植物雌激素 (香豆醇及二羥基異黃酮) 對抗Ab及LPS誘發之毒性在小鼠星狀神經膠細胞的保護效果

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题名:	植物雌激素 (香豆醇及二羥基異黃酮) 對抗Ab及LPS誘發之毒性在小鼠星狀神經膠細胞的保護效果
作者:	劉滿海
贡献者:	藥學系(博士班)
关键词:	香豆醇二羥基異黃酮星狀神經膠細胞
日期:	2010
上传时间:	2010-10-20 12:54:41 (UTC+8)
摘要:	從流行病學及回朔以往病例顯示雌激素補充療法(ERT)可以降低阿滋海默氏症發生率,植物雌激素已經被建議可以當作與雌激素補充療法二者具選擇之潛力藥物.本研究主要證明香豆醇在小鼠體外試驗是否具有類雌激素作用,並且研究植物雌激素daidzein和香豆醇(coumestrol)之神經保護及抗氧化效果. 以加入兩種毒性物質(LPS(脂多醣)及A??(類澱粉蛋白胜肽))至星狀神經膠細胞之模式,探討daidzein和香豆醇(coumestrol)對於星狀神經膠細胞保護之效果.細胞活性可以MTT去分析,對於細胞保護之效果與路徑可以經由測定特殊基因表現和蛋白質含量之改變.結果證明daidzein和香豆醇(coumestrol)可以顯著增加細胞活性,但再加入 LPS及A?珓廗\|降低細胞活性.本研究主要是探討在受到Aβ和LPS的刺激之前，先加入具有抗發炎作用的藥物 daidzein及香豆醇(coumestrol)，是否能減少誘導發炎的物質產生。結果顯示daidzein香豆醇(coumestrol)皆可以降低細胞白介素第一因子??(interleukin-1??(IL-1??))、細胞白介素第六因子 (interleukin-6 (IL-6)) 和腫瘤壞死因子α(tumor necrosis factor-alpha (TNF-α))的mRNA表現及蛋白質含量. 神經退化疾病之路徑仍是不明確,尚有許多阿滋海默氏症的假設,我們結果提供daidzein和香豆醇是既安全又有神經保護作用及有效抑制發炎反應,在新生鼠星狀神經膠細胞模式中 daidzein 和 coumestrol 最適當之劑量分別為10-12M ,10-9M.此結果顯示其在阿滋海默氏症之預防及治療上具有發展之潛力. Phytoestrogens have been proposed as potential alternatives to ERT in treatment of AD. The purpose of this study was to demonstrate the in vitro effects of Daidzein and coumestrol on mice glial cells to determine whether coumestrol exert estrogen agonist effect in neural tissue and investigate its neuroprotective and anti-inflammatory efficacy. Different concentrations of daidzein and coumestrol were tested for their neuroprotective efficacy against two toxic insults, lipopolysaccharide (LPS) and amyloid-beta-peptide(25-35)[Aβ(25–35)] neurotoxicity. Neuronal mitochondrial activity was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, The protective efficacy and pathway were examined by their specific gene expression and protein changes. Results of these studies demonstrated that daidzein and coumestrol induced a modest but significant increase in MTT levels, the reduction in MTT levels following exposure to LPS and ??-amyloid25–35. The present study is to see whether daidzein and coumestrol, known to have anti-inflammation activity, is able to inhibit the production of proinflammatory mediators by using two stimulants, Aβ and lipopolysaccharide (LPS). The results indicate that daidzein and coumestrol are able to down-regulated mRNA expression of IL-1,IL-6 and TNF-α under Aβ and LPS treatments . The pathway of neurodegrative disease is not very clear and there are many hypothesis about Alzheimer’s disease)(AD). Our results provide that daidzein and coumestrol are both safe neuroprotective agents and effective in inhibiting the inflammation with optimum dose at 10-12M and 10-9M on neonatal mice astrocyte cells model, respectively. However, the facts need to be validated by further studies both in vitro and in vivo.
關聯:	93頁
描述:	(一)論文目次目錄頁數中文摘要 1 英文摘要 2 第一章序論 1-1 前言 4 1-2 研究背景 5 1-3具有發展潛力之阿茲海默氏症治療方法 7 1-4研究目的 8 第二章文獻回顧 2-1 神經膠細胞之簡介 9 2-2阿茲海默氏症(Alzhmer’s disease)之假說 10 2-3阿茲海默氏症(Alzhmer’s disease)之研究介紹 11 2-4植物雌激素之介紹 12 2-5雌激素接受體 14 2-6 脂多醣(LPS)之介紹 15 第三章材料與方法 3-1 材料 17 3-2 方法 21 3-2-1 試藥配製 21 3-2-2 星狀神經膠細胞培養 24 3-2-3 細胞活性分析 25 3-2-4 Griess reaction 一氧化氮(NO) 26 3-2-5 即時(real-time)定量反轉錄聚合酶連鎖反應 27 3-2-6西方墨點法 (Western blotting) 29 3-2-7免疫染色法 (Immunocytochemistry) 30 3-2-8 IL1-??,IL-6,TNF-?? 之PROTEIN 測定方法 31 第四章結果與討論 4-1 MTT assay 32 4-1-1 Coumestrol對astrocyte的影響 32 4-1-2 Daidzein對astrocyte的影響 32 4-1-3 Aβ刺激astrocyte的影響 33 4-1-4 脂多醣刺激astrocyte的影響 33 4-2 一氧化氮 (NO ) assay 34 4-2-1 Daidzein及coumestrol對脂多醣刺激astrocyte產生NO的影響 34 4-3 ER-?悀?-?? 之受體免疫染色 36 4-4 Daidzein及Coumestrol比較其降低NO效果及對ERb/ERa比值之影響 37 4-5 Coumestrol對astrocyte的影響 38 4-5-1 Coumestrol對 Aβ 刺激astrocyte的影響 38 4-5-2 Coumestrol對脂多醣刺激astrocyte的影響 38 4-6 Coumestrol對T47D乳癌細胞株的影響 39 4-7 Coumestrol對於雌激素受體(ER)之路徑探討 39 4-8 Coumestrol在新生老鼠之神經膠細胞基因表現之影響 40 4-8-1 Coumestrol對Astrocyte的ER-??,?? mRNA影響 40 4-8-2 Coumestrol對Aβ刺激 Astrocyte IL-1??,IL-6及TNF-?? mRNA之表現量 41 4-8-3 Coumestrol對脂多醣刺激 Astrocyte mRNA之表現量 43 4-9 Coumestrol對於脂多醣和A?珨今oIL1??,IL6及TNF-?? protein含量之影響 45 4-9-1 Coumestrol對於A?珨今oIL1??,IL6及TNF-?? protein含量之影響 45 4-9-2 Coumestrol對於脂多醣誘發IL1??,IL6及TNF-?? protein含量之影響 46 第五章總結 52 第六章參考文獻 54 (二)參考文獻參考文獻曹善文 (2005) 特殊植化物對於人類單核球細胞株(THP-1)在LPS刺激下之功能性基因組研究,國立台灣大學植物研究所碩士論文. 林鈺珊 (2007) 二羥基異黃酮對星狀神經膠細胞的抗發炎作用,台北醫學大學藥學系碩士論文. Adachi T, Ono Y, Koh K B, Takashima K, Tainaka H, Matsuno Y, Nakagawa S, Todaka E, Sakurai K, Fukata H, Iguchi T, Komiyama M, Mori C (2004) Long-term alteration of gene expression without morphological change in testis after neonatal exposure to genistein in mice: toxicogenomic analysis using cDNA microarray. Food Chem Toxicol. 42(3): 445 - 452. Alic N O, Docagne F, Lesne S, MacKenzie E T, Nouvelot A, Buisson A, Vivien D (2000) "Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain. J Cereb Blood Flow Metab. 20(6): 956-66 Alonso D, Dorronsoro I, Rubio L, Munoz P, Garcia-Palomero E, Del Monte M, Bidon-Chanal A, Orozco M, Luque F J, Castro A, Medina M, Martinez A (2005 ) Donepezil-tacrine hybrid related derivatives as new dual binding site inhibitors of AChE. Bioorg Med Chem. 13(24): 6588-6597. Arechabala B, Coiffard C, Rivalland P, Coiffard L J, Roeck-Holtzhauer Y (1999 ) Comparison of cytotoxicity of various surfactants tested on normal human fibroblast cultures using the neutral red test MTT assay and LDH release. J Appl Toxicol.19: 163-165. Behl C, Widmann M, Trapp T, and Holsboer F (1995) 17β-estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun. 216: 473–482. Behl C, Skutella T, Lezoualc’h F, Post A, Widmann M, Newton C J, and Holsboer F (1997) Neuroprotection against Oxidative Stress by Estrogens:Structure-Activity Relationship. Mol Pharmacol 51: 535–541. Belcher SM, Zsarnovszky A (2001) Estrogenic actions in the brain: Estrogen, phytoestrogens and rapid intracellular signaling mechanisms. J Pharmacol Exp Ther. 299: 408-414. Bhathena SJ, Velasquez MT (2002) Beneficial role of dietary phytoestrogens in obesity and diabetes. Am J Clin Nutr. 76: 1191-201. Brookmeyer R, Gray S, Kawas C (1998) Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 88: 1337-1342. Chang EC, Frasor J, Komm B, Katzenellenbogen BS (2006) Impact of estrogen receptor beta on gene networks regulated by estrogen receptor alpha in breast cancer cells. Endocrinology .147(10):4831 - 4842. Chuen-Neu Wang, Chih-Wen Chi, Yun-Lian Lini, Chhieh-Fu Chen and Yond Young, Ji Shiao (2001) The neuroprotective effects of phytoestrogens on amyloid beta protein-induced toxicity are mediated by abrogating the activation of caspase cascade in rat cortical neurons. J of Biological Chemistry. 276 (7): 5287-5295. Colditz G A (1999) Hormones and breast cancer evidence and implications for consideration of risks and benefits of hormone replacement therapy. J Women’s Health 8 ( 3 ) : 347-57 Cordey M, Gundimeda U, Gopalakrishna R, Pike CJ (2003) Estrogen activates protein kinase C in neurons role in neuroprotection. J Neurochem. 84: 1340-1348. Cuzzocrea S, Bruscoli S, Crisafulli C, Mazzon E, Agostini M, Muia C, Esposito E, Di Virgilio R, Meli R, Vegeto E, Maggi A, Riccardi C (2007) Estrogen Receptor Antagonist Fulvestrant (ICI 182,780) Inhibits the Anti-Inflammatory Effect of Glucocorticoids. Mol Pharmacol. 71(1): 132 - 144. Davis AM, Ellersieck MR, Grimm KM, Rosenfeld CS (2006) The effects of the selective estrogen receptor modulators methyl-piperidino-pyrazole (MPP) and raloxifene in normal and cancerous endometrial cell lines and in the murine uterus. Mol Reprod Dev. 73(8): 1034 - 1044. Dixon-Shanies D, Shaikh N (1999) Growth inhibition of human breast cancer cells by herbs and phytoestrogens. Oncol Rep.6:1383-7. Eikelenboom P, Rozemuller AJ, Hoozemans JJ, Veerhuis R, van Gool WA (2000) Neuroinflammation and Alzheimer disease clinical and therapeutic implications. Alzheimer Dis Assoc Disord. 14 Suppl 1: S54-61. Elliston JF, Fawell SE, Klein-Hitpass L, Tsai SY, Tsai MJ, Parker MG, O'Malley BW. (1990). Mechanism of estrogen receptordependent transcription in a cell-freesystem. Mol Cell Biol. 10: 6607-6612. Eriksson G, Zetterstrom M, Cortes Toro V, Bartfai T, Iverfeldt K (1998) Hypersensitive cytokine response to beta-amyloid 25-35 in astroglial cells from IL-1 receptor type I-deficient mice. Int J Mol Med .1(1): 201 - 206. Esler, W P and Wolfe, M S (2001)A portrait of Alzheimer secretases--new featuresand familiar faces. Science. 293: 1449-1454 Fillit H M (2002) The role of hormone replacement therapy in the prevention of Alzheimer disease. Arch Intern Med.162: 1934-1942. Frei K, M U, Leist T P, Zinkernagel R M, Schwab M E, Fontana A (1989) On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol. 19(4): 689-694 Gadient RA, (1997) Interleukin-6 (IL-6)--a molecule with both beneficial and destructive potentials. Prog Neurobiol. 52(5): 379-390 Gandy S ( 2003) Estrogen and neurodegeneration. Neurochem Res. 28: 1003-1008. Garcia-Segura L M, Naftolin F, Hutchison JB, Azcoitia I,Chowen JA (1999)Role of astroglia in estrogen regulation of synaptic plasticity and brain repair. J Neurobiol. 40:574-584. Gibbons H M, Dragunow M (2006) Microglia induce neural cell death via a proximity-dependent mechanism involving nitric oxide. Brain Res. 1084: 1 - 15. Giunta S, Galeazzi R, Valli M B, Corder E H, Galeazzi L (2004) Transferrin neutralization of amyloid beta 25–35 cytotoxicity. Clinica Chimica Acta. 350: 129 – 136. Goodman Y, Bruce, A J, Cheng B, and Mattson M P (1996) Alzheimer's Disease-Associated Neurotoxic Mechanisms and Neuroprotective Strategies J. Neurochem. 66: 1836–1844. Green P S, Bishop J, and Simpkins J W (1997)17a-Estradiol Exerts Neuroprotective Effects on SK-N-SH Cells J Neurosci. 17: 511–515. Gutierrez-Zepeda A, Santell R, Wu Z, Brown M, Wu Y-J, Khan I, Link C D, Baolu Zhao and Luo Y (2005) Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans. BMC Neurosci. 25: 6-54. Haass and Mandelkow (1999) Proteolysis by presenilins and the renaissance of tau. Trends Cell Biol. 9:241-244. Halliday G, Robinson SR, Shepherd C, Kril J (2000) Alzheimer’s disease and inflammation a review of cellular and therapeutic mechanisms. Clin Exp Pharmacol Physiol .27:1-8. Hardy J and Selkoe D J (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 297: 353-356. Herber D L, R L, Wilson D, Wilson N, Mason J E, Morgan D, Gordon M N (2004) Time-dependent reduction in Abeta levels after intracranial LPS administration in APP transgenic mice. Exp Neurol. 190(1): 245-53. Hutabarat L S, Greenfield H, Mulholland M (2000) Quantitative determination of isoflavones and coumestrol in soybean by column liquid chromatography. J Chromatogr A .886 ( 1-2 ) : 55-63. Jacobs M N, Lewis D F (2002) Steroid hormone receptors and dietary ligands: A selected review. Proc Nutr Soc. 61:105-122. Jeffrey M, Holzbeierlein, James McIntosh and J.Brantley Thrasher (2005)The role of soy phytoestrogens in prostate cancer：Curr Opin Urol. 15(1):17-22. Katzenellenbogen BS, Choi I, Delage-Mourroux R, Ediger TR, Martini PG, Montano M, Sun J, Weis K, Katzenellenbogen JA (2000).Molecular mechanisms of estrogen action, Selective ligands and receptor pharmacology. J Steroid Biochem Mol Biol. 74: 279-285. Kim H, Bang O Y, Jung M W, Ha S D, Hong H S, Huh K, Kim S U, Mook-Jung I (2001) Neuroprotective effects of estrogen against beta-amyloid toxicity are mediated by estrogen receptors in cultured neuronal cells. Neurosci Lett. 302: 58-62. Koh J Y, Yang L L and Cotman C W (1990) Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res. 533: 315 – 320. Kuen-Jer Tsai, Yueh-Chiao Tsai, and Che-Kun James Shen (2007) G-CSF rescues the memory impairment of animal models of Alzheimer’s disease. J of Exp Med. 204: 1273–1280. Kuiper G G, Lemmen J G, Carlsson B, Corton J C, Safe S H, van der Saag PT, van der Burg B, Gustafsson JA (1998)Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor beta. Endocrinology. 139: 4252-4263. Larry R S (2009) Encyclopedia of Neuroscience. Academic Publishing, CA,USA. LeBlanc ES, Janowsky J, Chan BK, Nelson HD (2001)Hormone replacement therapy and cognition: systematic review and metaanalysis. JAMA. 285:1489-1499. Levine A J, Battista M (2004)Estrogen replacement therapy effects on the cognitive functioning and clinical course of women with Alzheimer's disease. Arch Clin Neuropsychol. 19(6): 769 – 778. Li R, Shen Y (2005)Estrogen and brain: synthesis, function and diseases. Front Biosci 10: 257-267. Li L N (1997) Water soluble active components of Salvia miltiorrhiza and related plants. J Chin Pharm Sci. 6(2): 57-63. Liu Y, Peterson D A, Kimura H, Schubert D (1997) Mechanism of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. J Neurochem 69: 581-593. Ling Z, Zhu Y, Tong CW, Snyder JA, Lipton JW, Carvey PM (2006) Progressive dopamine neuron loss following supra-nigral lipopolysaccharide (LPS) infusion into rats exposed to LPS prenatally. Exp Neurol. 199: 499 - 512. Lobner D (2000) Comparison of the LDH and MTT assays for quantifying cell death: validity for neuronal apoptosis? J Neurosci Methods. 96: 147-152. Luine V N (1985) Estradiol increases acetyltransferase activity in specific basal forebrain nuclei and projection areas of the female rat brain. Experimental Neurology. 89: 484–490 Lucius R, S J (1996) Postnatal retinal ganglion cells in vitro: protection against reactive oxygen species (ROS)-induced axonal degeneration by cocultured astrocytes. Brain Res. 743(1-2): 56-62. Lund T D, West T W, Tian L Y, Bu L H, Simmons D L, Setchell K D, Adlercreutz H, Lephart E D (2001)Visual spatial memory is enhanced in female rats (but inhibited in males) by dietary soy phytoestrogens. BMC Neurosci. 2:20. Maeda Y, M M, Hori O, Kuwabara K, Ogawa S, Yan S D, Ohtsuki T, Kinoshita T, Kamada T, Stern DM. (1994). Hypoxia/reoxygenation-mediated induction of astrocyte interleukin 6: a paracrine mechanism potentially enhancing neuron survival. J Exp Med. 180(6): 2297-2308. Marilyn M. M, Andrew A. M, and Nell S B (2001) Estrogen Replacement Therapy for the Potential Treatment or Prevention of Alzheimer's Disease. Ann. N.Y. Acad. Sci. 949: 223-234. Matejuk A, Adlard K, Zamora A, Silverman M, Vandenbark A A, Offner H (2001) 17 Beta-estradiol inhibits cytokine, chemokine, and chemokine receptor mRNA expression in the central nervous system of female mice with experimental autoimmune encephalomyelitis. J Neurosci Res. 65: 529-542. Minke Tang and Juntian Zhang (2002) Prostate apoptosis response-4 involved in the protective effect of Salvianolic Acid B against amyloid beta peptide-induced damage in pc12 cells. Jpn J Pharmacol. 88: 422-427. Miltyk W, Craciunescu C N, Fischer L, Jeffcoat R A, Koch M A, Lopaczynski W, Mahoney C, Crowell J, Paglieri J, Zeisel S H (2003) Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer. Am J Clin Nutr. 77: 875-882. Morale MC, Serra PA, L'Episcopo F, Tirolo C, Caniglia S, Testa N, Gennuso F, Giaquinta G, Rocchitta G, Desole M S, Miele E, Marchetti B (2006) Estrogen, neuroinflammation and neuroprotection in Parkinson's disease: Glia dictates resistance versus vulnerability to neurodegeneration. Neuroscience. 138(3): 869-878. Morgan D M (1998) Tetrazolium (MTT) assay for cellular viability and activity. Methods Mol Biol .79: 179-183. Murphy G M , Yang L, Cordell B (1998) Macrophage Colony-stimulating Factor Augments β -Amyloid-induced Interleukin-1, Interleukin-6, and Nitric Oxide Production by Microglial Cells. J Biol Chem. 273( 33): 20967 - 20971. Naslund J, H V, Mohs R, Davis K L, Davies P, Greengard P, Buxbaum J D (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA. 283(12): 1571-1577. Nathan CF (1987) Secretory products of macrophages. J. Clin. Invest. 79: 319-323. Nikov G N, Hopkins N E, Boue S, Alworth W L (2000) Interactions of dietary estrogens with human estrogen receptors and the effect on estrogen receptor-estrogen response element complex formation. Environ Health Perspect. 108: 867-872. Paech K, Webb P, Kuiper G G, Nilsson S, Gustafsson J, Kushner P J, Scanlan T S (1997) Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP1 sites. Science. 277:1508-1510. Patisaul H B, Whittenp L, Young L J (1999) Regulation of estrogen receptor data mRNA in the brain opposite effects of 17-β-estraditol and phytoestrogen, coumestrol. Molecular brain research. 67: 165-171. Peter P (2000)The immune system. Garland Publishing, London, 201-219. Peterson P K, Hu S, Salak-Johnson J, Molitor T W, Chao C C (1997) Differential production of and migratory response to beta chemokines by human microglia and astrocytes. J Infect Dis.175(2): 478 – 481. Pike C J, Walencewicz A J, Glabe C G and Cotman C W (1991) In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 563: 311 – 314. Price D L, Tanzi R E, Borchelt D R, Sisodia S S (1998)Alzheimer's disease: genetic studies and transgenic models. Annu Rev Genet.32:461-93. Robert B ,Ezio G. (1997) Alzhimer disease From Molecular Biolgy to Therapy. Birkhauser Boston.675:187-199. Roof R L, Hall E D (2000) Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats. J Neurotrauma. 17: 1155-1169. Sano M, Ernesto C, Thomas R G, Klauber M R, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman C W, Pfeiffer E, Schneider L S, Thal LJ (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 336(17): 1216 - 1222. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird T D, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen, M ,Peskind E, Poorkaj P, Schellenberg G., Tanzi R, Wasco W, Lannfelt L,Selkoe D , Younkin S (1996)Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat .Med. 2: 864-870. Selkoe D J (1997) Alzheimer's disease: genotypes, phenotypes, and treatments. Science. 275: 630-631. Selkoe D J, Watson D J, Lander A D (1997) Heparin-binding properties of the amyloidogenic peptides Abeta and amylin. Dependence on aggregation state and inhibition by Congo red. J Biol Chem. 272(50):31617-24. Shyu W C, Lin S Z, Yang H I (2004)Functional Recovery of Stroke Rats Induced by Granulocyte Colony-Stimulating Factor–Stimulated Stem Cells. Circulation. 110:1847-1854. Simmons M L, (1994). Roles for protein kinases in the induction of nitric oxide synthase in astrocytes. Glia. 11(3): 227-34. Song TT, Hendrich S, Murphy PA (1999)Estrogenic activity of glycitein, a soy isoflavone. J Agric Food Chem. 47: 1607-1610. Stahl S, Chun T Y, Gray W G (1998) Phytoestrogens act as estrogen agonists in an estrogen-responsive pituitary cell line. Toxicol Appl Pharmacol. 152: 41-48. Thal L J, Thomas R G, Mulnard R, Sano M, Grundman M, Schneider L (2003) Estrogen levels do not correlate with improvement in cognition. Arch Neurol. 60: 209 - 212. Tom T , Margie B, Linda C, Amanda G, Johannes R (2001) Estrogen and Raloxifene activites on amyloid –beta-induced inflammatory reaction. Microvascular Research. 61: 28-39. Yankner B A, Duffy L K , Kirschner D A (1990)Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science. 250: 279 – 282. Yoon B K, Kim D K, Kang Y, Kim J W, Shin M H, Na D L(2003)Hormone replacement therapy in postmenopausal women with Alzheimer's disease: a randomized, prospective study. Fertil Steril .79: 274-280. Zec R F, Trivedi M A (2002) Effects of hormone replacement therapy on cognitive aging and dementia risk in postmenopausal women a review of ongoing large-scale, long-term clinical trials. Climacteric. 5: 122-134. Zeng H, Chen Q, Zhao B (2004) Genistein ameliorates beta-amyloid peptide (25-35)-induced hippocampal neuronal apoptosis. Free Radic Biol Med. 36: 180-188. Zhao L, Chen Q, Diaz Brinton R. (2002).Neuroprotective and neurotrophic efficacy of phytoestrogens in cultured hippocampal neurons. Exp Biol Med .227: 509-519.
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