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研究生: 陳婷妤
Chen, Ting-Yu
論文名稱: 中草藥純物質 Baicalein 衍生物作為治療阿茲海默氏症藥物開發之探討
The Development of Drugs from Baicalein Derivatives for Alzheimer's Disease Treatment
指導教授: 林炎壽
Lin, Yenshou
口試委員: 林炎壽
Lin, Yenshou
李冠群
Lee, Guan-Chiun
楊文欽
Yang, Wen-Chin
口試日期: 2023/05/05
學位類別: 碩士
Master
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2023
畢業學年度: 111
語文別: 中文
論文頁數: 64
中文關鍵詞: 阿茲海默氏症中草藥β-類澱粉蛋白黃芩素麩胺酸
研究方法: 實驗設計法
DOI URL: http://doi.org/10.6345/NTNU202300953
論文種類: 學術論文
相關次數: 點閱:129下載:0
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  • 目錄I 摘要 III ABSTRACT IV 第一章、 緒論 1 一. 阿茲海默氏症 1 二. 𝛽-類澱粉蛋白之生成 2 三. 𝛽-類澱粉蛋白之致病之分子機轉3 四. 現今治療阿茲海默氏症之臨床藥物4 五. 黃芩素於阿茲海默氏症上的治療效果5 第二章、 研究動機與目的6 第三章、 材料與實驗方法 7 一. 藥品7 二. 小鼠大腦皮質神經細胞初級培養 8 三. 細胞免疫螢光染色法9 四. 細胞存活度檢測9 五. 𝛽-類澱粉蛋白寡聚體製備10 六. 蛋白質斑點印漬分析 10 七. DIBAC4(3) 膜電位螢光染劑進行藥物篩選 11 八. 利用 FURA2-AM 檢測藥物對鈣離子的影響 11 九. 西方墨點法 12 十. 實驗動物與藥物給予 13 十一. 基因型檢測 14 十二. 新物體識別測試 (NOVEL OBJECT RECOGNITION TEST) 14 十三. 莫氏水迷津實驗 (MORRIS WATER MAZE TEST) 15 十四. 巴恩斯迷宮 (BARNES MAZE TEST) 16 十五. 檢測血清中 GOT、GPT 與肝臟、腎臟組織 H&E 染色切片17 十六. 統計分析 17 第四章、 結果 19 一. BE 衍生物對神經細胞之毒性測試19 二. BE1 不能減緩 A𝛽寡聚體誘導的神經不正常去極化 19 三. BE2 能減緩 A𝛽寡聚體誘導的神經不正常去極化 20 四. BE2 相較於 BE 具有較低的有效濃度能減緩 AMPA 誘導的神經不正常去極化21 五. BE2 與 BE 皆能減緩過量的 NMDA 誘導的神經不正常去極化 22 六. BE2 相較於 BE 能更有效的減緩過量的 NMDA 誘導的鈣離子流入23 七. BE2 能改善 A𝛽刺激對 ERK 訊息傳遞路徑影響 24 八. BE2 能改善過量的 NMDA 刺激對 ERK 訊息傳遞路徑影響 24 九. BE2 對於小鼠並不會影響其體重及一些基本生理參數 25 十. 給予六個月大 J20 小鼠 BE2 能改善其認知行為 26 十一. 給予六個月大 J20 小鼠 BE2 能改善其空間記憶行為 26 第五章、 討論 29 附錄 57 參考文獻61

    A. Armstrong, R. (2013) Review articleWhat causes alzheimer’s disease? Folia Neuropathologica, 51, 169-188.
    Alberdi, E., Sánchez-Gómez, M.V., Cavaliere, F., Pérez-Samartín, A., Zugaza, J.L., Trullas, R., Domercq, M. & Matute, C. (2010) Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium, 47, 264-272.
    Apostolova, L.G. (2016) Alzheimer Disease. Continuum (Minneap Minn), 22, 419-434.
    Arendt, T., Holzer, M., Stöbe, A., Gärtner, U., Lüth, H.J., Brückner, M.K. & Ueberham, U. (2000) Activated mitogenic signaling induces a process of dedifferentiation in Alzheimer's disease that eventually results in cell death. Ann N Y Acad Sci, 920, 249-255.
    Bang, S., Li, W., Ha, T.K.Q., Lee, C., Oh, W.K. & Shim, S.H. (2018) Anti-influenza effect of the major flavonoids from Salvia plebeia R.Br. via inhibition of influenza H1N1 virus neuraminidase. Nat Prod Res, 32, 1224-1228.
    Barnes, C.A. (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol, 93, 74-104.
    Bitan, G., Kirkitadze, M.D., Lomakin, A., Vollers, S.S., Benedek, G.B. & Teplow, D.B. (2003) Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A, 100, 330-335.
    Breijyeh, Z. & Karaman, R. (2020) Comprehensive review on Alzheimer's disease: causes and treatment. Molecules, 25.
    Brewer, G.J. & Torricelli, J.R. (2007) Isolation and culture of adult neurons and neurospheres. Nat Protoc, 2, 1490-1498.
    Chartier-Harlin, M.C., Crawford, F., Houlden, H., Warren, A., Hughes, D., Fidani, L., Goate, A., Rossor, M., Roques, P., Hardy, J. & et al. (1991) Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature, 353, 844-846.
    Cong, Y., Wu, S., Han, J., Chen, J., Liu, H., Sun, Q., Wu, Y. & Fang, Y. (2016) Pharmacokinetics of homoplantaginin in rats following intravenous, peritoneal injection and oral administration. J Pharm Biomed Anal, 129, 405-409.
    Crews, L. & Masliah, E. (2010) Molecular mechanisms of neurodegeneration in Alzheimer's disease. Hum Mol Genet, 19, R12-20.
    De-Paula, V.J., Radanovic, M., Diniz, B.S. & Forlenza, O.V. (2012) Alzheimer's disease. Subcell Biochem, 65, 329-352.
    Dinda, B., Dinda, S., DasSharma, S., Banik, R., Chakraborty, A. & Dinda, M. (2017) Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders. Eur J Med Chem, 131, 68-80.
    Dubois, B., Hampel, H., Feldman, H.H., Scheltens, P., Aisen, P., Andrieu, S., Bakardjian, H., Benali, H., Bertram, L., Blennow, K., Broich, K., Cavedo, E., Crutch, S., Dartigues, J.F., Duyckaerts, C., Epelbaum, S., Frisoni, G.B., Gauthier, S., Genthon, R., Gouw, A.A., Habert, M.O., Holtzman, D.M., Kivipelto, M., Lista, S., Molinuevo, J.L., O'Bryant, S.E., Rabinovici, G.D., Rowe, C., Salloway, S., Schneider, L.S., Sperling, R., Teichmann, M., Carrillo, M.C., Cummings, J. & Jack, C.R., Jr. (2016) Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement, 12, 292-323.
    Ennaceur, A. & Delacour, J. (1988) A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav Brain Res, 31, 47-59.
    Godyń, J., Jończyk, J., Panek, D. & Malawska, B. (2016) Therapeutic strategies for Alzheimer's disease in clinical trials. Pharmacol Rep, 68, 127-138.
    Gu, X.H., Xu, L.J., Liu, Z.Q., Wei, B., Yang, Y.J., Xu, G.G., Yin, X.P. & Wang, W. (2016) The flavonoid baicalein rescues synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease. Behav Brain Res, 311, 309-321.
    Guntupalli, S., Widagdo, J. & Anggono, V. (2016) Amyloid-β-Induced dysregulation of AMPA receptor trafficking. Neural Plast, 2016, 3204519-3204519.
    He, B., Zhang, B., Wu, F., Wang, L., Shi, X., Qin, W., Lin, Y., Ma, S. & Liang, J. (2016) Homoplantaginin inhibits palmitic acid-induced endothelial cells inflammation by suppressing TLR4 and NLRP3 inflammasome. J Cardiovasc Pharmacol, 67, 93-101.
    Heysieattalab, S., Doostmohammadi, J., Darvishmolla, M., Saeedi, N., Hosseinmardi, N., Gholami, M., Janahmadi, M. & Choopani, S. (2021) Non-selective COX inhibitors impair memory formation and short-term but not long-term synaptic plasticity. Naunyn Schmiedebergs Arch Pharmacol, 394, 1879-1891.
    Howard, R., McShane, R., Lindesay, J., Ritchie, C., Baldwin, A., Barber, R., Burns, A., Dening, T., Findlay, D., Holmes, C., Hughes, A., Jacoby, R., Jones, R., Jones, R., McKeith, I., Macharouthu, A., O'Brien, J., Passmore, P., Sheehan, B., Juszczak, E., Katona, C., Hills, R., Knapp, M., Ballard, C., Brown, R., Banerjee, S., Onions, C., Griffin, M., Adams, J., Gray, R., Johnson, T., Bentham, P. & Phillips, P. (2012) Donepezil and memantine for moderate-to-severe Alzheimer's disease. N Engl J Med, 366, 893-903.
    Ji, S., Li, R., Wang, Q., Miao, W.J., Li, Z.W., Si, L.L., Qiao, X., Yu, S.W., Zhou, D.M. & Ye, M. (2015) Anti-H1N1 virus, cytotoxic and Nrf2 activation activities of chemical constituents from Scutellaria baicalensis. J Ethnopharmacol, 176, 475-484.
    Kayed, R., Head, E., Sarsoza, F., Saing, T., Cotman, C.W., Necula, M., Margol, L., Wu, J., Breydo, L., Thompson, J.L., Rasool, S., Gurlo, T., Butler, P. & Glabe, C.G. (2007) Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener, 2, 18.
    Kervern, M., Angeli, A., Nicole, O., Léveillé, F., Parent, B., Villette, V., Buisson, A. & Dutar, P. (2012) Selective Impairment of Some Forms of Synaptic Plasticity by Oligomeric Amyloid-β Peptide in the Mouse Hippocampus: Implication of Extrasynaptic NMDA Receptors. Journal of Alzheimer's Disease, 32, 183-196.
    Kirouac, L., Rajic, A.J., Cribbs, D.H. & Padmanabhan, J. (2017) Activation of Ras-ERK signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta facilitates neurodegeneration in Alzheimer's Disease. eNeuro, 4.
    Koch, G., Di Lorenzo, F., Bonnì, S., Ponzo, V., Caltagirone, C. & Martorana, A. (2012) Impaired LTP- but not LTD-Like cortical plasticity in Alzheimer's Disease patients. Journal of Alzheimer's Disease, 31, 593-599.
    Kumar, M., Kasala, E.R., Bodduluru, L.N., Dahiya, V. & Lahkar, M. (2016) Baicalein protects isoproterenol induced myocardial ischemic injury in male Wistar rats by mitigating oxidative stress and inflammation. Inflamm Res, 65, 613-622.
    Leger, M., Quiedeville, A., Bouet, V., Haelewyn, B., Boulouard, M., Schumann-Bard, P. & Freret, T. (2013) Object recognition test in mice. Nat Protoc, 8, 2531-2537.
    Li, C., Lin, G. & Zuo, Z. (2011) Pharmacological effects and pharmacokinetics properties of Radix Scutellariae and its bioactive flavones. Biopharm Drug Dispos, 32, 427-445.
    Li, J., Wu, Y., Zhang, S., Zhang, J., Ji, F., Bo, W., Guo, X. & Li, Z. (2015) Baicalein protect pancreatic injury in rats with severe acute pancreatitis by inhibiting pro-inflammatory cytokines expression. Biochemical and Biophysical Research Communications, 466, 664-669.
    Lilja, A.M., Porras, O., Storelli, E., Nordberg, A. & Marutle, A. (2011) Functional interactions of fibrillar and oligomeric Amyloid-β with alpha7 nicotinic receptors in Alzheimer's Disease. Journal of Alzheimer's Disease, 23, 335-347.
    Lin, T.-S., Tsai, H.-J., Lee, C.-H., Song, Y.-Q., Huang, R.-S., Hsieh-Li, H.-M., Liang, M.-C. & Lin, Y. (2017) An improved drugs screening system reveals that Baicalein ameliorates the Aβ/AMPA/NMDA-induced depolarization of neuron. Journal of Alzheimer's Disease, 56, 959-976.
    Liu, A., Huang, L., Fan, H., Fang, H., Yang, Y., Liu, S., Hu, J., Hu, Q., Dirsch, O. & Dahmen, U. (2015) Baicalein pretreatment protects against liver ischemia/reperfusion injury via inhibition of NF-κB pathway in mice. Int Immunopharmacol, 24, 72-79.
    Marucci, G., Buccioni, M., Ben, D.D., Lambertucci, C., Volpini, R. & Amenta, F. (2021) Efficacy of acetylcholinesterase inhibitors in Alzheimer's disease. Neuropharmacology, 190, 108352.
    Morris, R. (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods, 11, 47-60.
    Pitts, M.W. (2018) Barnes maze procedure for spatial learning and memory in mice. Bio Protoc, 8, e2744.
    Qu, X.J., Xia, X., Wang, Y.S., Song, M.J., Liu, L.L., Xie, Y.Y., Cheng, Y.N., Liu, X.J., Qiu, L.L., Xiang, L., Gao, J.J., Zhang, X.F. & Cui, S.X. (2009) Protective effects of Salvia plebeia compound homoplantaginin on hepatocyte injury. Food Chem Toxicol, 47, 1710-1715.
    Rogers, L.J. & Vallortigara, G. (2008) From antenna to antenna: lateral shift of olfactory memory recall by honeybees. PLoS One, 3, e2340.
    Sakaguchi, Y. & Sakurai, Y. (2020) Left-right functional difference of the rat dorsal hippocampus for short-term memory and long-term memory. Behav Brain Res, 382, 112478.
    Selkoe, D.J. & Hardy, J. (2016) The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med, 8, 595-608.
    Shock, T.R., Thompson, J., Yates, J.R., 3rd & Madhani, H.D. (2009) Hog1 mitogen-activated protein kinase (MAPK) interrupts signal transduction between the Kss1 MAPK and the Tec1 transcription factor to maintain pathway specificity. Eukaryot Cell, 8, 606-616.
    Song, Z., He, C., Yu, W., Yang, M., Li, Z., Li, P., Zhu, X., Xiao, C. & Cheng, S. (2022) Baicalin attenuated Aβ (1-42)-induced apoptosis in SH-SY5Y Cells by inhibiting the Ras-ERK signaling pathway. Biomed Res Int, 2022, 9491755.
    Sudhakaran, I.P. & Ramaswami, M. (2017) Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains. RNA Biol, 14, 568-586.
    Suzuki, A., Stern, S.A., Bozdagi, O., Huntley, G.W., Walker, R.H., Magistretti, P.J. & Alberini, C.M. (2011) Astrocyte-neuron lactate transport is required for long-term memory formation. Cell, 144, 810-823.
    Texidó, L., Martín-Satué, M., Alberdi, E., Solsona, C. & Matute, C. (2011) Amyloid β peptide oligomers directly activate NMDA receptors. Cell Calcium, 49, 184-190.
    Tiwari, S., Atluri, V., Kaushik, A., Yndart, A. & Nair, M. (2019) Alzheimer's disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine, 14, 5541-5554.
    Ungureanu, A.A., Benilova, I., Krylychkina, O., Braeken, D., De Strooper, B., Van Haesendonck, C., Dotti, C.G. & Bartic, C. (2016) Amyloid beta oligomers induce neuronal elasticity changes in age-dependent manner: a force spectroscopy study on living hippocampal neurons. Sci Rep, 6, 25841.
    Wang, Z., Chen, Y., Li, X., Sultana, P., Yin, M. & Wang, Z. (2019) Amyloid-β(1-42) dynamically regulates the migration of neural stem/progenitor cells via MAPK-ERK pathway. Chem Biol Interact, 298, 96-103.
    Wattmo, C., Minthon, L. & Wallin Å, K. (2016) Mild versus moderate stages of Alzheimer's disease: three-year outcomes in a routine clinical setting of cholinesterase inhibitor therapy. Alzheimers Res Ther, 8, 7.
    Webster, S.J., Bachstetter, A.D., Nelson, P.T., Schmitt, F.A. & Van Eldik, L.J. (2014) Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front Genet, 5, 88.

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