOD的活性,与AD模型组比较,差异显著(p<0.01,p<0.05)。血清学炎症因子(IL-1、IL-6、TNF-α)检测结果显示,通天草提取物各组均能在一定程度上降低Aβ诱发的炎症因子分泌,特别是高剂量醇提物对各炎症因子的抑制作用更加明显。
5、大鼠海马组织的免疫组化结果显示,通天草提取物能抑制Aβ诱导的海马GFAP蛋白的表达,诱导抗凋亡蛋白bcl-2同时抑制促凋亡蛋白bax蛋白的表达,使bcl-2/bax的比值增加。此外,高剂量的通天草提取物(醇提物和水提物)能明显抑制诱导型一氧化氮合酶(iNOS)的表达,同时促进神经元型一氧化氮合酶(nNOS)的表达
6、RT-PCR结果显示,通天草提取物能明显降低Aβ前体APP mRNA的表达,同时降低APP的β-裂解酶BACE1mRNA表达,高剂量醇提物的抑制作用尤为明显。此外,通天草提取物(特别是醇提物)能明显降低NF-κB mRNA的表达,同时增强其抑制因子IκB mRNA的表达。HSP70的表达在AD模型组并无显著变化(与阴性对照组比较,p>0.05)。
结论
1、采用脑内注射Aβ蛋白,成功建立了Aβ诱导的AD大鼠模型。
2、通天草提取物能明显改善AD大鼠的学习记忆能力,高剂量醇提物的作用与西药治疗组相似。通天草提取物能部分改善Aβ对大鼠海马神经元细胞的病理学表现。通天草提取物能明显抑制血清中Aβ1-40水平,该作用与抑制Aβ前体物APP mRNA的表达、降低APP裂解酶BACE1mRNA的表达有关。
3、通天草提取物保护AD大鼠的可能分子机制如下
(1)通过诱导GSH-Px和T-SOD的活性、抑制MDA生成而增强抗氧化能力;
(2)通过抑制炎症因子IL-1、IL-6和TNF-α的分泌,降低Aβ引起的炎性损伤,该作用与NF-κB/IκB调节通路及iNOS有关。
(3)通过诱导bcl-2蛋白同时抑制bax蛋白的表达,抑制海马神经细胞凋亡；通过抑制海马星形胶质细胞中GFAP蛋白的表达来增加神经突触的传递能力；通过诱导nNOS的表达来发挥神经保护作用。
Objective:To study the protective effects of extracts from waternut Herb on Alzheimer's disease(AD)and its molecular mechanisms in rats.
Methods:Waternut Herb extracts were prepared into aqueous extract and alcohol extract in our lab. The screened rats were randomly divided into eight groups:negative group, sham operated group, Alzheimer's disease (AD) model group, positive therapy group, two alcohol extract groups with high or low dose and two aqueous extract groups with high or low dose. Alzheimer's disease (AD) model in rats was established by subdural injection with β-amyloid protein (Aβ,10μg/rat). Morris water maze was used to test the learning and memory abilities of rats; Pathological changes were observed under light microscope (HE staining) and transmission electron microscope; The activities of GSH-Px, T-SOD and the content of MDA in the serum were individually determined by spectrophotometric method. Also ELISA assays were performed to measure the levels of IL-1, IL-6and TNF-α in the serum. The expressions of NOS (including nNOS and iNOS), bcl-2/bax and GFAP proteins in the tissue of cormu ammon (CA) were detected by immunohistochemistry technique. And the transcriptional expressions of NF-κB/IκB, HSP70, APP and BACE1genes in CA tissue were measured by reverse-transcription PCR (RT-PCR) method.
Results
1. AD model in rats was successfully established and qualified by the results of Morris water maze test and pathological evidences. Escape latency period was significantly prolonged in the AD group (45.5±6.25s), compared with negative group (24.5±5.75s). Similarly, numbers of times across platform were largely decreased in the AD group (1.7±0.89) comparing with (3.2±1.27) in the negative group. Under the transmission electron microscope, slides of AD group showed that cell compartment among the nerve cells were extremely broadened with much less synapse and confluence of synaptic vesicle, as well as severe swelling. And also cell membrane and nuclear membrane were shrinked and partly confluenced with abnormal karyomorphism, heterochromatin aggregation as well as the evident damages of organelles such as mitochondria, ribosome, lysoome and lipofuscin accumulation.
2. Waternut Herb extracts obviously improved the capabilities of learning and memory in AD rats. Low and high alcohol extract extremely shortened the escape latency period in dose-dependent way (34.5±7.25s and24.0±6.5s respectively), significant with AD model (45.5±7.3s). Especially, similar effect was observed in both high alcohol extract group and positive therapy group. Meanwhile, the numbers of times crossing platform were increased by the individual Waternut Herb extracts in the different extent with the most evident effect in high alcolhol extract group.
3. Pathological examinations by HE staining showed that the quantities of nerve cells in the tissue of CA were significantly increased by the treatment with high alcohol extract, with improved karyomorphism and tight arrange. Also the evidence from transmission electron microscope exhibited that clear cell limit, tighter conjunction and relative normal of nuclear karyomorphism, ribosome, mitochrondria and liposuscin, accompanying with swelling micrangium and astrocyte (AS) in the positive therapy group. High aqueous and alcohol extracts improved, in some extent, pathological appearances such as cell shrinkage, numbers of synapses, nuclear karyomorphism. It should be noted that a large number of autophagosome were observed in the low dose of alcohol extract.
4. All Waternut Herb extracts significantly inhibited Aβ1-40level compared with its level (316.8±28.2pg/mL) in AD model (p<0.05, p<0.01), with the most evident in alcohol extracts. Alcohol extracts (both low and high doses) and high aqueous extract decreased the contents of MDA, meanwhile increased the activity of GSH-Px in the serum of rats. All the extracts enhanced the activities of T-SOD compared with AD model (p<0.01,p<0.05). The secretion of inflammatory factors such as IL-1, IL-6and TNF-α in the serum were also obviously suppressed by all extracts, with the most inhibitory effect in the high alcohol extract group.
5. Waternut Herb extracts inhibited the expression of GFAP protein, induced the anti-apoptotic protein bcl-2expression, and meanwhile reduced bax apoptotic protein expression which lead to the increase of bcl-2/bax ratio in CA. In addition, both aqueous and alcohol extracts with high doses lessened the expression of induced-NOS(iNOS), while enhanced the expression of neron-type NOS(nNOS).
6. Waternut Herb extracts down-regulated APP mRNA expression, the precursor of Aβ and BACE1mRNA, β-site App cleaving enzyme of APP. Additionally, all extracts (especially for alcohol extract) largely inhibited the expression of NF-κB mRNA, while increased IκB mRNA expression, an inhibitor of NF-κB. There is no observed difference in the expression of HSP70between negative group and AD model group (p>0.05).
Conclusions
1. Alzheimer's disease model in rat was successfully by subdural injection with β-amyloid protein (Aβ,10μg/rat).
2. Waternut Herb extracts present the therapeutic effect on AD rats.
3. The molecular mechanisms were involved in the inhibition of neuron cell apoptosis and inflammatory factors secretion, as well as in the improvement of anti-oxidant capabilities.
方法：通天草提取物由本实验室提取并制成水提物和醇提物。将初筛后的大鼠随机分成以下8组：阴性对照组、假手术组、AD模型组、西药治疗组、通天草醇提物低剂量组和高剂量组、水提物低剂量组和高剂量组。采用脑内注射Aβ1-40(10μg/鼠),建立大鼠老年痴呆模型,然后给予通天草提取物治疗28d。采用Morris水迷宫实验检测大鼠的学习记忆等行为学能力；采用HE染色和透射电镜对海马组织进行病理学检测；血清中GSH-Px和T-SOD的活力以及MDA含量采用分光光度法进行测定；采用ELISA法检测血清中IL-1、IL-6、TNF-α的水平；采用免疫组织化学方法检测nNOS、iNOS、bcl-2、bax、GFAP蛋白的表达；采用RT-PCR法检测海马组织中NF-κB、IκB、H SP70、APP和BACE1mRNA的表达。
结果
1、通过Morris水迷宫实验和病理学检测结果,可以肯定本实验成功建立了Aβ诱导的AD大鼠模型。主要表现为逃避潜伏期明显延长AD模型组为(45.5±6.25)s,明显高于阴性对照组(24.5±5.75)s。AD模型组的穿越跳台次数(1.7±0.89)明显低于阴性对照组(3.2±1.27)。透射电镜结果显示,AD模型组海马神经元细胞间隔增大,突触明显减少,突触小泡融合,肿胀明显；神经元细胞皱缩明显,核膜皱缩并出现阶段性融合,核形异常,异染色质聚集,细胞器如线粒体、核糖体、溶酶体损伤明显,脂褐素异常增多
2、通天草提取物能明显改善AD大鼠的学习记忆能力。低、高剂量的醇提物投予动物后,能以剂量依赖方式明显缩短大鼠的逃避潜伏期,分别为(34.5±7.25)s和(24.0±6.5)s,与AD模型组(45.5±7.3)比较,差异有统计学意义；高剂量醇提物的降低作用与西药治疗组相似。同时通天草提取物各组均在不同程度上增加了大鼠穿越跳台的次数,高剂量醇提物的作用尤为明显
3、病理学HE染色结果可见,高剂量醇提物作用组大鼠海马区神经元细胞数量较AD模型组明显增多,神经元细胞核形态及排列紧密度上均明显改善,类似于西药治疗组。透射电镜可见,与AD模型组大鼠海马神经元细胞(细胞膜、细胞器等)的明显损伤相比,西药治疗组神经元细胞间界限清晰,连接较紧密,核形基本正常,核糖体、线粒体结构基本正常,脂褐素增多不明显,但仍可见毛细血管及星形胶质细胞肿胀；高剂量的通天草水提物和醇提物组海马神经元细胞皱缩不明显,突触数量有一定的增加,神经元细胞核尚欠规则,低剂量醇提物组可见大量的自噬体存在。
4、血清学检测结果发现,通天草提取物各组能明显抑制血清中Aβ1-40水平,与AD模型组(316.8±28.2pg/mL)相比,差异有显著性(p<0.05,p<0.01),醇提物的作用更明显。通天草醇提物(高、低剂量)和水提物高剂量组能明显降低MDA水平,同时增加GSH-Px的活性；通天草提取物各组均能增加T-SOD的活性,与AD模型组比较,差异显著(p<0.01,p<0.05)。血清学炎症因子(IL-1、IL-6、TNF-α)检测结果显示,通天草提取物各组均能在一定程度上降低Aβ诱发的炎症因子分泌,特别是高剂量醇提物对各炎症因子的抑制作用更加明显。
5、大鼠海马组织的免疫组化结果显示,通天草提取物能抑制Aβ诱导的海马GFAP蛋白的表达,诱导抗凋亡蛋白bcl-2同时抑制促凋亡蛋白bax蛋白的表达,使bcl-2/bax的比值增加。此外,高剂量的通天草提取物(醇提物和水提物)能明显抑制诱导型一氧化氮合酶(iNOS)的表达,同时促进神经元型一氧化氮合酶(nNOS)的表达
6、RT-PCR结果显示,通天草提取物能明显降低Aβ前体APP mRNA的表达,同时降低APP的β-裂解酶BACE1mRNA表达,高剂量醇提物的抑制作用尤为明显。此外,通天草提取物(特别是醇提物)能明显降低NF-κB mRNA的表达,同时增强其抑制因子IκB mRNA的表达。HSP70的表达在AD模型组并无显著变化(与阴性对照组比较,p>0.05)。
结论
1、采用脑内注射Aβ蛋白,成功建立了Aβ诱导的AD大鼠模型。
2、通天草提取物能明显改善AD大鼠的学习记忆能力,高剂量醇提物的作用与西药治疗组相似。通天草提取物能部分改善Aβ对大鼠海马神经元细胞的病理学表现。通天草提取物能明显抑制血清中Aβ1-40水平,该作用与抑制Aβ前体物APP mRNA的表达、降低APP裂解酶BACE1mRNA的表达有关。
3、通天草提取物保护AD大鼠的可能分子机制如下
(1)通过诱导GSH-Px和T-SOD的活性、抑制MDA生成而增强抗氧化能力;
(2)通过抑制炎症因子IL-1、IL-6和TNF-α的分泌,降低Aβ引起的炎性损伤,该作用与NF-κB/IκB调节通路及iNOS有关。
(3)通过诱导bcl-2蛋白同时抑制bax蛋白的表达,抑制海马神经细胞凋亡；通过抑制海马星形胶质细胞中GFAP蛋白的表达来增加神经突触的传递能力；通过诱导nNOS的表达来发挥神经保护作用。
Objective:To study the protective effects of extracts from waternut Herb on Alzheimer's disease(AD)and its molecular mechanisms in rats.
Methods:Waternut Herb extracts were prepared into aqueous extract and alcohol extract in our lab. The screened rats were randomly divided into eight groups:negative group, sham operated group, Alzheimer's disease (AD) model group, positive therapy group, two alcohol extract groups with high or low dose and two aqueous extract groups with high or low dose. Alzheimer's disease (AD) model in rats was established by subdural injection with β-amyloid protein (Aβ,10μg/rat). Morris water maze was used to test the learning and memory abilities of rats; Pathological changes were observed under light microscope (HE staining) and transmission electron microscope; The activities of GSH-Px, T-SOD and the content of MDA in the serum were individually determined by spectrophotometric method. Also ELISA assays were performed to measure the levels of IL-1, IL-6and TNF-α in the serum. The expressions of NOS (including nNOS and iNOS), bcl-2/bax and GFAP proteins in the tissue of cormu ammon (CA) were detected by immunohistochemistry technique. And the transcriptional expressions of NF-κB/IκB, HSP70, APP and BACE1genes in CA tissue were measured by reverse-transcription PCR (RT-PCR) method.
Results
1. AD model in rats was successfully established and qualified by the results of Morris water maze test and pathological evidences. Escape latency period was significantly prolonged in the AD group (45.5±6.25s), compared with negative group (24.5±5.75s). Similarly, numbers of times across platform were largely decreased in the AD group (1.7±0.89) comparing with (3.2±1.27) in the negative group. Under the transmission electron microscope, slides of AD group showed that cell compartment among the nerve cells were extremely broadened with much less synapse and confluence of synaptic vesicle, as well as severe swelling. And also cell membrane and nuclear membrane were shrinked and partly confluenced with abnormal karyomorphism, heterochromatin aggregation as well as the evident damages of organelles such as mitochondria, ribosome, lysoome and lipofuscin accumulation.
2. Waternut Herb extracts obviously improved the capabilities of learning and memory in AD rats. Low and high alcohol extract extremely shortened the escape latency period in dose-dependent way (34.5±7.25s and24.0±6.5s respectively), significant with AD model (45.5±7.3s). Especially, similar effect was observed in both high alcohol extract group and positive therapy group. Meanwhile, the numbers of times crossing platform were increased by the individual Waternut Herb extracts in the different extent with the most evident effect in high alcolhol extract group.
3. Pathological examinations by HE staining showed that the quantities of nerve cells in the tissue of CA were significantly increased by the treatment with high alcohol extract, with improved karyomorphism and tight arrange. Also the evidence from transmission electron microscope exhibited that clear cell limit, tighter conjunction and relative normal of nuclear karyomorphism, ribosome, mitochrondria and liposuscin, accompanying with swelling micrangium and astrocyte (AS) in the positive therapy group. High aqueous and alcohol extracts improved, in some extent, pathological appearances such as cell shrinkage, numbers of synapses, nuclear karyomorphism. It should be noted that a large number of autophagosome were observed in the low dose of alcohol extract.
4. All Waternut Herb extracts significantly inhibited Aβ1-40level compared with its level (316.8±28.2pg/mL) in AD model (p<0.05, p<0.01), with the most evident in alcohol extracts. Alcohol extracts (both low and high doses) and high aqueous extract decreased the contents of MDA, meanwhile increased the activity of GSH-Px in the serum of rats. All the extracts enhanced the activities of T-SOD compared with AD model (p<0.01,p<0.05). The secretion of inflammatory factors such as IL-1, IL-6and TNF-α in the serum were also obviously suppressed by all extracts, with the most inhibitory effect in the high alcohol extract group.
5. Waternut Herb extracts inhibited the expression of GFAP protein, induced the anti-apoptotic protein bcl-2expression, and meanwhile reduced bax apoptotic protein expression which lead to the increase of bcl-2/bax ratio in CA. In addition, both aqueous and alcohol extracts with high doses lessened the expression of induced-NOS(iNOS), while enhanced the expression of neron-type NOS(nNOS).
6. Waternut Herb extracts down-regulated APP mRNA expression, the precursor of Aβ and BACE1mRNA, β-site App cleaving enzyme of APP. Additionally, all extracts (especially for alcohol extract) largely inhibited the expression of NF-κB mRNA, while increased IκB mRNA expression, an inhibitor of NF-κB. There is no observed difference in the expression of HSP70between negative group and AD model group (p>0.05).
Conclusions
1. Alzheimer's disease model in rat was successfully by subdural injection with β-amyloid protein (Aβ,10μg/rat).
2. Waternut Herb extracts present the therapeutic effect on AD rats.
3. The molecular mechanisms were involved in the inhibition of neuron cell apoptosis and inflammatory factors secretion, as well as in the improvement of anti-oxidant capabilities.
引文
[1]盛树力.老年性痴呆及相关疾病北京科学技术文献出版社,2006,1：43,292-303,93
[2]仇成轩,施侣元.进一步重视我国老年痴呆流行病学研究中国流行病学杂志,2005；26(12)：931-933)
[3]Luengo-Fernandez, Leal S, Gray A. Dementia 2010.Health Economics Research Cenfre, University of Oxfordfor the Alzheimer's Research Trust [online]. Available from URL:hffp://www.dementia2010.org/[Accessed2010 Nov 29]
[4]王树国.填髓祛邪合剂治疗血管性痴呆54例.山西中医2007；23(4)：19-20.
[5]魏铁力,陈英群,邓頲.心脑血管疾病常用药物探密中国医药学,2002；17(增刊)：290-291.
[6]Kovacs GG, AlafuzofT I, Al-Sarraj S, et al. Mixed brain pathologies in dementia:the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord 2008-26 (4)-343-50
[7]American Psychiatric Association. Diagnostic and Statis-tical Manual of Mental Disorders (4th edition). Arlington, US:American Psychiatric Publishing Inc,2000
[8]Cummings JL. Dementia with Lewy bodies:molecular pathogenesis and implications for classirication. J Geriatr Psychiatry Neurol 2004; 17 (3):112-9
[9]Desmond DW. Vascular dementia. Clin Neurosci Res 2004; 3 (6):437-48
[10]McKeith L Cummings J. Behavioural changes and psychological symptoms in dementia disorders. Lancet Neurol2005; 4 (11):735-42
[11]Munoz-Torrero D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer's disease. Curr Med Chem 2008; 15 (24):2433-55
[12]Ballard CG, Chalmers KA, Todd C, et al. Cholinesterase inhibitors reduce cortical Aβ in dementia with Lewy bodies. Neurology 2007; 68 (20):1726-9
[13]Muth K, Schonmeyer R, Matura S, et al. Mild cognitive impairment in the elderly is associated with volume loss of the cholinergic basal forebrain region. Bio] Psychiatry 2010; 67 (6):588-91
[14]Kendziorra K, Wolf H, Meyer PM, et al. Decreased cerebral α4β2* nicotinic acetylcholine receptor availabiUty in patients with mild cognitive impairment and Alzheimer's disease assessed with positron emission tomography. Eur Nucl Med Mol Imaging 2011; 38 (3): 515-25
[15]Diniz BS, Pinto Jr JA, Gonzaga ML, et al. To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci 2009; 259 (4):248-56
[16]Pogacic Kramp V, Herrling P. List of drugs in development for neurodegenerative diseases: update for June 2010. Neurodegener Dis 2011; 8 (1-2):44-94
[17]Nicholson CD. Pharmacology of nootropics and metabolically active compounds in relation to their use in dementia. Psychopharmacology 1990; 101 (2):147-59
[18]Ellis JR, Nathan PJ, Villemagne VL, et al. Galantamineinduced improvements in cognitive function are not related to alterations in α4β2 nicotinic receptors in early Alzheimer's disease as measured in vivo by 2-['*F]fluoroA-85380 PET. Psychopharmacology 2009; 202 (1-3): 79-91
[19]Penner J, Rupsingh R. Smith M, et al. Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(1):104-10
[20]LiQ, Fang J, Yang M, et al. Galantamine inhibits calpaincalcineurin signaling activated by β-amyloid in human neuroblastoma SH-SY5Y cells. Neurosci Lett 2010; 480 (3):173-7
[21]Li Q, Wu D, Zhang L, et al. Effects of galantamine on p-amyloid release and β-site cleaving etizyme 1 expression in differentiated human neuroblastoma SH-SY5Y cells.Exp Gerontol 2010; 45 (11):842-7
[22]Matharu B, Gibson G, Parsons R, et al. Galantamine inhibits β-amyioid aggregation and cytotoxicity. J Neurol Sei 2009; 280 (1-2):49-58
[23]Melo JB, Sousa C, Garcao P, et al. Galantamine protects against oxidative stress induced by amyloid-β peptide in cortical neurons. Eur J Neurosci 2009; 29 (3):455-64
[24]Liu X, Xu K, Yan M, et al. Protective effects of gaiantarnine against Aβ-induced PC 12 cell apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum stress. Neurochem Int 2010; 57 (5):588-99
[25]Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006; 1:CD005593
[26]Rodda J, Morgan S, Walker Z. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer's disease? A systematic review of randomized, placebocontrolled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr 2009; 21 (5):813-24
[27]Small G. Erkinjuntti T, Kurz A, et al. Galantamine in the treatment of cognitive decline in patients with vascular dementia or Alzheimer's disease with cerebrovascular disease. CNS Drugs 2003; 17 (12):905-14
[28]Litvinenko IV, Odinak MM, Mogil'naya VI, etal. Efficacy and safety of galantamine (Reminyl) for dementia in patients with Parkinson's disease (an opencontrolled trial). Neurosci Behav Physiol 2008; 38 (9):937-45
[29]Loy C, Schneider L. Galantamine for Alzheimer's disease and mild cognitive impairment. Coehrane Database Syst Rev 2006; 25:CD001747
[30]Tangwongchai S, Thavichachart N, Senanarong V, etal.Galantamine for the treatment of BPSD in Thai patients wifh possible Alzheimer's disease with or without cerebrovascular disease. Am J Alzheimers Dis Other Demen 2009; 23 (6):593-601
[31]Lockhart IA, Mitchell SA, Kelly S. Safety and tolerability of donepezil, rivastigmine and galantamine for patients wifh Alzheimer's disease:systematic review of the "realworld" evidence. Dement Geriatr Cogn Disord 2009; 28 (5):389-403
[32]Leonard AK, Sileno AP, Macevilly C, et al. Development of a novel high-concenfrafion galantamine formulation suitable for intranasal delivery. J Pharm Sei 2005; 94 (8):1736-46
[33]Maelicke A, Hoeffle-Maas A, Ludwig J, et al. Memogain is a galanfamine pro-drug having dramatically reduced adverse effeefs and enhanced efficacy. J Mol Neurosci 2010-40(1-2): 135-7
[34]Loizzo MR, Tundis R, Menichini F, et al. Natural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders:an update. Curr Med Chem 2008; 15 (12):1209-28
[35]Houghton PJ, Ren YH, Howes MJ. Acetylcholinesterase inhibitors from plants and fungi. Nat Prod Rep 2006;23(2):181-99
[36]Jin Z. Amaryllidaceae and Sceletium alkaloids. Naf Prod Rep 2009; 26 (3):363-81
[37]McNuIfy J, Nair JJ, Little JRL, et al. Structure-aetivity studies on aeetylcholinesterase inhibition in fhe lycorine series of Amaryllidaeeae alkaloids. Bioorg Med ChemLett 2010; 20 (17):5290-4
[38]Williams P, Sorribas A, Howes M-JR. Natural products as a source of Alzheimer's drug leads. Nat Prod Rep 2011;28 (Ⅰ):48-77
[39]Howes M-JR, Houghton PJ. Acetylcholinesterase inhibitors of natural origin. Int J Biomed Pharm Sei 2009;3 (SI 1):67-86
[40]Yoshida S, Suzuki N. Antiamnesie and cholinomimetic side-effects of the cholinesterase inhibitors, physostigmine, tacrine and NIK-247 in rats. Eur J Pharmacol 1993; 250(1):117-24
[41]Thai LJ, Ferguson JM, Mintzer J, et al. A 24-week randomized trial of controlled release physostigmine in patients with Alzheimer's disease. Neurology 1999; 52 (6):1146-52
[42]Coelho F, Birks J. Physostigmine for Alzheimer's disease. Cochrane Database Syst Rev 2001; 2:CD001499
[43]Braida D, Sala M. Eptastigmine:ten years of pharmacology, toxicology, pharmacokinetie, and clinical studies. CNS Drug Rev 2001; 7 (4):369-86
[44]Kamal MA, Al-Jafari AA, Yu QS, et al. Kinetic analysis of the inhibition of human bufyrylcholinesterase with eymserine. Biochim Biophys Acta 2006; 1760 (2):200-6
[45]Kamal MA, Klein P, Yu QS, et al. Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental Alzheimer fherapeufic, bisnorcymserine. J Alzheimers Dis 2006; 10(1):43-51
[46]Kamal MA, Qu X, Yu Q-S, et al. Tetrahydrofurobenzofuran cymserine, a potent butyryleholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis. J Neural Transm 2008; 115 (6):889-98
[47]Butler MS. Natural products to drugs:natural productderived compounds in clinical trials. Nat Prod Rep 2008-25 (3):475-516
[48]Fink DM, Palermo MG, Bores GM, et al. Imino 1,2,3,4-tetrahydrocyclopent indole carbamates as dual inhibitors of aeetylcholinesterase and monoamine oxidase. Bioorg Med Chem Lett 1996; 6 (6):625-30
[49]Toda N, Kaneko T, Kogen H. Development of an efficient therapeutic agent for Alzheimer's disease:design and synthesis of dual inhibitors of acetyleholinesterase and serotonin transporter. Chem Pharm Bull 2010; 58 (3):273-87
[50]Tang LL, Wang R, Tang XC. Effeets of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PCI 2 eells. Acta Pharmacol Sin 2005; 26 (6):673-8
[51]Wang R, Yan H, Tang XC. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 2006; 27 (1):1-26
[52]Wang BS, Wang H, Wei ZH, et al. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease:an updated meta-analysis. J Neural Transm 2009; 116 (4):457-65
[53]Hao Z, Liu M, Liu Z, et al. Huperzine A for vascular dementia. Cochrane Database Syst Rev 2009; 2:CDOO7365
[54]Ronco C, Sorin G, Nachon F, et al. Synthesis and structure-aetivity relationship of huprine derivatives as human acetylcholinesterase inhibitors. Bioorg Med Chem 2009-17 (13): 4523-36
[55]Camps P, Cusack B, Mallender WD, et al. Huprine X is a novel high-affinity inhibitor of acetylcholinesterase that is of interest for treatment of Alzheimer's disease. Mol Pharmacol 2000; 57 (2):409-17
[56]Merlini L, Pinza M. Trends in searching for new cognition enhancing drugs. Prog Neuropsyehopharmacol Biol Psychiatry 1989; 13 (Suppl.):S61-75
[57]Deshmukh R, Sharma V, Mehan S, et al. Amelioration of intracerebroventricular strepfozotocin induced cognitive dysfunction and oxidative stress by vinpocetine:a PDE1 inhibitor. Eur J Pharmacol 2009; 620 (1-3):49-56
[58]Erdo SL, Molnar P, Lakics P, et al. Vincamine and vincanol are potent blockers of voltage-gated Na+ channels. Eur J Pharmacol 1996; 314 (1-2):69-73
[59]Nyakas C, Felszeghy K, Szabo R, et al. Neuroprotective effects of vinpocetine and its major metabolite cis-apovincaminic acid on NMDA-induced neurotoxicity in a rat entorhinal cortex lesion model. CNS Neurosci Ther 2009; 15(2):89-99
[60]Akhondzadeh S, Abbasi SH. Herbal medicine in the treatment of Alzheimer's disease. Am J Alzheimers Dis Other Demen 2006; 21 (2):113-8
[61]Valikovics A. Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions. Ideggyogy Sz 2007; 60 (7-8):301-10
[62]Szatmari SZ, Whitehouse PJ. Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev 2003; 1:CD003119
[63]Khanavi M, Pourmoslemi S, Farahanikia B, et al. Cytotoxicity of Vinca minor. Pharm Biol 2010; 48(1):96-100
[64]Howes M-JR, Houghton PJ. Traditional medicine for memory enhancement. In:Ramawat KG, editor. Herbal drugs:ethnomedicine to modem medicine. New York:Springer,2009:239-91
[65]Elbaz A, Moisan F. Update in the epidemiology of Parkinson's disease. Curr Opin Neurol 2008; 21 (4):454-60
[66]Dome P, Lazary J, Kalapos MP, et al. Smoking, nicotine and neuropsychiatrie disorders. Neurosci Biobehav Rev 2010; 34 (3):295-342
[67]Levin ED, Christopher CN. Lobeline-induced learning improvement of rats in the radialarm-maze. Pharmacol Biochem Behav 2003; 76 (1):133-9
[68]Romero J, Martinez Orgado J. Cannabinoids and neurodegenerative diseases. CNS Neurol Disord Drug Targets 2009; 8 (6):440-50
[69]Esposito G, De Filippis D, Camuccio R, et al. The marijuana component cannabidiol inhibits β-amyloidinduced tau protein hyperphosphorylation through Wnt/β-catenin pathway rescue in PC 12 cells. J Mol Med 2006; 84 (3):253-8
[70]Janero DR, Vadivel SK, Makriyannis A. Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders:drug-discovery strategies. Int Rev Psychiatry 2009; 21 (2):122-33
[71]Orgado JM, Fernandez-Ruiz J, Romero J. The endocannabinoid system in neuropathological states. Int Rev Psychiatry 2009; 21 (2):172-80
[72]Walther S, Mahlberg R, Eichmann U, et al. A-9-Tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology 2(X)6; 185 (4):524-8
[73]Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 2006; 39 (4):421-9
[74]Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol for the treatment of psychosis in Parkinson's disease. J Psychopharmacol 2009; 23 (8):979-83
[75]Krishnan S, Cairns R, Howard R. Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev 2009; 2:CD007204
[76]Kim J, Lee HJ, Lee KW. Naturally occurring phytochemicals for the prevention of Alzheimer's disease. J Neurochem 2010; 112(6):1415-30
[77]Ng T-P, Chiam P-C, Lee T, et al. Curry consumption and cognitive function in the elderly. Am J Epidemiol 2006; 164 (9):898-906
[78]Kim DS, Kim JY. Total synthesis of calebin A, preparation of its analogues, and their neuronal cell protectivityagainst (3-amyloid insult. Bioorg Med Chem Lett 2001; 11 (18):2541-3
[79]Park SY, Kim DS. Discovery of natural products from Curcuma tonga that protect cells from β-amyloid insult:a drug discovery effort against Alzheimer's disease. J Nat Prod 2002; 65 (9): 1227-31
[80]Shimmyo Y, Kihara T, Akaike A, et al. Bpigallocatechin-3-gallate and curcumin suppress amyloid β-induced β-site APP cleaving enzyme-1 upregulation. Neuroreport 2008; 19(13): 1329-33
[81]Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis 2004; 6 (4):367-77
[82]Pal R, Cristan EA, Schnittker K, et al. Rescue of ER oxidoreductase function through polyphenolic phytochemical intervention:implications for subcellular traffic and neurodegenerative disorders. Biochem Biophys Res Commun 2010; 392 (4):567-71
[83]Agrawal R, Mishra B, Tyagi E, et al. Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat. Pharmacol Res2010; 61 (3): 247-52
[84]Awasthi H, Tota S, Hanif K, et al. Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow. Life Sei 2010; 86 (3-4):87-94
[85]Kumar A, Dogra S, Prakash A. Protective effect of curcumin (Curcuma tonga), against aluminium toxicity:possible behavioral and biochemical alterations in rats. Behav Brain Res 2009; 205 (2):384-90
[86]Yaari R, Kumar S, Tariot PN. Non-cholinergic drug development for Alzheimer's disease. Expert Opin Drug Discov 2008; 3 (7):745-60
[87]Narlawar R, Baumann K, Schubenel R, et al. Curcumin derivatives inhibit or modulate β-amyloid precursor protein metabolism. Neurodegener Dis 2007; 4 (2-3):88-93
[88]Maher P, Akaishi T, Schubert D, et al. A pyrazole derivative of curcumin enhances memory. Neurobiol Aging 2010; 31 (4):706-9
[89]Baum L, Lam CW, Cheung SK, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J ClinPsychopharmacol 2008; 28(1):110-3
[90]Collins MA, Neafsey EJ, Mukamal KJ, et al. Alcohol in moderation, cardioprotection, and neuroprotection:epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 2009; 33 (2):206-19
[91]Solfrizzi V, D'lntrono A, Colacicco AM, et al. Alcohol consumption, mild cognitive impairment, and progression to dementia. Neurology 2007; 68 (21):1790-9
[92]Mehlig K, Skoog 1, Guo X, et al. Alcoholic beverages and incidence of dementia:34-Year follow-up of the prospective population study of women in Goteborg. Am J Epidemiol 2008; 167 (6):684-9
[93]Rocha-Gonzalez HI, Ambriz-Tututi M, Granados-Soto V. Resveratroi:a natural compound with pharmacological potential in neurodegenerative diseases. CNS Neurosci Ther 2008; 14 (3):234-47
[94]Panza F, Capurso C, D'lntrono A, et al. Alcohol drinking, cognitive functions in older age, predementia, and dementia syndromes. J Alzheimers Dis 2(H)9; 17(1):7-31
[95]Jang JH, Surh YJ. Protective effect of resveratrol on β-amyloid-induced oxidative PC12 cell death. Free Radie Biol Med 2003; 34 (8):1100-10
[96]Rossi M, Caruso F, Opazo C, et al. Crystal and molecular structure of piceatannol; scavenging features of resveratrol and piceatannol on hydroxyl and peroxyl radicals and docking with transthyretin. J Agrie Food Chem 2008-56(22):10557-66
[97]Vingtdeux V, Dreses-Werringloer U, Zhao H, et al. Therapeutic potential of resveratrol in Alzheimer's disease. BMC Neurosci 2008; 9 Suppl.2:S6
[98]Pallas M, Casadesus G, Smith MA, et al. Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res 2009; 6 (I):70-81
[99]Kumar A, Naidu PS, Seghal N, et al. Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats. Pharmacology 2007; 79 (1):17-26
[100]Karuppagounder SS, Pinto JT, Xu H, et al. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease. Neurochem Int 2008; 54 (2): 111-8
[101]Ma X, Tan C, Zhu D, Gang DR, Xiao P. Huperzine A from Huperziaspeciesdan ethnopharmacological review. J Ethnopharmacol 2007; 113:15-34.
[102]Wang R, Yan H, Tang XC. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 2006; 27:1-26.
[103]Wang R, Tang XC. Neuroprotective effects of huperzine A:a natural cholinesterase inhibitor for the treatment of Alzheimer's disease. Neurosignals 2005; 14:71-8.
[104]Hualiang J, Xiaomin L, Donglu B. Progress in clinical, pharmacological, chemical and structural biological studies of huperzine A:a drug of traditional Chinese medicine origin for the treatment of Alzheimer's disease. Curr Med Chem 2003; 10:2231-52.
[105]Gao X, Tang XC. Huperzine A attenuates mitochondrial dysfunction in beta-amyloid-treated PC 12 cells by reducing oxygen free radicals accumulation and improving mitochondrial energy metabolism. J Neurosci Res 2006; 83:1048-57.
[106]Zhang HY, Yan H, Tang XC. Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-alpha in intracerebroventricular beta-amyloid-(1-40) infused rats and human embryonic kidney 293 Swedish mutant cells. Neurosci Lett 2004; 360:21-4.
[107]Yang CY, Lv ZP, Zheng CG. Efficacy and reliability of huperzineAinmild and moderate Alzheimer's disease. Chin J Clin Rehabil 2003; 7:4258-9.
[108]Tang LL,Wang R, Tang XC. Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC 12 cells. Acta Pharmacol Sin 2005; 26:673-8.
[109]Wang ZF, Tang LL, Yan H,Wang YJ, Tang XC. Effects of huperzine A on memory deficits and neurotrophic factors production after transient cerebral ischemia and reperfusion in mice. Pharmacol Biochem Behav 2006; 83:603-11.
[110]Tang XC, Jin GZ, Xu B. Neuropharmacologic actions of lycoramine and galanthamine. Acta Pharm Sin 1963; 10:465-73.
[111]Wang Y, Huang L, Tang X, Zhang H. Retrospect and prospect of active principle from Chinese herbs in the treatment of dementia. Acta Pharm Sin 2010; 31:649-64.
[112]Barnes CA, Meltzer J, Houston F, Orr G, McGann K, Wenk GL. Chronic treatment of old rats with donepezil or galantamine:effects on memory, hippocampal plasticity and nicotinic receptors. Neuroscience 2000; 99:17-23.
[113]Belluardo N, Mudo G, Blum M, Fuxe K. Central nicotinic receptors, neurotrophic factors and neuroprotection. Behav Brain Res 2000; 113:21-34.
[114]Shimohama S, GreenwaldDL, ShafronDH, AkaikaA, MaedaT,Kaneko S, et al. Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage. Brain Res 1998; 779:359-63.
[115]Giunta B, Ehrhart J, Townsend K, Sun N, Vendrame M, Shytle D, et al. Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gp120. Brain Res Bull 2004; 64:165-70.
[116]Repantis D, Laisney O, Heuser I. Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals:a systematic review. Pharmacol Res 2010; 61:473-81.
[117]Ezoulin MJ, Ombetta JE, Dutertre-Catella H, Warnet JM, Massicot F. Antioxidative properties of galantamine on neuronal damage induced by hydrogen peroxide in SK-N-SH cells. Neurotoxicology 2008; 29:270-7.
[118]Cao XZ, Zhang LM, Shen YE, Zhou SS, Jiang GH. NMDA receptors mediate the effect of galantamin on the cognitive function of Alzheimer's disease in rats. J Apop Nerv Dis 2006; 23:678-80.
[119]Mulder J, Harkany T, Czollner K, Cremers TI, Keijser JN, Nyakas C, et al. Galantamine-induced behavioral recovery after sublethal excitotoxic lesions to the rat medial septum. Behav Brain Res 2005; 163:33-41.
[120]Moriguchi S, Marszalec W, Zhao X, Yeh JZ, Narahashi T. Mechanism of action of galantamine on N-methyl-D-aspartate receptors in rat cortical neurons. J Pharmacol Exp Ther 2004;310:933-42.
[121]Melo JB, Sousa C, Garcao P, Oliveira CR, Agostinho P. Galantamine protects against oxidative stress induced by amyloid-beta peptide in cortical neurons. Eur J Neurosci 2009; 29:455-64.
[122]Matharu B, Gibson G, Parsons R, Huckerby TN, Moore SA, Cooper LJ, et al. Galantamine inhibits beta-amyloid aggregation and cytotoxicity. J Neurol Sci 2009; 280:49-58.
[123]Arias E, Ales E, Gabilan NH, Cano-Abad MF, Villarroya M, Garcia AG, et al. Galantamine prevents apoptosis induced by beta-amyloid and thapsigargin:involvement of nicotinic acetylcholine receptors. Neuropharmacology 2004; 46:103-14.
[124]Gertz H-J, Kiefer M. Review about Ginkgo biloba special extract EGb 761 (Ginkgo). Curr Pharm Des 2004; 10(3)-261-4
[125]Saddichha S, Pandey V. Alzheimer's and non-Alzheimer's dementia:a critical review of pharmacological and nonpharmacological strategies. Am J Alzheimers Dis Other Demen 2008; 23 (2):150-61
[126]Chan P-C, Xia Q, Fu PP. Ginkgo biloba leaf extract:biological, medicinal, and toxicological effects. J Environ Sei Health C Environ Carcinog Ecotoxicol Rev 2007; 25 (3):211-44
[127]Das A, Shanker G, Nath C, et al. A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba:anticholinesterase and cognitive enhancing activities. Pharmcol Biochem Behav 2002; 73 (4):893-900
[128]Birks J, Grimley EV, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2002; 4:CD003120
[129]Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2007; 2:CD003120
[130]Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2009;1:CD003120
[131]Kaschel R. Ginkgo biloba:specificity of neuropsychological improvement-a selective review in search of differential effects. Hum Psychopharmaol 2009; 24 (5):345-70
[132]Weinmann S, Roll S, Schwarzbach C, et al. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr 2010; 10:14
[133]DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloha for prevention of dementia:a randomized controlled trial [published erratum appears in JAMA 2008; 300 (23): 2730]. JAMA 2008; 300 (39):2253-62
[134]Andrieu S, Ousset P-J, Coley N, et al. GuidAge study:a 5-year double bhnd, randomised trial of EGb 761 for the prevention of Alzheimer's disease in elderly subjects with memory complaints, I:rationale, design and baseline data. Curr Alzheimer Res 2008; 5 (4):406-15
[135]Yancheva S, IhI R, Nikolova G, et al. Ginkgo biloba extract EGb 761R, donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatrie features:a randomised, double-blind, exploratory trial. Aging Ment Health 2009; 13(2):183-90
[136]Yasui-Furukori N, Furukori H, Kaneda A,et al. The effects of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of donepezil. J Clin Pharmacol 2004; 44 (5): 538-42
[137]Barnes J, Anderson LA, Phillipson JD. Herbal medicines.3rd ed. London:Pharmaceutical Press,2007
[138]Scripnikov A, Khomenko A, Napryeyenko O. Effects of Ginkgo biloba extract EGb 761-on neuropsychiatrie symptoms of dementia:findings from a randomised controlled trial. Wien Med Wochenschr 2007; 157 (13-14)-295-300
[139]Leistner E, Drewke C. Ginkgo biloba and ginkgotoxin. J Nat Prod 2010; 73 (1):86-92
[140]Xiao Q, Wang C, Li J, et al. Ginkgolide B protects hippocampal neurons from apoptosis induced by β-amyloid 25-35 partly via up-regulation of brain-derived neurotrophic factor. Eur J Pharmacol 2010; 647 (1-3):48-54
[141]Bate C, Tayebi M, Williams A. Ginkgolides protect against amyloid-β. Mol Neurodegener 2008 Jan 7; 3:1
[142]Shi C, Wu F, Yew DT, et al. Bilobalide prevents apoptosis through activation ofthe PI3K/Akt pathway in SH-SY5Y cells. Apoptosis 2010; 15 (6):715-27
[143]Gertz HJ, Kiefer M. Review about Ginkgo biloba special extract EGb 761 (Ginkgo). Curr Pharm Des 2004; 10:261-4.
[144]Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN. Effects of Ginkgo biloba in dementia:systematic review and meta-analysis. BMC Geriatr 2010; 10:1-14.
[145]Lu G, Wu Y, Mak YT, Wai SM, Feng ZT, Rudd JA, et al. Molecular evidence of the neuroprotective effect of Ginkgo biloba (EGb761) using bax/bcl-2 ratio after brain ischemia in senescence-accelerated mice, strain prone-8. Brain Res 2006; 1090:23-8.
[146]Calapai G, Crupi A, Firenzuoli F, Marciano MC, Squadrito F, Inferrera G, et al. Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis. Life Sci 2000; 67:2673-83.
[147]Eckert A, Kreil U, Kressmann S, Schindowski K, Leutner S, Lutz S, et al. Effects of Egb761 Ginkgo biloba extract on mitochondrial function and oxidative stress. Pharmacopsychiatry 2003; 36:15-23.
[148]Li FM, Duan XM, Wang JJ, Fang HL. Effects of Ginkgo biloba extract on MitoKATP in focal cerebral ischemia-reperfusion rats. Chin Arch Tradit Chin Med 2008; 26:1462-6.
[149]Kasper S, Schubert H. Ginkgo biloba extract EGb 761(R) in the treatment of dementia: evidence of efficacy and tolerability. Fortschr Neurol Psychiatr 2009; 77:494-506.
[150]Wang SY, Liu XM, Wang JX, Liu YX, Yuang DX. Effect of EGb on GFAP in focal cerebral ischemia-reperfusion injury rats. Anatomy Res 2008; 30:115-7
[151]Kang TH, Murakami Y, Takayama H, Kitajima M, Aimi N, Watanabe H, et al. Protective effect of rhynchophylline and isorhynchophylline on invitro ischemia-induced neuronal damage in the hippocampus:putative neurotransmitter receptors involved in their action. Life Sci 2004; 76:331-43.
[152]Wirths O, Malthaup G, Bayer TA. A modified b-amyloid hypothesis:intraneuronal accumulation of the b-amyloid peptidedthe first step of a fatal cascade. J Neurochem 2004; 91:513-20.
[153]Chung IW, Moore NA, Oh WK, O'Neill MF, Ahn JS, Park JB, et al. Behavioural pharmacology of polygalasaponins indicates potential antipsychotic efficacy. Pharmacol Biochem Behav 2002; 71:191-5.
[154]Kim HM, Lee EH, Lee HJ, Shin SB, Lyu TY, Kim YS, et al. Effect of Polygala tenuifolia root extract on the tumor necrosis factor-alphasecretion from mouse astrocytes. J Ethnopharmacol 1998; 161:201-8.
[155]Lv J, Jia H, Jiang Y, Ruan Y, Liu Z, Yue W, et al. Tenuifolin, an extract derived from tenuigenin, inhibits amyloid-b secretion in vitro. Acta Physiol 2009;196:419-25.
[156]Jia H, Jiang Y, Ruan Y, Zhang Y, Ma X, Zhang J, et al. Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid betaprotein in cultured cells. Neurosci Lett 2004; 367:123-8.
[157]Schwarz K, Ternes W. Antioxidative constituents of Rosmarinus officinalis and Salvia officinalis. Ⅱ. Isolation of carnosic acid and formation of other phenolic diterpenes. Z Lebensm Unters Forsch 1992; 195:99-103.
[158]Lu J, Zheng YL, Wu DM, Luo L, Sun DX, Shan Q. Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. Biochem Pharmacol 2007; 74:1078-90.
[159]Sofic E, Sapcanin A, Tahirovic I, Gavrankapetanovic I, Jellinger K, Reynolds GP, et al. Antioxidant capacity in postmortem brain tissues of Parkinson's and Alzheimer's diseases. J Neural Transm Suppl 2006; 71:39-43.
[160]Akhondzadeh S, NoroozianM, MohammadiM, Ohadinia S, Jamshidi AH, KhaniM. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease:a double blind, randomized and placebocontrolled trial. J Clin Pharm Ther 2003; 28:53-9.
[161]Chung YK, Heo HJ, Kim EK, Kim HK, Huh TL, Lim Y. Inhibitory effect of ursolic acid purified from Origanum majorana L on the acetylcholinesterase. Mol Cells 2001; 11:137-43.
[162]Porat Y, Abramowitz A, Gazit E. Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 2006; 67:23-37.
[163]Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent antiamyloiaogenic effects for Alzhemer's beta-amyloid fibrils in vitro.J Neurosci Res 2004;75:742-50.
[164]Chen YJ, Zeng SJ, Hsu JT, Horng JT, Yang HM, Shih SR, et al.Amantadine as a regulator of internal ribosome entry site. Acta Pharmacol Sin 2008; 29:1327-33.
[165]Wu TY, Chen CP. Dual action of memantine in Alzheimer disease:a hypothesis. Taiwan J Obstet Gynecol 2009; 48:273-7.
[166]Wu TY, Chen CP, Jinn TR. Alzheimer's disease:aging, insomnia and epigenetics. Taiwan J Obstet Gynecol 2010; 49:468-72.
[167]王晋平,赵贞.血管性痴呆动物模型研究进展.山西中医学院学报,2008；9(5)：60-62
[168]张峰,张继国,王丽华,等.黄精多糖对东莨菪碱致小鼠记忆获得障碍的改善作用.现代中西医结合杂志,2007；16(36)：5410-5412
[169]范郁山,陈芒华.浅刺调督法对老年性痴呆模型行为学的影响.辽宁中医药大学学报,2008,10(5)：177-178
[170]Oddo S, Caccamo A, Shepherd J D, et al. Triple transgenic model of Alzheimer's disease with plaques and tangles:intracellular Aβ and synaptic dysfunction. Neuron,2003,39(3):409
[171]李亚明,朱粹青,林水淼,等.老年性痴呆大鼠模型建立的研究.老年医学与保健,2001,7(4)：214-217
[172]Hob A, Nitta A, Nadai M, et al. Dysfunction of cholinergic and dopaminergic neuronal system s in beta-amyloid protein-infused rats. J Neurochem,1996,66(3):1113
[173]王雅琼,闫福岭,鲁国.Aβ25-35杏仁核注射对大鼠海马tau蛋白磷酸化和AchE的影响.实用神经疾病杂志,实用神经疾病杂志,2005,8(4)：34-35
[174]Lin X, Koelsch G, Wu S, et al. Human aspartic protease memapsin2 cleaves the beta-secretase site of beta-amyloid precursor protin. Proc. Natl. Acad. Sci,2000, 97(4):1456-1460
[175]Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature,1999,402(6761):533-537
[176]Young Ho Koh, Christine AF, Bradley TH, et al. BACE is degraded via the lysosomal pathway. Biol Chem,2005,280(37):32499-32504
[177]Michelle AC, Weihui Zhou, Hong Qing, et al. Transcriptional regulation of BACE1, the β-amyioid precursor proteinβ-Secretase, by Spl. Molecular and Cellular Biology, 2004,24(2):865-874
[178]Lucie K, Nicoletta K, Petra S, et al. Lipids as modulators of proteolytic activity of BACE. Bio1.Chem,2005,280(44)：36815-3682
[179]王国卿,封丽芳,夏作理.星形胶质细胞的生物学功能与神经元修复。中国临床康复,2005,9(1)：146-148
[180]Min K. J. Yang M S. Jou I, et al.Protein kinase A medi ates microglial activation induced by plasminogen and gangliosides. Exp Mol Med,2004,36(5):461-467.
[181]Albrecht P J, Dahl J P, Stoltzfus O K. et al. Ciliary neurotrophic factor activates spinal cord astrocytes,stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival. Exp Neurol,2002,173(1):46-62.
[182]Hua TM, Li XR, He LH,et al. Functional degradation of visual cortical cells in old cats. Neurobiol Aging,2006,27(1):155-162
[183]Caccuri R L, Lacono R F, WeissenbacherM C, et al Long-lasting astrocyte reaction to persistent Junin virus infection of rat cortical neurons.J Neural Transm,2003,110(8): 847-857
[184]Beattie E C, Stellwagen D, Morishita W, et al.Control of synaptic strength by glial TNF alpha.Science,2002,295(5563):2282-2285.
[185]王建彪,竺可青.星形胶质细胞对神经元作用的研究进展.浙江大学学报.医学版,2008,37(5)：531-536.
[186]Shi Q, Gibson GE. Oxidative stress and transcriptional regulation in Alzheimer disease. Alzheimer Dis Assoc Disord 2007,21:276-291.
[187]吴海燕,杨云霞.氧化应激与老年痴呆症的发生发展关系。四川生理科学杂志,2007,29(3)：124-126
[188]盛树力.表观遗传学与阿尔茨海默病并研究,中国神经免疫学与神经病学杂志,2010；17(6)：395-398
[189]陈勤.抗衰老研究实验方法[M].北京：中国医学科技出版社,1996：412
[190]任非,龚淑英.银杏叶提取物治疗老年痴呆症,中国临床康复,2005;9(32)：166-168
[191]Kumar A, Dogra S, Prakash A. Protective effect of naringin:a citrus flavonoid, against colchicine-induced cognitive dysfunction and oxidative damage in rats. Med Food,2010; 13:976-984.
[192]Tachibana H, Koga K, Fujimura Y, Yamada K. A receptor for green tea polyphenol EGCG. Nature Struc Mole Biol,2004,11(3):380-381
[193]Guo SH, Bezard E, Zhao BL. Protective effect of green tea polyphenols on the SH-SY5Y cells against 6-OHDA induced apoptosis through ROS-NO pathway. Free Rad Biol Med,2005,39(4):682-695
[194]de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. J Alzheimers Dis,2006,9:167-181
[195]Swerdlow RH, Khan SM. A"mitochondrial cascade hypothesis"for sporadic Alzheimer's disease. Med Hypotheses,2004,63:8-20.
[196]Swerdlow RH, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis:an update. Exp Neurol,2009,218:308-315.
[197]LaFerla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci,2007,8:499-509.
[198]Keil U, Bonert A, Marques CA, et al. Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem,2004,279: 50310-50320.
[199]Baloyannis SJ. Dendritic pathology in Alzheimer's disease. J Neurol Sci,2009,283: 153-157.
[200]Yao J, Irwin RW, Zhao L, et al. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A,2009, 106:14670-14675.
[201]Moreira PI, Siedlak SL, Wang X, et al. Autophagocytosis of mitochondria is prominent in Alzheimer disease. J Neuropathol Exp Neurol,2007,66:525-532.
[202]Fattoretti P, Balietti M, Casoli T, et alDecreased numeric density of succinic dehydrogenase-positive mitochondria in CA1 pyramidal neurons of 3xTg-AD mice. Rejuvenation Res,2010,13:144-147.
[203]Hansson Petersen CA, Alikhani N, Behbahani H, et al. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae.Proc Natl Acad Sci U S A,2008,105:13145-13150.
[204]Takuma K, Yao J, Huang J, et al. ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J,2005,19:597-598.
[205]Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res,2005, 8:3-5.
[206]Moreira PI, Siedlak SL, Wang X, et al. Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy,2007,3:614-615.
[207]Giro G, Sakakura CE, Gongalves D, et al. Effect of 17 betaestrad iol and alend ronate on the removal torque of osseoin tegrated titanium implants in ovariectomized rats. J Pefodontol,2007,78(7):1316-1321.
[208]Licastro F, Grimaldi LM, Bonafe M, et al.Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain.Neurobiology Aging,2003,24(7):921-926.
[209]Benveniste EN, Nguyen VT, O'Keefe GM. Immunological aspects of microglia:relevance to Alzheimer's disease. Neurochem Int,2001;39(5-6):381-391.
[210]Findeis MA. The role of amyloid β peptide 42 in Alzheimer's disease. Pharmacology Ther, 2007; 116(2):266-286.
[211]FeigeU, PollaBS. Heatshockproteins:the HSP70 family. Experientia,1994,50:979-986
[212]Hartl FU, Hard HM. Molecular chaperon esinthe cytosol:from nascent chain to folded protein. Science,2002; 295:1852-1858
[213]张雪梅,柯开富,邱一华,彭聿平.细胞因子在阿尔茨海默病的发生和发展中的作用,交通医学,2011；25(2)：140-144
[214]鲍娟,杨期东,罗红波,苗旺,郭伟新.阿尔茨海默病大鼠海马热休克蛋白70表达变化的研究。脑与神经疾病杂志,2008；16(5)：594-597
[215]Christopher G, Susanne W, Jason E. Hea shock protein 70 and 90 inhibit early stages of amyloid β-(1-42) aggregation in vitro. J.Biol.Chem,2006,281:33182-33191
[216]Jeremy DM, Michael DS. Inhaled nitric oxide and neuroprotection in preterm infants. Clin Perinatol,2008;35(4):793-807
[217]Zhang L, Dawson VL, Dawson TM. Role of nitric oxide in Parkinson disease. Pharmacol Thera.2006,109(2):33-40.
[218]Anil K, Anant S.Possible nitric oxide modulation in protective effect (curcuma longa, zingiberaceae) against sleep deprivation-induced behavioral alterations and oxidative damage in mice. Phytomedicine 2008;15(8):577-586.
[219]Vincent AM, Maiese K. Nitro oxide induction of neuronal endonuclease activity in programmed cell death. Exp Cell Res,1999;246:240-243
[220]徐建华,吴斌,陈达伟,孙滢.帕金森病大鼠中枢神经一氧化氮合成酶活性研究.海军医学杂志2011,3(4)：245-248.
[221]谢海,战同霞,钟明强.原花青素对老年痴呆患者脑功能的影响.中国误诊学杂志,2008；8(24)：5866-5867
[222]任非,龚淑英.银杏叶提取物治疗老年痴呆症.中国临床康复,2005；9(32)：166-168
[2]仇成轩,施侣元.进一步重视我国老年痴呆流行病学研究中国流行病学杂志,2005；26(12)：931-933)
[3]Luengo-Fernandez, Leal S, Gray A. Dementia 2010.Health Economics Research Cenfre, University of Oxfordfor the Alzheimer's Research Trust [online]. Available from URL:hffp://www.dementia2010.org/[Accessed2010 Nov 29]
[4]王树国.填髓祛邪合剂治疗血管性痴呆54例.山西中医2007；23(4)：19-20.
[5]魏铁力,陈英群,邓頲.心脑血管疾病常用药物探密中国医药学,2002；17(增刊)：290-291.
[6]Kovacs GG, AlafuzofT I, Al-Sarraj S, et al. Mixed brain pathologies in dementia:the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord 2008-26 (4)-343-50
[7]American Psychiatric Association. Diagnostic and Statis-tical Manual of Mental Disorders (4th edition). Arlington, US:American Psychiatric Publishing Inc,2000
[8]Cummings JL. Dementia with Lewy bodies:molecular pathogenesis and implications for classirication. J Geriatr Psychiatry Neurol 2004; 17 (3):112-9
[9]Desmond DW. Vascular dementia. Clin Neurosci Res 2004; 3 (6):437-48
[10]McKeith L Cummings J. Behavioural changes and psychological symptoms in dementia disorders. Lancet Neurol2005; 4 (11):735-42
[11]Munoz-Torrero D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer's disease. Curr Med Chem 2008; 15 (24):2433-55
[12]Ballard CG, Chalmers KA, Todd C, et al. Cholinesterase inhibitors reduce cortical Aβ in dementia with Lewy bodies. Neurology 2007; 68 (20):1726-9
[13]Muth K, Schonmeyer R, Matura S, et al. Mild cognitive impairment in the elderly is associated with volume loss of the cholinergic basal forebrain region. Bio] Psychiatry 2010; 67 (6):588-91
[14]Kendziorra K, Wolf H, Meyer PM, et al. Decreased cerebral α4β2* nicotinic acetylcholine receptor availabiUty in patients with mild cognitive impairment and Alzheimer's disease assessed with positron emission tomography. Eur Nucl Med Mol Imaging 2011; 38 (3): 515-25
[15]Diniz BS, Pinto Jr JA, Gonzaga ML, et al. To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci 2009; 259 (4):248-56
[16]Pogacic Kramp V, Herrling P. List of drugs in development for neurodegenerative diseases: update for June 2010. Neurodegener Dis 2011; 8 (1-2):44-94
[17]Nicholson CD. Pharmacology of nootropics and metabolically active compounds in relation to their use in dementia. Psychopharmacology 1990; 101 (2):147-59
[18]Ellis JR, Nathan PJ, Villemagne VL, et al. Galantamineinduced improvements in cognitive function are not related to alterations in α4β2 nicotinic receptors in early Alzheimer's disease as measured in vivo by 2-['*F]fluoroA-85380 PET. Psychopharmacology 2009; 202 (1-3): 79-91
[19]Penner J, Rupsingh R. Smith M, et al. Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(1):104-10
[20]LiQ, Fang J, Yang M, et al. Galantamine inhibits calpaincalcineurin signaling activated by β-amyloid in human neuroblastoma SH-SY5Y cells. Neurosci Lett 2010; 480 (3):173-7
[21]Li Q, Wu D, Zhang L, et al. Effects of galantamine on p-amyloid release and β-site cleaving etizyme 1 expression in differentiated human neuroblastoma SH-SY5Y cells.Exp Gerontol 2010; 45 (11):842-7
[22]Matharu B, Gibson G, Parsons R, et al. Galantamine inhibits β-amyioid aggregation and cytotoxicity. J Neurol Sei 2009; 280 (1-2):49-58
[23]Melo JB, Sousa C, Garcao P, et al. Galantamine protects against oxidative stress induced by amyloid-β peptide in cortical neurons. Eur J Neurosci 2009; 29 (3):455-64
[24]Liu X, Xu K, Yan M, et al. Protective effects of gaiantarnine against Aβ-induced PC 12 cell apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum stress. Neurochem Int 2010; 57 (5):588-99
[25]Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev 2006; 1:CD005593
[26]Rodda J, Morgan S, Walker Z. Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer's disease? A systematic review of randomized, placebocontrolled trials of donepezil, rivastigmine and galantamine. Int Psychogeriatr 2009; 21 (5):813-24
[27]Small G. Erkinjuntti T, Kurz A, et al. Galantamine in the treatment of cognitive decline in patients with vascular dementia or Alzheimer's disease with cerebrovascular disease. CNS Drugs 2003; 17 (12):905-14
[28]Litvinenko IV, Odinak MM, Mogil'naya VI, etal. Efficacy and safety of galantamine (Reminyl) for dementia in patients with Parkinson's disease (an opencontrolled trial). Neurosci Behav Physiol 2008; 38 (9):937-45
[29]Loy C, Schneider L. Galantamine for Alzheimer's disease and mild cognitive impairment. Coehrane Database Syst Rev 2006; 25:CD001747
[30]Tangwongchai S, Thavichachart N, Senanarong V, etal.Galantamine for the treatment of BPSD in Thai patients wifh possible Alzheimer's disease with or without cerebrovascular disease. Am J Alzheimers Dis Other Demen 2009; 23 (6):593-601
[31]Lockhart IA, Mitchell SA, Kelly S. Safety and tolerability of donepezil, rivastigmine and galantamine for patients wifh Alzheimer's disease:systematic review of the "realworld" evidence. Dement Geriatr Cogn Disord 2009; 28 (5):389-403
[32]Leonard AK, Sileno AP, Macevilly C, et al. Development of a novel high-concenfrafion galantamine formulation suitable for intranasal delivery. J Pharm Sei 2005; 94 (8):1736-46
[33]Maelicke A, Hoeffle-Maas A, Ludwig J, et al. Memogain is a galanfamine pro-drug having dramatically reduced adverse effeefs and enhanced efficacy. J Mol Neurosci 2010-40(1-2): 135-7
[34]Loizzo MR, Tundis R, Menichini F, et al. Natural products and their derivatives as cholinesterase inhibitors in the treatment of neurodegenerative disorders:an update. Curr Med Chem 2008; 15 (12):1209-28
[35]Houghton PJ, Ren YH, Howes MJ. Acetylcholinesterase inhibitors from plants and fungi. Nat Prod Rep 2006;23(2):181-99
[36]Jin Z. Amaryllidaceae and Sceletium alkaloids. Naf Prod Rep 2009; 26 (3):363-81
[37]McNuIfy J, Nair JJ, Little JRL, et al. Structure-aetivity studies on aeetylcholinesterase inhibition in fhe lycorine series of Amaryllidaeeae alkaloids. Bioorg Med ChemLett 2010; 20 (17):5290-4
[38]Williams P, Sorribas A, Howes M-JR. Natural products as a source of Alzheimer's drug leads. Nat Prod Rep 2011;28 (Ⅰ):48-77
[39]Howes M-JR, Houghton PJ. Acetylcholinesterase inhibitors of natural origin. Int J Biomed Pharm Sei 2009;3 (SI 1):67-86
[40]Yoshida S, Suzuki N. Antiamnesie and cholinomimetic side-effects of the cholinesterase inhibitors, physostigmine, tacrine and NIK-247 in rats. Eur J Pharmacol 1993; 250(1):117-24
[41]Thai LJ, Ferguson JM, Mintzer J, et al. A 24-week randomized trial of controlled release physostigmine in patients with Alzheimer's disease. Neurology 1999; 52 (6):1146-52
[42]Coelho F, Birks J. Physostigmine for Alzheimer's disease. Cochrane Database Syst Rev 2001; 2:CD001499
[43]Braida D, Sala M. Eptastigmine:ten years of pharmacology, toxicology, pharmacokinetie, and clinical studies. CNS Drug Rev 2001; 7 (4):369-86
[44]Kamal MA, Al-Jafari AA, Yu QS, et al. Kinetic analysis of the inhibition of human bufyrylcholinesterase with eymserine. Biochim Biophys Acta 2006; 1760 (2):200-6
[45]Kamal MA, Klein P, Yu QS, et al. Kinetics of human serum butyrylcholinesterase and its inhibition by a novel experimental Alzheimer fherapeufic, bisnorcymserine. J Alzheimers Dis 2006; 10(1):43-51
[46]Kamal MA, Qu X, Yu Q-S, et al. Tetrahydrofurobenzofuran cymserine, a potent butyryleholinesterase inhibitor and experimental Alzheimer drug candidate, enzyme kinetic analysis. J Neural Transm 2008; 115 (6):889-98
[47]Butler MS. Natural products to drugs:natural productderived compounds in clinical trials. Nat Prod Rep 2008-25 (3):475-516
[48]Fink DM, Palermo MG, Bores GM, et al. Imino 1,2,3,4-tetrahydrocyclopent indole carbamates as dual inhibitors of aeetylcholinesterase and monoamine oxidase. Bioorg Med Chem Lett 1996; 6 (6):625-30
[49]Toda N, Kaneko T, Kogen H. Development of an efficient therapeutic agent for Alzheimer's disease:design and synthesis of dual inhibitors of acetyleholinesterase and serotonin transporter. Chem Pharm Bull 2010; 58 (3):273-87
[50]Tang LL, Wang R, Tang XC. Effeets of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PCI 2 eells. Acta Pharmacol Sin 2005; 26 (6):673-8
[51]Wang R, Yan H, Tang XC. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 2006; 27 (1):1-26
[52]Wang BS, Wang H, Wei ZH, et al. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease:an updated meta-analysis. J Neural Transm 2009; 116 (4):457-65
[53]Hao Z, Liu M, Liu Z, et al. Huperzine A for vascular dementia. Cochrane Database Syst Rev 2009; 2:CDOO7365
[54]Ronco C, Sorin G, Nachon F, et al. Synthesis and structure-aetivity relationship of huprine derivatives as human acetylcholinesterase inhibitors. Bioorg Med Chem 2009-17 (13): 4523-36
[55]Camps P, Cusack B, Mallender WD, et al. Huprine X is a novel high-affinity inhibitor of acetylcholinesterase that is of interest for treatment of Alzheimer's disease. Mol Pharmacol 2000; 57 (2):409-17
[56]Merlini L, Pinza M. Trends in searching for new cognition enhancing drugs. Prog Neuropsyehopharmacol Biol Psychiatry 1989; 13 (Suppl.):S61-75
[57]Deshmukh R, Sharma V, Mehan S, et al. Amelioration of intracerebroventricular strepfozotocin induced cognitive dysfunction and oxidative stress by vinpocetine:a PDE1 inhibitor. Eur J Pharmacol 2009; 620 (1-3):49-56
[58]Erdo SL, Molnar P, Lakics P, et al. Vincamine and vincanol are potent blockers of voltage-gated Na+ channels. Eur J Pharmacol 1996; 314 (1-2):69-73
[59]Nyakas C, Felszeghy K, Szabo R, et al. Neuroprotective effects of vinpocetine and its major metabolite cis-apovincaminic acid on NMDA-induced neurotoxicity in a rat entorhinal cortex lesion model. CNS Neurosci Ther 2009; 15(2):89-99
[60]Akhondzadeh S, Abbasi SH. Herbal medicine in the treatment of Alzheimer's disease. Am J Alzheimers Dis Other Demen 2006; 21 (2):113-8
[61]Valikovics A. Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions. Ideggyogy Sz 2007; 60 (7-8):301-10
[62]Szatmari SZ, Whitehouse PJ. Vinpocetine for cognitive impairment and dementia. Cochrane Database Syst Rev 2003; 1:CD003119
[63]Khanavi M, Pourmoslemi S, Farahanikia B, et al. Cytotoxicity of Vinca minor. Pharm Biol 2010; 48(1):96-100
[64]Howes M-JR, Houghton PJ. Traditional medicine for memory enhancement. In:Ramawat KG, editor. Herbal drugs:ethnomedicine to modem medicine. New York:Springer,2009:239-91
[65]Elbaz A, Moisan F. Update in the epidemiology of Parkinson's disease. Curr Opin Neurol 2008; 21 (4):454-60
[66]Dome P, Lazary J, Kalapos MP, et al. Smoking, nicotine and neuropsychiatrie disorders. Neurosci Biobehav Rev 2010; 34 (3):295-342
[67]Levin ED, Christopher CN. Lobeline-induced learning improvement of rats in the radialarm-maze. Pharmacol Biochem Behav 2003; 76 (1):133-9
[68]Romero J, Martinez Orgado J. Cannabinoids and neurodegenerative diseases. CNS Neurol Disord Drug Targets 2009; 8 (6):440-50
[69]Esposito G, De Filippis D, Camuccio R, et al. The marijuana component cannabidiol inhibits β-amyloidinduced tau protein hyperphosphorylation through Wnt/β-catenin pathway rescue in PC 12 cells. J Mol Med 2006; 84 (3):253-8
[70]Janero DR, Vadivel SK, Makriyannis A. Pharmacotherapeutic modulation of the endocannabinoid signalling system in psychiatric disorders:drug-discovery strategies. Int Rev Psychiatry 2009; 21 (2):122-33
[71]Orgado JM, Fernandez-Ruiz J, Romero J. The endocannabinoid system in neuropathological states. Int Rev Psychiatry 2009; 21 (2):172-80
[72]Walther S, Mahlberg R, Eichmann U, et al. A-9-Tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology 2(X)6; 185 (4):524-8
[73]Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 2006; 39 (4):421-9
[74]Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol for the treatment of psychosis in Parkinson's disease. J Psychopharmacol 2009; 23 (8):979-83
[75]Krishnan S, Cairns R, Howard R. Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev 2009; 2:CD007204
[76]Kim J, Lee HJ, Lee KW. Naturally occurring phytochemicals for the prevention of Alzheimer's disease. J Neurochem 2010; 112(6):1415-30
[77]Ng T-P, Chiam P-C, Lee T, et al. Curry consumption and cognitive function in the elderly. Am J Epidemiol 2006; 164 (9):898-906
[78]Kim DS, Kim JY. Total synthesis of calebin A, preparation of its analogues, and their neuronal cell protectivityagainst (3-amyloid insult. Bioorg Med Chem Lett 2001; 11 (18):2541-3
[79]Park SY, Kim DS. Discovery of natural products from Curcuma tonga that protect cells from β-amyloid insult:a drug discovery effort against Alzheimer's disease. J Nat Prod 2002; 65 (9): 1227-31
[80]Shimmyo Y, Kihara T, Akaike A, et al. Bpigallocatechin-3-gallate and curcumin suppress amyloid β-induced β-site APP cleaving enzyme-1 upregulation. Neuroreport 2008; 19(13): 1329-33
[81]Baum L, Ng A. Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer's disease animal models. J Alzheimers Dis 2004; 6 (4):367-77
[82]Pal R, Cristan EA, Schnittker K, et al. Rescue of ER oxidoreductase function through polyphenolic phytochemical intervention:implications for subcellular traffic and neurodegenerative disorders. Biochem Biophys Res Commun 2010; 392 (4):567-71
[83]Agrawal R, Mishra B, Tyagi E, et al. Effect of curcumin on brain insulin receptors and memory functions in STZ (ICV) induced dementia model of rat. Pharmacol Res2010; 61 (3): 247-52
[84]Awasthi H, Tota S, Hanif K, et al. Protective effect of curcumin against intracerebral streptozotocin induced impairment in memory and cerebral blood flow. Life Sei 2010; 86 (3-4):87-94
[85]Kumar A, Dogra S, Prakash A. Protective effect of curcumin (Curcuma tonga), against aluminium toxicity:possible behavioral and biochemical alterations in rats. Behav Brain Res 2009; 205 (2):384-90
[86]Yaari R, Kumar S, Tariot PN. Non-cholinergic drug development for Alzheimer's disease. Expert Opin Drug Discov 2008; 3 (7):745-60
[87]Narlawar R, Baumann K, Schubenel R, et al. Curcumin derivatives inhibit or modulate β-amyloid precursor protein metabolism. Neurodegener Dis 2007; 4 (2-3):88-93
[88]Maher P, Akaishi T, Schubert D, et al. A pyrazole derivative of curcumin enhances memory. Neurobiol Aging 2010; 31 (4):706-9
[89]Baum L, Lam CW, Cheung SK, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J ClinPsychopharmacol 2008; 28(1):110-3
[90]Collins MA, Neafsey EJ, Mukamal KJ, et al. Alcohol in moderation, cardioprotection, and neuroprotection:epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res 2009; 33 (2):206-19
[91]Solfrizzi V, D'lntrono A, Colacicco AM, et al. Alcohol consumption, mild cognitive impairment, and progression to dementia. Neurology 2007; 68 (21):1790-9
[92]Mehlig K, Skoog 1, Guo X, et al. Alcoholic beverages and incidence of dementia:34-Year follow-up of the prospective population study of women in Goteborg. Am J Epidemiol 2008; 167 (6):684-9
[93]Rocha-Gonzalez HI, Ambriz-Tututi M, Granados-Soto V. Resveratroi:a natural compound with pharmacological potential in neurodegenerative diseases. CNS Neurosci Ther 2008; 14 (3):234-47
[94]Panza F, Capurso C, D'lntrono A, et al. Alcohol drinking, cognitive functions in older age, predementia, and dementia syndromes. J Alzheimers Dis 2(H)9; 17(1):7-31
[95]Jang JH, Surh YJ. Protective effect of resveratrol on β-amyloid-induced oxidative PC12 cell death. Free Radie Biol Med 2003; 34 (8):1100-10
[96]Rossi M, Caruso F, Opazo C, et al. Crystal and molecular structure of piceatannol; scavenging features of resveratrol and piceatannol on hydroxyl and peroxyl radicals and docking with transthyretin. J Agrie Food Chem 2008-56(22):10557-66
[97]Vingtdeux V, Dreses-Werringloer U, Zhao H, et al. Therapeutic potential of resveratrol in Alzheimer's disease. BMC Neurosci 2008; 9 Suppl.2:S6
[98]Pallas M, Casadesus G, Smith MA, et al. Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res 2009; 6 (I):70-81
[99]Kumar A, Naidu PS, Seghal N, et al. Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats. Pharmacology 2007; 79 (1):17-26
[100]Karuppagounder SS, Pinto JT, Xu H, et al. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease. Neurochem Int 2008; 54 (2): 111-8
[101]Ma X, Tan C, Zhu D, Gang DR, Xiao P. Huperzine A from Huperziaspeciesdan ethnopharmacological review. J Ethnopharmacol 2007; 113:15-34.
[102]Wang R, Yan H, Tang XC. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin 2006; 27:1-26.
[103]Wang R, Tang XC. Neuroprotective effects of huperzine A:a natural cholinesterase inhibitor for the treatment of Alzheimer's disease. Neurosignals 2005; 14:71-8.
[104]Hualiang J, Xiaomin L, Donglu B. Progress in clinical, pharmacological, chemical and structural biological studies of huperzine A:a drug of traditional Chinese medicine origin for the treatment of Alzheimer's disease. Curr Med Chem 2003; 10:2231-52.
[105]Gao X, Tang XC. Huperzine A attenuates mitochondrial dysfunction in beta-amyloid-treated PC 12 cells by reducing oxygen free radicals accumulation and improving mitochondrial energy metabolism. J Neurosci Res 2006; 83:1048-57.
[106]Zhang HY, Yan H, Tang XC. Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-alpha in intracerebroventricular beta-amyloid-(1-40) infused rats and human embryonic kidney 293 Swedish mutant cells. Neurosci Lett 2004; 360:21-4.
[107]Yang CY, Lv ZP, Zheng CG. Efficacy and reliability of huperzineAinmild and moderate Alzheimer's disease. Chin J Clin Rehabil 2003; 7:4258-9.
[108]Tang LL,Wang R, Tang XC. Effects of huperzine A on secretion of nerve growth factor in cultured rat cortical astrocytes and neurite outgrowth in rat PC 12 cells. Acta Pharmacol Sin 2005; 26:673-8.
[109]Wang ZF, Tang LL, Yan H,Wang YJ, Tang XC. Effects of huperzine A on memory deficits and neurotrophic factors production after transient cerebral ischemia and reperfusion in mice. Pharmacol Biochem Behav 2006; 83:603-11.
[110]Tang XC, Jin GZ, Xu B. Neuropharmacologic actions of lycoramine and galanthamine. Acta Pharm Sin 1963; 10:465-73.
[111]Wang Y, Huang L, Tang X, Zhang H. Retrospect and prospect of active principle from Chinese herbs in the treatment of dementia. Acta Pharm Sin 2010; 31:649-64.
[112]Barnes CA, Meltzer J, Houston F, Orr G, McGann K, Wenk GL. Chronic treatment of old rats with donepezil or galantamine:effects on memory, hippocampal plasticity and nicotinic receptors. Neuroscience 2000; 99:17-23.
[113]Belluardo N, Mudo G, Blum M, Fuxe K. Central nicotinic receptors, neurotrophic factors and neuroprotection. Behav Brain Res 2000; 113:21-34.
[114]Shimohama S, GreenwaldDL, ShafronDH, AkaikaA, MaedaT,Kaneko S, et al. Nicotinic alpha 7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage. Brain Res 1998; 779:359-63.
[115]Giunta B, Ehrhart J, Townsend K, Sun N, Vendrame M, Shytle D, et al. Galantamine and nicotine have a synergistic effect on inhibition of microglial activation induced by HIV-1 gp120. Brain Res Bull 2004; 64:165-70.
[116]Repantis D, Laisney O, Heuser I. Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals:a systematic review. Pharmacol Res 2010; 61:473-81.
[117]Ezoulin MJ, Ombetta JE, Dutertre-Catella H, Warnet JM, Massicot F. Antioxidative properties of galantamine on neuronal damage induced by hydrogen peroxide in SK-N-SH cells. Neurotoxicology 2008; 29:270-7.
[118]Cao XZ, Zhang LM, Shen YE, Zhou SS, Jiang GH. NMDA receptors mediate the effect of galantamin on the cognitive function of Alzheimer's disease in rats. J Apop Nerv Dis 2006; 23:678-80.
[119]Mulder J, Harkany T, Czollner K, Cremers TI, Keijser JN, Nyakas C, et al. Galantamine-induced behavioral recovery after sublethal excitotoxic lesions to the rat medial septum. Behav Brain Res 2005; 163:33-41.
[120]Moriguchi S, Marszalec W, Zhao X, Yeh JZ, Narahashi T. Mechanism of action of galantamine on N-methyl-D-aspartate receptors in rat cortical neurons. J Pharmacol Exp Ther 2004;310:933-42.
[121]Melo JB, Sousa C, Garcao P, Oliveira CR, Agostinho P. Galantamine protects against oxidative stress induced by amyloid-beta peptide in cortical neurons. Eur J Neurosci 2009; 29:455-64.
[122]Matharu B, Gibson G, Parsons R, Huckerby TN, Moore SA, Cooper LJ, et al. Galantamine inhibits beta-amyloid aggregation and cytotoxicity. J Neurol Sci 2009; 280:49-58.
[123]Arias E, Ales E, Gabilan NH, Cano-Abad MF, Villarroya M, Garcia AG, et al. Galantamine prevents apoptosis induced by beta-amyloid and thapsigargin:involvement of nicotinic acetylcholine receptors. Neuropharmacology 2004; 46:103-14.
[124]Gertz H-J, Kiefer M. Review about Ginkgo biloba special extract EGb 761 (Ginkgo). Curr Pharm Des 2004; 10(3)-261-4
[125]Saddichha S, Pandey V. Alzheimer's and non-Alzheimer's dementia:a critical review of pharmacological and nonpharmacological strategies. Am J Alzheimers Dis Other Demen 2008; 23 (2):150-61
[126]Chan P-C, Xia Q, Fu PP. Ginkgo biloba leaf extract:biological, medicinal, and toxicological effects. J Environ Sei Health C Environ Carcinog Ecotoxicol Rev 2007; 25 (3):211-44
[127]Das A, Shanker G, Nath C, et al. A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba:anticholinesterase and cognitive enhancing activities. Pharmcol Biochem Behav 2002; 73 (4):893-900
[128]Birks J, Grimley EV, Van Dongen M. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2002; 4:CD003120
[129]Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2007; 2:CD003120
[130]Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2009;1:CD003120
[131]Kaschel R. Ginkgo biloba:specificity of neuropsychological improvement-a selective review in search of differential effects. Hum Psychopharmaol 2009; 24 (5):345-70
[132]Weinmann S, Roll S, Schwarzbach C, et al. Effects of Ginkgo biloba in dementia: systematic review and meta-analysis. BMC Geriatr 2010; 10:14
[133]DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloha for prevention of dementia:a randomized controlled trial [published erratum appears in JAMA 2008; 300 (23): 2730]. JAMA 2008; 300 (39):2253-62
[134]Andrieu S, Ousset P-J, Coley N, et al. GuidAge study:a 5-year double bhnd, randomised trial of EGb 761 for the prevention of Alzheimer's disease in elderly subjects with memory complaints, I:rationale, design and baseline data. Curr Alzheimer Res 2008; 5 (4):406-15
[135]Yancheva S, IhI R, Nikolova G, et al. Ginkgo biloba extract EGb 761R, donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatrie features:a randomised, double-blind, exploratory trial. Aging Ment Health 2009; 13(2):183-90
[136]Yasui-Furukori N, Furukori H, Kaneda A,et al. The effects of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of donepezil. J Clin Pharmacol 2004; 44 (5): 538-42
[137]Barnes J, Anderson LA, Phillipson JD. Herbal medicines.3rd ed. London:Pharmaceutical Press,2007
[138]Scripnikov A, Khomenko A, Napryeyenko O. Effects of Ginkgo biloba extract EGb 761-on neuropsychiatrie symptoms of dementia:findings from a randomised controlled trial. Wien Med Wochenschr 2007; 157 (13-14)-295-300
[139]Leistner E, Drewke C. Ginkgo biloba and ginkgotoxin. J Nat Prod 2010; 73 (1):86-92
[140]Xiao Q, Wang C, Li J, et al. Ginkgolide B protects hippocampal neurons from apoptosis induced by β-amyloid 25-35 partly via up-regulation of brain-derived neurotrophic factor. Eur J Pharmacol 2010; 647 (1-3):48-54
[141]Bate C, Tayebi M, Williams A. Ginkgolides protect against amyloid-β. Mol Neurodegener 2008 Jan 7; 3:1
[142]Shi C, Wu F, Yew DT, et al. Bilobalide prevents apoptosis through activation ofthe PI3K/Akt pathway in SH-SY5Y cells. Apoptosis 2010; 15 (6):715-27
[143]Gertz HJ, Kiefer M. Review about Ginkgo biloba special extract EGb 761 (Ginkgo). Curr Pharm Des 2004; 10:261-4.
[144]Weinmann S, Roll S, Schwarzbach C, Vauth C, Willich SN. Effects of Ginkgo biloba in dementia:systematic review and meta-analysis. BMC Geriatr 2010; 10:1-14.
[145]Lu G, Wu Y, Mak YT, Wai SM, Feng ZT, Rudd JA, et al. Molecular evidence of the neuroprotective effect of Ginkgo biloba (EGb761) using bax/bcl-2 ratio after brain ischemia in senescence-accelerated mice, strain prone-8. Brain Res 2006; 1090:23-8.
[146]Calapai G, Crupi A, Firenzuoli F, Marciano MC, Squadrito F, Inferrera G, et al. Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis. Life Sci 2000; 67:2673-83.
[147]Eckert A, Kreil U, Kressmann S, Schindowski K, Leutner S, Lutz S, et al. Effects of Egb761 Ginkgo biloba extract on mitochondrial function and oxidative stress. Pharmacopsychiatry 2003; 36:15-23.
[148]Li FM, Duan XM, Wang JJ, Fang HL. Effects of Ginkgo biloba extract on MitoKATP in focal cerebral ischemia-reperfusion rats. Chin Arch Tradit Chin Med 2008; 26:1462-6.
[149]Kasper S, Schubert H. Ginkgo biloba extract EGb 761(R) in the treatment of dementia: evidence of efficacy and tolerability. Fortschr Neurol Psychiatr 2009; 77:494-506.
[150]Wang SY, Liu XM, Wang JX, Liu YX, Yuang DX. Effect of EGb on GFAP in focal cerebral ischemia-reperfusion injury rats. Anatomy Res 2008; 30:115-7
[151]Kang TH, Murakami Y, Takayama H, Kitajima M, Aimi N, Watanabe H, et al. Protective effect of rhynchophylline and isorhynchophylline on invitro ischemia-induced neuronal damage in the hippocampus:putative neurotransmitter receptors involved in their action. Life Sci 2004; 76:331-43.
[152]Wirths O, Malthaup G, Bayer TA. A modified b-amyloid hypothesis:intraneuronal accumulation of the b-amyloid peptidedthe first step of a fatal cascade. J Neurochem 2004; 91:513-20.
[153]Chung IW, Moore NA, Oh WK, O'Neill MF, Ahn JS, Park JB, et al. Behavioural pharmacology of polygalasaponins indicates potential antipsychotic efficacy. Pharmacol Biochem Behav 2002; 71:191-5.
[154]Kim HM, Lee EH, Lee HJ, Shin SB, Lyu TY, Kim YS, et al. Effect of Polygala tenuifolia root extract on the tumor necrosis factor-alphasecretion from mouse astrocytes. J Ethnopharmacol 1998; 161:201-8.
[155]Lv J, Jia H, Jiang Y, Ruan Y, Liu Z, Yue W, et al. Tenuifolin, an extract derived from tenuigenin, inhibits amyloid-b secretion in vitro. Acta Physiol 2009;196:419-25.
[156]Jia H, Jiang Y, Ruan Y, Zhang Y, Ma X, Zhang J, et al. Tenuigenin treatment decreases secretion of the Alzheimer's disease amyloid betaprotein in cultured cells. Neurosci Lett 2004; 367:123-8.
[157]Schwarz K, Ternes W. Antioxidative constituents of Rosmarinus officinalis and Salvia officinalis. Ⅱ. Isolation of carnosic acid and formation of other phenolic diterpenes. Z Lebensm Unters Forsch 1992; 195:99-103.
[158]Lu J, Zheng YL, Wu DM, Luo L, Sun DX, Shan Q. Ursolic acid ameliorates cognition deficits and attenuates oxidative damage in the brain of senescent mice induced by D-galactose. Biochem Pharmacol 2007; 74:1078-90.
[159]Sofic E, Sapcanin A, Tahirovic I, Gavrankapetanovic I, Jellinger K, Reynolds GP, et al. Antioxidant capacity in postmortem brain tissues of Parkinson's and Alzheimer's diseases. J Neural Transm Suppl 2006; 71:39-43.
[160]Akhondzadeh S, NoroozianM, MohammadiM, Ohadinia S, Jamshidi AH, KhaniM. Salvia officinalis extract in the treatment of patients with mild to moderate Alzheimer's disease:a double blind, randomized and placebocontrolled trial. J Clin Pharm Ther 2003; 28:53-9.
[161]Chung YK, Heo HJ, Kim EK, Kim HK, Huh TL, Lim Y. Inhibitory effect of ursolic acid purified from Origanum majorana L on the acetylcholinesterase. Mol Cells 2001; 11:137-43.
[162]Porat Y, Abramowitz A, Gazit E. Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism. Chem Biol Drug Des 2006; 67:23-37.
[163]Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent antiamyloiaogenic effects for Alzhemer's beta-amyloid fibrils in vitro.J Neurosci Res 2004;75:742-50.
[164]Chen YJ, Zeng SJ, Hsu JT, Horng JT, Yang HM, Shih SR, et al.Amantadine as a regulator of internal ribosome entry site. Acta Pharmacol Sin 2008; 29:1327-33.
[165]Wu TY, Chen CP. Dual action of memantine in Alzheimer disease:a hypothesis. Taiwan J Obstet Gynecol 2009; 48:273-7.
[166]Wu TY, Chen CP, Jinn TR. Alzheimer's disease:aging, insomnia and epigenetics. Taiwan J Obstet Gynecol 2010; 49:468-72.
[167]王晋平,赵贞.血管性痴呆动物模型研究进展.山西中医学院学报,2008；9(5)：60-62
[168]张峰,张继国,王丽华,等.黄精多糖对东莨菪碱致小鼠记忆获得障碍的改善作用.现代中西医结合杂志,2007；16(36)：5410-5412
[169]范郁山,陈芒华.浅刺调督法对老年性痴呆模型行为学的影响.辽宁中医药大学学报,2008,10(5)：177-178
[170]Oddo S, Caccamo A, Shepherd J D, et al. Triple transgenic model of Alzheimer's disease with plaques and tangles:intracellular Aβ and synaptic dysfunction. Neuron,2003,39(3):409
[171]李亚明,朱粹青,林水淼,等.老年性痴呆大鼠模型建立的研究.老年医学与保健,2001,7(4)：214-217
[172]Hob A, Nitta A, Nadai M, et al. Dysfunction of cholinergic and dopaminergic neuronal system s in beta-amyloid protein-infused rats. J Neurochem,1996,66(3):1113
[173]王雅琼,闫福岭,鲁国.Aβ25-35杏仁核注射对大鼠海马tau蛋白磷酸化和AchE的影响.实用神经疾病杂志,实用神经疾病杂志,2005,8(4)：34-35
[174]Lin X, Koelsch G, Wu S, et al. Human aspartic protease memapsin2 cleaves the beta-secretase site of beta-amyloid precursor protin. Proc. Natl. Acad. Sci,2000, 97(4):1456-1460
[175]Yan R, Bienkowski MJ, Shuck ME, et al. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature,1999,402(6761):533-537
[176]Young Ho Koh, Christine AF, Bradley TH, et al. BACE is degraded via the lysosomal pathway. Biol Chem,2005,280(37):32499-32504
[177]Michelle AC, Weihui Zhou, Hong Qing, et al. Transcriptional regulation of BACE1, the β-amyioid precursor proteinβ-Secretase, by Spl. Molecular and Cellular Biology, 2004,24(2):865-874
[178]Lucie K, Nicoletta K, Petra S, et al. Lipids as modulators of proteolytic activity of BACE. Bio1.Chem,2005,280(44)：36815-3682
[179]王国卿,封丽芳,夏作理.星形胶质细胞的生物学功能与神经元修复。中国临床康复,2005,9(1)：146-148
[180]Min K. J. Yang M S. Jou I, et al.Protein kinase A medi ates microglial activation induced by plasminogen and gangliosides. Exp Mol Med,2004,36(5):461-467.
[181]Albrecht P J, Dahl J P, Stoltzfus O K. et al. Ciliary neurotrophic factor activates spinal cord astrocytes,stimulating their production and release of fibroblast growth factor-2, to increase motor neuron survival. Exp Neurol,2002,173(1):46-62.
[182]Hua TM, Li XR, He LH,et al. Functional degradation of visual cortical cells in old cats. Neurobiol Aging,2006,27(1):155-162
[183]Caccuri R L, Lacono R F, WeissenbacherM C, et al Long-lasting astrocyte reaction to persistent Junin virus infection of rat cortical neurons.J Neural Transm,2003,110(8): 847-857
[184]Beattie E C, Stellwagen D, Morishita W, et al.Control of synaptic strength by glial TNF alpha.Science,2002,295(5563):2282-2285.
[185]王建彪,竺可青.星形胶质细胞对神经元作用的研究进展.浙江大学学报.医学版,2008,37(5)：531-536.
[186]Shi Q, Gibson GE. Oxidative stress and transcriptional regulation in Alzheimer disease. Alzheimer Dis Assoc Disord 2007,21:276-291.
[187]吴海燕,杨云霞.氧化应激与老年痴呆症的发生发展关系。四川生理科学杂志,2007,29(3)：124-126
[188]盛树力.表观遗传学与阿尔茨海默病并研究,中国神经免疫学与神经病学杂志,2010；17(6)：395-398
[189]陈勤.抗衰老研究实验方法[M].北京：中国医学科技出版社,1996：412
[190]任非,龚淑英.银杏叶提取物治疗老年痴呆症,中国临床康复,2005;9(32)：166-168
[191]Kumar A, Dogra S, Prakash A. Protective effect of naringin:a citrus flavonoid, against colchicine-induced cognitive dysfunction and oxidative damage in rats. Med Food,2010; 13:976-984.
[192]Tachibana H, Koga K, Fujimura Y, Yamada K. A receptor for green tea polyphenol EGCG. Nature Struc Mole Biol,2004,11(3):380-381
[193]Guo SH, Bezard E, Zhao BL. Protective effect of green tea polyphenols on the SH-SY5Y cells against 6-OHDA induced apoptosis through ROS-NO pathway. Free Rad Biol Med,2005,39(4):682-695
[194]de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. J Alzheimers Dis,2006,9:167-181
[195]Swerdlow RH, Khan SM. A"mitochondrial cascade hypothesis"for sporadic Alzheimer's disease. Med Hypotheses,2004,63:8-20.
[196]Swerdlow RH, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis:an update. Exp Neurol,2009,218:308-315.
[197]LaFerla FM, Green KN, Oddo S. Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci,2007,8:499-509.
[198]Keil U, Bonert A, Marques CA, et al. Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis. J Biol Chem,2004,279: 50310-50320.
[199]Baloyannis SJ. Dendritic pathology in Alzheimer's disease. J Neurol Sci,2009,283: 153-157.
[200]Yao J, Irwin RW, Zhao L, et al. Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A,2009, 106:14670-14675.
[201]Moreira PI, Siedlak SL, Wang X, et al. Autophagocytosis of mitochondria is prominent in Alzheimer disease. J Neuropathol Exp Neurol,2007,66:525-532.
[202]Fattoretti P, Balietti M, Casoli T, et alDecreased numeric density of succinic dehydrogenase-positive mitochondria in CA1 pyramidal neurons of 3xTg-AD mice. Rejuvenation Res,2010,13:144-147.
[203]Hansson Petersen CA, Alikhani N, Behbahani H, et al. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae.Proc Natl Acad Sci U S A,2008,105:13145-13150.
[204]Takuma K, Yao J, Huang J, et al. ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J,2005,19:597-598.
[205]Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res,2005, 8:3-5.
[206]Moreira PI, Siedlak SL, Wang X, et al. Increased autophagic degradation of mitochondria in Alzheimer disease. Autophagy,2007,3:614-615.
[207]Giro G, Sakakura CE, Gongalves D, et al. Effect of 17 betaestrad iol and alend ronate on the removal torque of osseoin tegrated titanium implants in ovariectomized rats. J Pefodontol,2007,78(7):1316-1321.
[208]Licastro F, Grimaldi LM, Bonafe M, et al.Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain.Neurobiology Aging,2003,24(7):921-926.
[209]Benveniste EN, Nguyen VT, O'Keefe GM. Immunological aspects of microglia:relevance to Alzheimer's disease. Neurochem Int,2001;39(5-6):381-391.
[210]Findeis MA. The role of amyloid β peptide 42 in Alzheimer's disease. Pharmacology Ther, 2007; 116(2):266-286.
[211]FeigeU, PollaBS. Heatshockproteins:the HSP70 family. Experientia,1994,50:979-986
[212]Hartl FU, Hard HM. Molecular chaperon esinthe cytosol:from nascent chain to folded protein. Science,2002; 295:1852-1858
[213]张雪梅,柯开富,邱一华,彭聿平.细胞因子在阿尔茨海默病的发生和发展中的作用,交通医学,2011；25(2)：140-144
[214]鲍娟,杨期东,罗红波,苗旺,郭伟新.阿尔茨海默病大鼠海马热休克蛋白70表达变化的研究。脑与神经疾病杂志,2008；16(5)：594-597
[215]Christopher G, Susanne W, Jason E. Hea shock protein 70 and 90 inhibit early stages of amyloid β-(1-42) aggregation in vitro. J.Biol.Chem,2006,281:33182-33191
[216]Jeremy DM, Michael DS. Inhaled nitric oxide and neuroprotection in preterm infants. Clin Perinatol,2008;35(4):793-807
[217]Zhang L, Dawson VL, Dawson TM. Role of nitric oxide in Parkinson disease. Pharmacol Thera.2006,109(2):33-40.
[218]Anil K, Anant S.Possible nitric oxide modulation in protective effect (curcuma longa, zingiberaceae) against sleep deprivation-induced behavioral alterations and oxidative damage in mice. Phytomedicine 2008;15(8):577-586.
[219]Vincent AM, Maiese K. Nitro oxide induction of neuronal endonuclease activity in programmed cell death. Exp Cell Res,1999;246:240-243
[220]徐建华,吴斌,陈达伟,孙滢.帕金森病大鼠中枢神经一氧化氮合成酶活性研究.海军医学杂志2011,3(4)：245-248.
[221]谢海,战同霞,钟明强.原花青素对老年痴呆患者脑功能的影响.中国误诊学杂志,2008；8(24)：5866-5867
[222]任非,龚淑英.银杏叶提取物治疗老年痴呆症.中国临床康复,2005；9(32)：166-168