反式白藜芦醇对痴呆大鼠的保护作用
摘要
目的观察反式白藜芦醇(TR)对Aβ25-35损伤大鼠海马的保护作用。方法大鼠经Morris水迷宫训练后,随机分为5组：(1)假手术组；(2)模型组；(3)—(5)分别为TR高、中、低剂量组。在大鼠双侧海马内注射Aβ25-35,制模后用TR干预,以旨在观察TR对Aβ25-35所致的神经毒性的影响。利用水迷宫检测各组大鼠的空间辨别和学习记忆能力；采用TUNEL法检测5组大鼠海马细胞凋亡情况；采用real-time RT-PCR法检测5组大鼠海马及皮质caspase-8,9、诱导型一氧化氮合酶(iNOS) mRNA表达。结果大鼠海马内注射Aβ25-35制模后在水迷宫中的逃避潜伏期和寻台搜索距离明显延长,海马caspase-8,9 mRNA、iNOS表达增加,大鼠海马组织凋亡细胞增加。而TR干预组表达减少,凋亡细胞也减少。第(1)组到第(5)组中PCR法检测caspase-8mRNA的表达量分别为0.27±0.09、1.34±0.87、0.24±0.09、0.29±0.06、0.64±0.15；各组caspase-9mRNA的表达量分别为0.34±0.07、0.98±0.17、0.32±0.13、0.44±0.18、0.91±0.25；各组iNOS mRNA表达分别为0.23±0.90、1.23±0.91、0.34±O.18、0.48±O.12、0.87±0.49。所有干预组与对照组相比(P<0.01)均有差异。TUNEL法检测各组大鼠海马标本,在荧光显微镜下海马细胞的凋亡指数分别为6±3、24±3、7±2、11±4、20±3(%),干预组与对照组相比(P<0.01)有差异。TUNEL法检测(1)到(5)组的凋亡指数(术后第11天)分别为：3.23±0.52、21.32±5.02、5.72±1.56、7.21±1.22、10.93±3.25(%)；(术后第11天)分别为3.21±0.29、16.31±4.27、5.13±2、7.12±1.78、9.84±2.66(%),同组凋亡指数相比没有差异(P>0.05)。结论TR可减轻Aβ25-35诱导的大鼠记忆减退,其机制可能部分与下调大鼠海马caspase-8,9、iNOSmRNA表达从而减少海马细胞凋亡有关。
Objective:To investigate the protective effects of the efficient ingredient of Polygonum cuspidatum trans-resveratrol (TR) on AD rats. Methods After being trained using Morris water maze, rats were randomly divided into 5 groups:(1) sham-operated-group; (2) model-group(3)-(5) were TR high, middle and low dose group, injecting Aβ25-35 to bilateral hippocampus in vivo modeling method. These three groups were treated with TR after the model was established. TR had been intervening in molding rats aim to observe the toxic effect of Aβ25-35.Morris water maze was used to test the ability of spatial learning and memory of rats in 5 groups; TUNEL assay was used to test apoptosis rate of hippocampus and the cortex around cells; Using real-time RT-PCR to detect the mRNA expression of caspase-8,9, inducible nitric oxide synthase (iNOS) in hippocampus and cortex. Results Molding rats by injecting AP25-35 to hippocampus decreased the abilities of spatial memory and increased the mRNA expressions of caspase-8,9 and iNOS mRNA in hippocampus. However, TR intervention group decreased expressions of caspase-8 and iNOS in hippocampus, apoptotic cells decreased also. The mRNA expression of caspase-8 from group (1) to group (5) were 0.27±0.09,1.34±0.87,0.24±0.09,0.29±0.06,0.64±0.15 respectively; The mRNA expression of caspase-9 from group (1) to group (5) were 0.34±0.07,0.98±0.17、0.32±0.13、0.44±0.18、0.91±0.25 respectively; The mRNA expression of iNOS in each group were 0.23±0.90,1.23±0.91,0.34±0.18,0.48±0.12,0.87±0.49 respectively, All intervention group compared with the control group were different (P<0.01). the hippocampus cells apoptotic index(AI) using TUNEL assay in each group were 6±3, 24±3,7±2,11±4,20±3(%) respectively under fluorescence microscope; AI in each group 11day after modeling were 3.23±0.52,21.32±5.02,5.72±1.56,7.21±1.22, 10.93±3.25(%) respectively; intervention group compared with the control group is different (P<0.01). and 17 day after modeling AI were 3.21±0.29,16.31±4.27,5.13±2, 7.12±1.78,9.84±2.66(%) respectively; Same group AI between the 11 day and 17 day is not different (P>0.01). Conclusion Treatment with different dose of TR can reduce Aβ25-35-induced memory impairment in rats. The mechanism may be partly associated with down regulating the mRNA expression of caspase-8 and iNOS in rat hippocampus, and reducing the cell apoptosis in hippocampus.
Objective:To investigate the protective effects of the efficient ingredient of Polygonum cuspidatum trans-resveratrol (TR) on AD rats. Methods After being trained using Morris water maze, rats were randomly divided into 5 groups:(1) sham-operated-group; (2) model-group(3)-(5) were TR high, middle and low dose group, injecting Aβ25-35 to bilateral hippocampus in vivo modeling method. These three groups were treated with TR after the model was established. TR had been intervening in molding rats aim to observe the toxic effect of Aβ25-35.Morris water maze was used to test the ability of spatial learning and memory of rats in 5 groups; TUNEL assay was used to test apoptosis rate of hippocampus and the cortex around cells; Using real-time RT-PCR to detect the mRNA expression of caspase-8,9, inducible nitric oxide synthase (iNOS) in hippocampus and cortex. Results Molding rats by injecting AP25-35 to hippocampus decreased the abilities of spatial memory and increased the mRNA expressions of caspase-8,9 and iNOS mRNA in hippocampus. However, TR intervention group decreased expressions of caspase-8 and iNOS in hippocampus, apoptotic cells decreased also. The mRNA expression of caspase-8 from group (1) to group (5) were 0.27±0.09,1.34±0.87,0.24±0.09,0.29±0.06,0.64±0.15 respectively; The mRNA expression of caspase-9 from group (1) to group (5) were 0.34±0.07,0.98±0.17、0.32±0.13、0.44±0.18、0.91±0.25 respectively; The mRNA expression of iNOS in each group were 0.23±0.90,1.23±0.91,0.34±0.18,0.48±0.12,0.87±0.49 respectively, All intervention group compared with the control group were different (P<0.01). the hippocampus cells apoptotic index(AI) using TUNEL assay in each group were 6±3, 24±3,7±2,11±4,20±3(%) respectively under fluorescence microscope; AI in each group 11day after modeling were 3.23±0.52,21.32±5.02,5.72±1.56,7.21±1.22, 10.93±3.25(%) respectively; intervention group compared with the control group is different (P<0.01). and 17 day after modeling AI were 3.21±0.29,16.31±4.27,5.13±2, 7.12±1.78,9.84±2.66(%) respectively; Same group AI between the 11 day and 17 day is not different (P>0.01). Conclusion Treatment with different dose of TR can reduce Aβ25-35-induced memory impairment in rats. The mechanism may be partly associated with down regulating the mRNA expression of caspase-8 and iNOS in rat hippocampus, and reducing the cell apoptosis in hippocampus.
引文
[1]马超,郝青南,马兵钢.白藜芦醇的药理功能及分离检测研究进展[J].北方园艺,2008,4：61-65.
[2]Luo SF, Jin XZ, Ye JF, et al. Advances in research on 3,4',5-trihydroxystilbene-3-β-D-glucoside,an effective component from Polygonum cuspididatum Siebet Zucc [J]. Chin J Pharmacol Toxicol,1999,13:1-4.
[3]Huang ZS, Wang ZW, Liu MP, et al. Protective effects of polydatin against CCl4-induced injury to primarily cultured rat hepatocytes[J]. World J Gastroenterol,1999, 5(1):41-44.
[4]Lee SH, Ryu SY, Kim HB, et al. Induction of apoptosis by 3,4'-dimethoxy-5-hydroxys-tilbene in human Promyeloid leukemic HL-60 cells[J]. Planta Med,2002,68(2):123-127.
[5]Zhang PW, Yu CL, Wang YZ, et al. Influence of 3,4',5-trihydroxystilbene-3-B-mono-D-glucoside on vascular endothelial epoprostenol and platelet aggregation [J]. Acta Pharmacol Sin,1995,16:265-268.
[6]周茂金,陈笑艳,钟大放.反式白藜芦醇葡糖苷在大鼠组织中的体外代谢研究[J].药学学报,2007,42(5)：520524.
[7]Yin Y, Huang L, Liu Y, et al. Effect of tanshinone on the levels of nitric oxide synthase and acetylcholinesterase in the brain of Alzheimer's disease rat model [J]. Clin Invest Med,2008,31(5):E248-257.
[8]方芳,晏勇,冯占辉,等.多因素损伤老年性痴呆动物模型的实验研究[J].重庆医学,2007,36(2)：147.
[9]Hebert LE, Beckett LA, Scherr PA, et al. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050 [J]. Alzhe Dis Assoc Disord, 2001,15:169-173.
[10]Gong QH, Wang Q, Shi JS, et al. Ma H. Inhibition of caspases and the intracellular free Ca+concentration are involved in resveratrol protection against apoptosis in rat primary neuroncultures [J]. Acta Pharmacol Sin,2007,28:1724-1730.
[11]Ohta K, Mizuno A, Ueda M, et al. Autophagy impairment stimulates PS1 expression and gamma-secretase activity [J]. Autophagy,2010,6(3) [Epub ahead of print].
[12]Vingtdeux V, Giliberto L, Zhao H, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism [J]. J Biol Chem, 2010,285(12):9100-9113.
[13]Wu QY, Li J, Feng ZT, et al. Bone marrow stromal cells of transgenic mice can improve the cognitive ability of an Alzheimer's disease ratmodel. Neurosci Lett,2007,417: 281-285.
[14]林茂,万章,王春梅.白藜芦醇对阿尔茨海默病小鼠记忆和抗氧化能力的影响[J].现代中西医结合杂志,2009,18(5)：484-486.
[15]龚其海,石京山,王茜,等.白藜芦醇对原代培养大鼠脑皮层神经元氧糖缺失损伤的保护[J].华西药学杂志,2007,22：502-505.
[16]Arif M, Chikuma T, Ahmed MM, et al. Effects of memantine on soluble Alphabeta (25-35)-induced changes in peptidergic and glial cells in Alzheimer's disease model rat brain regions [J]. Neuroscience,2009,164(3)1199-209.
[17]陈艳,王光楠,郭富祥,等.吡格列酮对脂多糖所致大鼠海马损伤的保护作用及其对iNOS和]IL-1β表达水平的影响[J].中国全科医学,2008,21：1930-1932.
[18]Abaraviciene SM, Lundquist I, Salehi A, et al. Rosiglitazone counteracts palmitate-induced beta-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities[J]. Cell Mol Life Sci,2008,65(14):2256-2265.
[19]Guha P, Dey A, Sarkar B, et al. Improved antiulcer and anticancer properties of a trans-resveratrol analog in mice[J]. J Pharmacol Exp Ther,2009,328 (3):829-838.
[20]Jang JH, Surh YJ. Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death [J]. Free Radic Biol Med,2003,34(8):1100-1110.
[21]Leroueta D, Jafarian-Tehrani M, Louin G, et al. Lack of iNOS induction in a severe model of transient focal cerebral ischemia in rats EJ7[J]. Exp Neurol,2005,195(1): 218-222.
[22]Ohta K, Mizuno A, Ueda M, et al. Autophagy impairment stimulates PS1 expression and gamma-secretase activity [J]. Autophagy,2010,6(3):[Epub ahead of print].
[23]Vingtdeux V, Giliberto L, Zhao H, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. [J]. J Biol Chem, 2010,285(12):9100-9113.
[1]吴海琴,张蓓,张桂莲,等.葛根素对血管性痴呆大鼠海马中低氧诱导因子-1a和红细胞生成素表达的影响[J].西安交通大学学报,2006,27(2)：132.
[2]Luo Y, Nie J, Gong QH, et al. Protective effects of icariin against learning and memory deficits induced by aluminium in rats [J]. Clin Exp Pharm-acol Physiol,2007,34 (8):792-795.
[3]Jang M, Cai L, Udeani GO, Slowing KV, et al. Cancer chemopreventive activity of resveratrol, erived from grapes [J]. Science,1997,275:218-220.
[4]张秀敏,朱小飞,何琪杨.干预衰老及老年性疾病的重要药物白藜芦醇[J].老年医学与保健,2009,15(4)：251-254.
[5]Ranney A, Petro MS. Resveratrol protects spatial learning in middle-aged C57BL/6 mice from effects of ethanol [J]. Behav Pharmacol,2009,20(4):330-336.
[6]靳玮,宋春风,吕佩源,等.反复缺血再灌注制备小鼠血管性痴呆模型的评价[J].疑难病杂志,2008,7(3)：131-137.
[7]Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported [J]. AMA,1989, 262(18):2551-2556.
[8]Hebert LE, Beckett LA, Scherr PA, et al. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050 [J]. Alzheimer Dis Assoc Disord,2001,15(4):169-173.
[9]HebertLE, Scherr PA, Bienias JL, et al. Alzheimer disease in the US population: prevalence estimates using the 2000 census [J]. Arch Neurol,2003,60(8):1119-1122.
[10]贾建平.神经病学(第六版)[M].北京：人民卫生出版社,2008：214-219.
[11]Cummings JL, Vinters HV, Cole GM, et al. Alzheimer's disease:etiologies, pathophysiology, cognitive reserve, and treatment opportunities [J]. Neurology,1998, 51(1):65-67.
[12]季雪莲,贾建平.阿尔茨海默病相关基因研究进展[J].中华老年心脑血管病杂志,2007,11(9)：788.
[13]Lee RK, Wurtman RJ. Regulation of APP synthesis and secretion by neuroimmunophilin ligands and cyclooxygenase inhibitors[J]. Ann NY Acad Sci,2000,261-268.
[14]Basu A, Krady JK, O'Malley M, et al. The Type 1 Interleukin-1 Receptor Is Essential for the Efficient Activation of Microglia and the Induction of Multiple Proinflammatory Mediators in Response to Brain Injury [J]. The Journal of Neuroscience,2002,22(14): 6071-6082.
[15]Zhao M, Cribbs DH, Anderson AJ, et al. The induction of the TNF alpha death domain signaling pathway in Alzheimer's disease brain [J]. Neurochemical Research,2003,28(2): 307-318.
[16]Jang M, Cai L, Udeani GO, Slowing KV, et al. Cancer chemopreventive activity of resveratrol, anatural product derived from grapes [J]. Science,1997,275:218-220.
[17]Suiko M, Sakakibara Y, Liu MC. Sulfation of Environmental Estrogen-like Chemicals by Human Cytosolic Sulfotransferases [J]. Biochem Biophys Res Commun,2000,267(10): 80-84.
[18]Bubber P, Haroutumian V, Fish G, et al. Mitochondrial abnormalities in Alzheimer brain:mechanistic implications [J]. Ann Neurol,200557(5):695-703.
[19]Blass J, Gibson GE. Cerebrometabolic aspects of delirium in relationship with dementia [J].Dement Geriatr Cogn Disord,1999,10(5):335-338.
[20]Anekonda TS.esveratrol-a boon for treating Alzheimer's disease? [J] Brain Res Rev, 2006,52(2):316-326.
[21]Ohta K, Mizuno A, Ueda M, et al. Autophagy impairment stimulates PS1 expression and gamma-secretase activity [J]. Autophagy,2010,6(3) [Epub ahead of print].
[22]Vingtdeux V, Giliberto L, Zhao H, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism [J]. J Biol Chem, 2010,285(12):9100-9113.
[23]Niels Andreasen, Henrik Zetterberg. Amyloid-Related Biomarkers for Alzheimer's Disease [J]. Current Medicinal Chemistry,2008,15(8):766-770.
[24]张书刚,张颖冬.β淀粉样蛋白致神经细胞凋亡机制的研究进展[J].中国临床神经科学,2008,16(3)：308-309.
[25]孙邈,李谧,王丽娜,等.β.淀粉样蛋白前体蛋白胞内结构域(AICD)与阿尔茨海默病[J].神经疾病与精神卫生,2008,8(4)：284-249.
[26]Arif MChikuma T, Ahmed MM, et al. Effects of memantine on soluble Alphabeta(25-35)-induced changes in peptidergic and glial cells in Alzheimer's disease model rat brain regions [J]. Neuroscience,2009,164(3):1199-209.
[27]龚其海、石京山、王茜,等.白藜芦醇对原代培养大鼠脑皮层神经元氧糖缺失损伤的保护[J].华西药学杂志,2007,22(5)：502-505.
[28]Aliev G, Palacios HH, Lipsitt AE, et al. Nitric oxide as an initiator of brain lesions during the development of Alzheimer disease [J].Neurotox Res,2009,16(3):293-305.
[29]Leroueta D, Jafarian-Tehrani M, Louin G, et al. Lack of iNOS induction in a severe model of transient focal cerebral ischemia in rats EJ7 [J]. Exp Neurol,2005,195(1): 218-228.
[30]ZhaO X, Rossl ME, Iadecola C. L-Arginine increases ischemic injury in wild-type mice but not in iNOS-deficient mice [J]. Brain Res,2003,966:308-311.
[31]韩君勇,陈运贞.大鼠心肌细胞缺氧预处理中COX2, iNOS和p38MAPK间信号转导关系的研究[J].中国病理生理杂志,2003,19(10)：1407-1410.
[32]陈秀琴,李景田,邹锦慧,等.iNOS与COX-2对H202预处理诱导的抗细胞凋亡的影响[J].中国老年学杂志,2009,29：1340-1341.
[33]Youn J, Lee JS, Na HK, et al. Resveratrol and piceatannol inhibit iNOS expression and NF-kappa B activation in dextran sulfate sodium-induced mouse colitis [J]. Nutr Cancer, 2009,61(6):847-854.
[34]Arif M, Chikuma T, Ahmed MM, et al. Effects of memantine on soluble Alphabeta (25-35)-induced changes in peptidergic and glial cells in Alzheimer's disease model rat brain regions [J]. Neuroscience,2009,164(3):1199-209.
[35]Guha P, Dey A, Sarkar B, et al. Improved antiulcer and anticancer properties of a trans-resveratrol analog in mice[J]. J Pharmacol Exp Ther,2009,328(3):829-838.
[2]Luo SF, Jin XZ, Ye JF, et al. Advances in research on 3,4',5-trihydroxystilbene-3-β-D-glucoside,an effective component from Polygonum cuspididatum Siebet Zucc [J]. Chin J Pharmacol Toxicol,1999,13:1-4.
[3]Huang ZS, Wang ZW, Liu MP, et al. Protective effects of polydatin against CCl4-induced injury to primarily cultured rat hepatocytes[J]. World J Gastroenterol,1999, 5(1):41-44.
[4]Lee SH, Ryu SY, Kim HB, et al. Induction of apoptosis by 3,4'-dimethoxy-5-hydroxys-tilbene in human Promyeloid leukemic HL-60 cells[J]. Planta Med,2002,68(2):123-127.
[5]Zhang PW, Yu CL, Wang YZ, et al. Influence of 3,4',5-trihydroxystilbene-3-B-mono-D-glucoside on vascular endothelial epoprostenol and platelet aggregation [J]. Acta Pharmacol Sin,1995,16:265-268.
[6]周茂金,陈笑艳,钟大放.反式白藜芦醇葡糖苷在大鼠组织中的体外代谢研究[J].药学学报,2007,42(5)：520524.
[7]Yin Y, Huang L, Liu Y, et al. Effect of tanshinone on the levels of nitric oxide synthase and acetylcholinesterase in the brain of Alzheimer's disease rat model [J]. Clin Invest Med,2008,31(5):E248-257.
[8]方芳,晏勇,冯占辉,等.多因素损伤老年性痴呆动物模型的实验研究[J].重庆医学,2007,36(2)：147.
[9]Hebert LE, Beckett LA, Scherr PA, et al. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050 [J]. Alzhe Dis Assoc Disord, 2001,15:169-173.
[10]Gong QH, Wang Q, Shi JS, et al. Ma H. Inhibition of caspases and the intracellular free Ca+concentration are involved in resveratrol protection against apoptosis in rat primary neuroncultures [J]. Acta Pharmacol Sin,2007,28:1724-1730.
[11]Ohta K, Mizuno A, Ueda M, et al. Autophagy impairment stimulates PS1 expression and gamma-secretase activity [J]. Autophagy,2010,6(3) [Epub ahead of print].
[12]Vingtdeux V, Giliberto L, Zhao H, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism [J]. J Biol Chem, 2010,285(12):9100-9113.
[13]Wu QY, Li J, Feng ZT, et al. Bone marrow stromal cells of transgenic mice can improve the cognitive ability of an Alzheimer's disease ratmodel. Neurosci Lett,2007,417: 281-285.
[14]林茂,万章,王春梅.白藜芦醇对阿尔茨海默病小鼠记忆和抗氧化能力的影响[J].现代中西医结合杂志,2009,18(5)：484-486.
[15]龚其海,石京山,王茜,等.白藜芦醇对原代培养大鼠脑皮层神经元氧糖缺失损伤的保护[J].华西药学杂志,2007,22：502-505.
[16]Arif M, Chikuma T, Ahmed MM, et al. Effects of memantine on soluble Alphabeta (25-35)-induced changes in peptidergic and glial cells in Alzheimer's disease model rat brain regions [J]. Neuroscience,2009,164(3)1199-209.
[17]陈艳,王光楠,郭富祥,等.吡格列酮对脂多糖所致大鼠海马损伤的保护作用及其对iNOS和]IL-1β表达水平的影响[J].中国全科医学,2008,21：1930-1932.
[18]Abaraviciene SM, Lundquist I, Salehi A, et al. Rosiglitazone counteracts palmitate-induced beta-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities[J]. Cell Mol Life Sci,2008,65(14):2256-2265.
[19]Guha P, Dey A, Sarkar B, et al. Improved antiulcer and anticancer properties of a trans-resveratrol analog in mice[J]. J Pharmacol Exp Ther,2009,328 (3):829-838.
[20]Jang JH, Surh YJ. Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death [J]. Free Radic Biol Med,2003,34(8):1100-1110.
[21]Leroueta D, Jafarian-Tehrani M, Louin G, et al. Lack of iNOS induction in a severe model of transient focal cerebral ischemia in rats EJ7[J]. Exp Neurol,2005,195(1): 218-222.
[22]Ohta K, Mizuno A, Ueda M, et al. Autophagy impairment stimulates PS1 expression and gamma-secretase activity [J]. Autophagy,2010,6(3):[Epub ahead of print].
[23]Vingtdeux V, Giliberto L, Zhao H, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. [J]. J Biol Chem, 2010,285(12):9100-9113.
[1]吴海琴,张蓓,张桂莲,等.葛根素对血管性痴呆大鼠海马中低氧诱导因子-1a和红细胞生成素表达的影响[J].西安交通大学学报,2006,27(2)：132.
[2]Luo Y, Nie J, Gong QH, et al. Protective effects of icariin against learning and memory deficits induced by aluminium in rats [J]. Clin Exp Pharm-acol Physiol,2007,34 (8):792-795.
[3]Jang M, Cai L, Udeani GO, Slowing KV, et al. Cancer chemopreventive activity of resveratrol, erived from grapes [J]. Science,1997,275:218-220.
[4]张秀敏,朱小飞,何琪杨.干预衰老及老年性疾病的重要药物白藜芦醇[J].老年医学与保健,2009,15(4)：251-254.
[5]Ranney A, Petro MS. Resveratrol protects spatial learning in middle-aged C57BL/6 mice from effects of ethanol [J]. Behav Pharmacol,2009,20(4):330-336.
[6]靳玮,宋春风,吕佩源,等.反复缺血再灌注制备小鼠血管性痴呆模型的评价[J].疑难病杂志,2008,7(3)：131-137.
[7]Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported [J]. AMA,1989, 262(18):2551-2556.
[8]Hebert LE, Beckett LA, Scherr PA, et al. Annual incidence of Alzheimer disease in the United States projected to the years 2000 through 2050 [J]. Alzheimer Dis Assoc Disord,2001,15(4):169-173.
[9]HebertLE, Scherr PA, Bienias JL, et al. Alzheimer disease in the US population: prevalence estimates using the 2000 census [J]. Arch Neurol,2003,60(8):1119-1122.
[10]贾建平.神经病学(第六版)[M].北京：人民卫生出版社,2008：214-219.
[11]Cummings JL, Vinters HV, Cole GM, et al. Alzheimer's disease:etiologies, pathophysiology, cognitive reserve, and treatment opportunities [J]. Neurology,1998, 51(1):65-67.
[12]季雪莲,贾建平.阿尔茨海默病相关基因研究进展[J].中华老年心脑血管病杂志,2007,11(9)：788.
[13]Lee RK, Wurtman RJ. Regulation of APP synthesis and secretion by neuroimmunophilin ligands and cyclooxygenase inhibitors[J]. Ann NY Acad Sci,2000,261-268.
[14]Basu A, Krady JK, O'Malley M, et al. The Type 1 Interleukin-1 Receptor Is Essential for the Efficient Activation of Microglia and the Induction of Multiple Proinflammatory Mediators in Response to Brain Injury [J]. The Journal of Neuroscience,2002,22(14): 6071-6082.
[15]Zhao M, Cribbs DH, Anderson AJ, et al. The induction of the TNF alpha death domain signaling pathway in Alzheimer's disease brain [J]. Neurochemical Research,2003,28(2): 307-318.
[16]Jang M, Cai L, Udeani GO, Slowing KV, et al. Cancer chemopreventive activity of resveratrol, anatural product derived from grapes [J]. Science,1997,275:218-220.
[17]Suiko M, Sakakibara Y, Liu MC. Sulfation of Environmental Estrogen-like Chemicals by Human Cytosolic Sulfotransferases [J]. Biochem Biophys Res Commun,2000,267(10): 80-84.
[18]Bubber P, Haroutumian V, Fish G, et al. Mitochondrial abnormalities in Alzheimer brain:mechanistic implications [J]. Ann Neurol,200557(5):695-703.
[19]Blass J, Gibson GE. Cerebrometabolic aspects of delirium in relationship with dementia [J].Dement Geriatr Cogn Disord,1999,10(5):335-338.
[20]Anekonda TS.esveratrol-a boon for treating Alzheimer's disease? [J] Brain Res Rev, 2006,52(2):316-326.
[21]Ohta K, Mizuno A, Ueda M, et al. Autophagy impairment stimulates PS1 expression and gamma-secretase activity [J]. Autophagy,2010,6(3) [Epub ahead of print].
[22]Vingtdeux V, Giliberto L, Zhao H, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism [J]. J Biol Chem, 2010,285(12):9100-9113.
[23]Niels Andreasen, Henrik Zetterberg. Amyloid-Related Biomarkers for Alzheimer's Disease [J]. Current Medicinal Chemistry,2008,15(8):766-770.
[24]张书刚,张颖冬.β淀粉样蛋白致神经细胞凋亡机制的研究进展[J].中国临床神经科学,2008,16(3)：308-309.
[25]孙邈,李谧,王丽娜,等.β.淀粉样蛋白前体蛋白胞内结构域(AICD)与阿尔茨海默病[J].神经疾病与精神卫生,2008,8(4)：284-249.
[26]Arif MChikuma T, Ahmed MM, et al. Effects of memantine on soluble Alphabeta(25-35)-induced changes in peptidergic and glial cells in Alzheimer's disease model rat brain regions [J]. Neuroscience,2009,164(3):1199-209.
[27]龚其海、石京山、王茜,等.白藜芦醇对原代培养大鼠脑皮层神经元氧糖缺失损伤的保护[J].华西药学杂志,2007,22(5)：502-505.
[28]Aliev G, Palacios HH, Lipsitt AE, et al. Nitric oxide as an initiator of brain lesions during the development of Alzheimer disease [J].Neurotox Res,2009,16(3):293-305.
[29]Leroueta D, Jafarian-Tehrani M, Louin G, et al. Lack of iNOS induction in a severe model of transient focal cerebral ischemia in rats EJ7 [J]. Exp Neurol,2005,195(1): 218-228.
[30]ZhaO X, Rossl ME, Iadecola C. L-Arginine increases ischemic injury in wild-type mice but not in iNOS-deficient mice [J]. Brain Res,2003,966:308-311.
[31]韩君勇,陈运贞.大鼠心肌细胞缺氧预处理中COX2, iNOS和p38MAPK间信号转导关系的研究[J].中国病理生理杂志,2003,19(10)：1407-1410.
[32]陈秀琴,李景田,邹锦慧,等.iNOS与COX-2对H202预处理诱导的抗细胞凋亡的影响[J].中国老年学杂志,2009,29：1340-1341.
[33]Youn J, Lee JS, Na HK, et al. Resveratrol and piceatannol inhibit iNOS expression and NF-kappa B activation in dextran sulfate sodium-induced mouse colitis [J]. Nutr Cancer, 2009,61(6):847-854.
[34]Arif M, Chikuma T, Ahmed MM, et al. Effects of memantine on soluble Alphabeta (25-35)-induced changes in peptidergic and glial cells in Alzheimer's disease model rat brain regions [J]. Neuroscience,2009,164(3):1199-209.
[35]Guha P, Dey A, Sarkar B, et al. Improved antiulcer and anticancer properties of a trans-resveratrol analog in mice[J]. J Pharmacol Exp Ther,2009,328(3):829-838.