臺灣博碩士論文加值系統

甲狀腺是人體重要的內分泌器官之一，其所分泌的甲狀腺素(Triiodothyronine，T3) 主要功能為調控細胞生長、促進新陳代謝、維持生長與發育的重要因子。反之，過量的T3確會使血液中纖維蛋白原(fibrinogen)上升，導致紅血球的聚集度增加，進而提高血液的黏度，造成血液流變異常。
腦部缺血，會使大鼠腦組織受到氧化傷害，並使得海馬迴（Hippocampus）中麩胱甘肽（glutathione, GSH ) 的含量減少，脂質過氧化的產物—丙二醛(malondial dehyde, MDA)大量產生，神經細胞受到損害，進一步造成水迷宮學習操作能力之障礙。因此，本實驗試著使用T3誘發高纖維蛋白鼠以評估大鼠所誘發之異常血液流變對其腦部認知行為之影響。動物使用8周齡之Sprague-Dawley雄性大白鼠(SD Rats)，以口服途徑給予T3（10 μg/100g BW/ day)連續20天，待大鼠產生高纖維蛋以及異常血液流變現象，再與以進行水迷津以及放射狀八爪迷宮的行為測試，以評估高纖維蛋所產生異常血液流變之大鼠，對腦部學習記憶的行為模式之影響。
實驗結果顯示，以T3誘發之甲狀腺亢進之大鼠其血液流變之參數無論是在全血黏度、紅血球聚集度以及血液中纖維蛋白原值，皆比正常之大鼠高；而大鼠之頸動脈在相位對比磁振造影（phase-contrast MRI）之觀測下，亦顯示甲狀腺亢進之大鼠，其頸動脈(carotid artery)之血流速率比控制組大鼠之頸動脈血流速率較慢。此外，我們實驗結果也發現在甲狀腺亢進大鼠之腦組織—海馬迴產生較大量之丙二醛，同時相對於正常之大鼠，腦組織中抗氧化之分子麩胱甘肽會大量的減少。最後，在動物迷宮的行為測試中也得知：甲狀腺亢進所引發之血液流變異常之大鼠，其學習能力較正常之大鼠較差。
　　綜合以上發現，利用T3誘發異常血液流變參數之大鼠，由於其血液流動異常將可能導致腦部發生氧化損傷以及海馬迴中丙二醛大量產生、麩胱甘肽的含量減少，進而造成水迷宮空間記憶以及放射狀八爪迷宮的行為學習操作能力之障礙。

Thyroid gland is one of the major endocrine organs in our body. It secretes thyroxine hormone, triiodothyronine (T3) which is a vital factor to our body metabolism, growth, development and differentiation processes. Otherwise, excessive T3 will raise the fibrinogen in the blood certainly leading to the erythrocyte aggregation increasingly, and the whole blood viscosity will enhance, creating the anomaly in hemorheological.
Cerebral ischemia will cause the oxidative damage of the brain tissue, hippocampus, including glutathione depletion and malondial dehyde production, and the neurons will damage, carry out an impaired spatial performance and a barrier for memory study processes observation in Morris water maze and eight-arm radial maze of rats. Therefore, in order to assess the influence of behavioral cognition of its brain, our experiment tries to use T3 to induce the rats with high fibrinogen levels in their blood, which has an anomaly in hemorheological. The male Sprague-Dawley rats of 8 weeks old are used to be as experimental animals, and induce rats with high fibrinogen in their blood, and those rats have anomalies in hemorheological by oral administration of T3 (10 μg/100g BW/ day) for 20 days, in order to estimate the influence on behavioral cognition of rats which have high fibrinogen levels in blood and bring about anomalies in hemorheological, then carrying on behavioral tests by water maze and eight-arm radial maze study.
The experimental result shows that the hemorheological parameters including whole blood viscosity, erythrocyte aggregation and the fibrinogen levels in blood of T3-induce hyperthyroidism rats were higher than those of the group with normal control. Under the observation of the phase-contrsat MRI, it shows that the blood flow of carotid arteries of hyperthyroidism rats were slowly than the normal control group. In addition, our experimental result finds that the brain tissue, hippocampus of hyperthyroidism rats arise a great quantity of malondial dehyde production, at the same time to the normal control group, the antioxidant molecule, glutathione knows a large amount of reduction. Finally, in animal behavioral test also to know: A rat with hyperthyroidism causes anomaly in hemorheological and its learning ability is worse than the normal control group.
From all results above, the T3-induced rats come about anomalies in hemorheological. The anomalies in hemorheological would cause not only the oxidative damage of brain but also the production of malondial dehyde and the glutathione depletion in hippocampus. In addition, it would cause the impaired spatial performance and hinder the memory study processes in Morris water maze and Eight-arm radial maze of rats.

中文摘要 i
英文摘要 iii
誌謝 v
目錄 vi
表目錄 viii
圖目錄 ix
第一章 緒論 1
1.1 前言 1
1.1.1甲狀腺素在人體的生理意義 1
1.1.2甲狀腺素受體（Thyroid Hormone Receptors） 3
1.1.3甲狀腺荷爾蒙反應位元（Thyroid Hormone Response Element） 5
1.1.4 纖維蛋白原 (Fibrinogen) 5
1.1.5 纖維蛋白原基因之調控 6
1.1.6 T3與Fibrinogen的相關係 7
1.1.7 T3調控血液凝集相關因子 8
1.1.8 T3調控纖維蛋白原之分子機制 9
1.2血液流變之異常現象 10
1.2.1血液的組成 10
1.2.2 血液流變 10
1.2.3 血液流變學參數的檢測原理 11
1.2.4 影響血漿黏度之因素 13
1.2.5 影響血液黏度之因素 14
1.2.6血液中氧氣的運輸 15
1.3 血液流變異常與常見臨床腦血管疾病之相關係 16
1.3.1 腦血管疾病概論 16
1.3.2 血液流變異常造成腦血管循環之病理 17
1.3.3 腦缺血對神經傳導造成退化的影響 17
1.3.4 腦缺血造成氧化損傷之機制 19
1.4腦部的記憶與學習 22
1.4.1海馬迴 22
1.4.2腦缺血與學習記憶之關係 23
1.4.3大鼠學習記憶之行為測試 24
1.5核磁共振造影(MRI) 26
1.5.1相位對比成像(Phase- contrast imaging)之原理 26
第二章 研究動機 28
第三章 材料與方法 29
3.1 實驗動物 29
3.2 實驗試藥 29
3.3 實驗儀器 30
3.4 實驗流程圖 35
3.5 實驗流程 36
第四章 結果 42
4.1血液生化值之檢測 43
4.1.1 血液中之Triiodothyronine(T3)與纖維蛋白原(Fibrinogen)之含量 43
4.1.2 全血球計數(Complete blood count，CBC) 44
4.1.3紅血球聚集度 45
4.1.4全血黏度 46
4.1.5氧氣運輸效率(Oxygen transport efficiency，TE) 47
4.1.6 MRI相位對比測量大鼠頸動脈之血流 48
4.2動物行為測試 49
4.2.1水迷宮之比較 49
4.2.2 放射狀八爪迷宮之比較 50
4.3腦組織氧化標的物MDA及GSH濃度之測定 51
第五章 討論 52
5.1三碘甲狀腺素對血液中生化參數值之影響 52
5.2利用三碘甲狀腺素誘發大鼠產生血液流變異常之現象 53
5.3血液流變異常對腦血管造成之影響 55
5.4血液流變異常造成腦組織之氧化損傷 57
5.5血液流變異常對腦部記憶所造成之影響 58
第六章 結論與未來展望 60
參考文獻 62






表目錄

表 4.1 控制組(Control)以及實驗組( T3 ) 全血球計數的值..............................44
表 4.2 控制組(Control)以及實驗組( T3 ) 全血黏度之比較...............................46
表4.3 控制組(Control)以及實驗組( T3 )水迷宮行為測試之之比較..................49
表4.4 控制組(Control)以及實驗組( T3 )放射狀八爪迷宮行為測試之之比較...50

















圖目錄

圖1.1 甲狀腺荷爾蒙合成示意......................................................................... .2
圖 1.2 Deiodination of T4 to T3 and reverse T3............................................ .2
圖1.3 Steroid/thyroid hormone receptor superfamily...........................................4
圖1.4 TR 之structure 與 function domain........................................................4
圖1.5 Fibrinogen 之分子結構............................................................................6
圖1.6 全血黏度與剪切率之函數關係圖.............................................................11
圖 1.7 全血雷射反向散射強度和時間關係圖.....................................................13
圖1.8 全血黏度與血比容..................................................................................14
圖 1.9 ischemic cascade......................................................................................18
圖1.10 海馬迴的構造.......................................................................................23
圖3.1 黏度儀....................................................................................................30
圖 3.2 Laser-assisted optical rotational cell analyser..........................................31
圖3.3 水迷宮....................................................................................................32
圖3.4 放射狀八爪迷宮....................................................................................33
圖3.5 斷頭檯...................................................................................................33
圖3.6 手持式超聲波處理器............................................................................34
圖3.7 核磁共振造影.......................................................................................34
圖3.8 放射狀八爪迷宮....................................................................................37
圖 4.1 控制組(Control)以及實驗組(T3)血液中T3以及Fibrinogen之總含量…43
圖 4.2 控制組(Control)以及實驗組(T3)血液中紅血球聚集度之比較.................45
圖 4.3控制組(Control)以及實驗組( T3 )氧氣運輸效率之比較(Oxygen transport efficiency) ................................................................................................47
圖 4.4控制組(Control)以及實驗組(T3)MRI相位對比測量頸動脈血流速之比較....……………………………………………………….................................................48
圖 4.5 控制組(Control)以及實驗組( T3 ) 腦組織氧化標的物Glutathione(GSH)及
MDA 濃度之比較..................................................................................51

[ 1 ] Oppenheimer JH, Schwartz HL, Mariash CN, Kinlaw WB, Wong NC and Freake HC, "Advance in our understanding of thyroid hormone action at the cellular level." Endocrine Reviews, vol.8, no. 3, 1987, pp.288-308.
[ 2 ] Shupnik MA, Ridgway EC and Chin WW, "Molecular biology of thyrotropin." Endocrine Review, vol.10, no. 4, 1989, pp.459-75.
[ 3 ] William S. Messer, "MBC 3320 Thyroid hormones. " Professor of Medicinal and Biological Chemistry at The University of Toledo, 2000.
[ 4 ] Dillmann W.H, "Biochemical basis of thyroid hormone action in the heart." American journal of medicine, vol.88, no. 6, 1990, pp.626-30.
[ 5 ] Vernon W. Lin, Diana D. Cardenas, Nancy C., M.D. Cutter, Margaret C. and M.D. Hammond, "Spinal Cord Medicine: Principles and Practice." 2002, American, ch.18 .
[ 6 ] Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, Leutz A, Beug H, Vennstrom B, "The c-erb-A protein is a high-affinity receptor for thyroid hormone. " Nature, vol.324 , 1986 , pp.635-640.
[ 7 ] Cary Weinberger, Catherine C. Thompson, Estelita S. Ong, Roger Lebo, Donald J. Gruol and Ronald M. Evans, " The c-erb-A gene encodes a thyroid hormone receptor. " Nature, vol.324, 1986 , pp.641-646.
[ 8 ] Mitchell A. Lazar , " Thyroid hormone receptors: multiple forms, multiple possibilities. " Endocrine Reviews, vol. 14, no. 2, 1993, pp.184–193.
[ 9 ] D Benbrook and M Pfahl , "A novel thyroid hormone receptor encoded by a cDNA clone from a human testis library. " Science. vol. 238. no. 4828, 1987, pp. 788 - 791.
[10] T Mitsuhashi, GE Tennyson and VM Nikodem, "Alternative splicing generates messages encoding rat c-erbA proteins that do not bind thyroid hormone. " Proc Natl Acad Sci USA, vol. 85, no. 16 ,1988, pp. 5804-5808.
[11] Koenig RJ, Lazar MA, Hodin RA, Brent GA, Larsen PR, Chin WW and Moore DD , "Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing. " Nature, vol. 337, 1989, pp.659-661.
[12] Hodin RA, Lazar MA, Wintman BI, Darling DS, Koenig RJ,Larsen PR, Moore DD and Chin WW, "Identification of a thyroid hormone receptor that is pituitary-specific. " Science, vol.244, no. 4900, 1989, pp.76-79.
[13] Cook CB, Kakucska I, Lechan RM and Koenig RJ , "Expression of thyroid
hormone receptor beta 2 in rat hypothalamus. " Endocrinology, vol.130, 1992, pp.1077-1079.
[14] Schwartz HL, Strait KA and Oppenheimer JH , "Molecular mechanisms of thyroid hormone action. A physiologic perspective. "Clin Lab Med , vol.13, no. 3, 1993, pp.543-561.
[15] Mitchell A. Lazar , " Thyroid hormone receptors: multiple forms, multiple possibilities. " Endocrine Reviews, vol. 14, no. 2, 1993, pp.184–193.
[16] Munoz A and Bernal J , "Biological activities of thyroid hormone receptors. " Eur J Endocrinol, vol. 137, no. 5, 1997, pp.433-445.
[17] Baniahmad A, Steiner C, Kohne AC and Renkawitz R , "Modular structure of a chicken lysozyme silencer: involvement of an unusual thyroid hormone receptor binding site. " Cell, vol.61,1990, pp.505-514.
[18] Colvin M. Redman CM and Xia H, "Fibrinogen biosynthesis. Assembly, intracellular degradation, and association with lipid synthesis and secretion. " Annals of the New York Academy of Sciences, vol.936,2001, pp.480-495.
[19] Herrick S, Blanc-Brude O, Gray A and Laurent G, "Fibrinogen." The international journal of biochemistry & cell biology, vol.31, no.7 , 1999, pp.741-746.
[20] Parise L V, "Integrin alpha(IIb)beta(3) signaling in platelet adhesion and aggregation", Current Opinion in Cell Biology, vol. 11, no.5, 1999, pp. 597-601.
[21] Hu CH, Harris JE, Davie EW and Chung DW. " Characterization of the 5''-flanking region of the gene for the alpha chain of human fibrinogen. " The Journal of biological chemistry, vol.270, no. 47,1995, pp.28342-28349.
[22] Dalmon J, Laurent M and Courtois G . "The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element. " Molecular and cellular biology, vol.13, no. 2, 1993, pp.1183-1193.
[23] Zhang Z, Fuentes NL and Fuller GM . "Characterization of the IL-6
responsive elements in the gamma fibrinogen gene promoter. " The Journal of biological chemistry, vol.270, no. 41, 1995, pp.24287-24291.
[24] Mizuguchi J, Hu CH, Cao Z, Loeb KR, Chung DW and Davie EW.
"Characterization of the 5''-flanking region of the gene for the gamma chain of human fibrinogen. " The Journal of biological chemistry, vol.270, no. 47, 1995, pp.28350-28356.
[25] Asselta R, Duga S, Modugno M, Malcovati M and Tenchini ML. "Identification of a glucocorticoid response element in the human gamma chain fibrinogen promoter." Thromb Haemost, vol.79, no. 6, 1998, pp.1144-1150.
[26] Burggraaf J, Lalezari S, Emeis JJ, Vischer UM, de Meyer PH, Pijl H and Cohen AF , "Endothelial function in patients with hyperthyroidism before and after treatment with propranolol and thiamazol." Thyroid, vol.11, no. 2, 2001, pp.153-160.
[27] Chadarevian R, Bruckert E, Leenhardt L, Giral P, Ankri A and Turpin G,"Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism." The Journal of clinical endocrinology and metabolism, vol.86 , no. 2 , 2001, pp.732-737.
[28] John C. Hoak, William R. Wilson, Emory D. Warner, Ernest O. Theilen, Glenna L. Fry and Fred L. Benoit, "Effects of Triiodothyronine-Induced Hypennetabolism on Factor VIII and Fibrinogen in Man." The Journal of Clinical Investigation, vol.48, no.4 ,1969, pp.768-774.
[29] Jeejeebhoy KN, Ho J, Greenberg GR, Phillips MJ, Bruce-Robertson A and Sodtke U. "Albumin, Fibrinogen and Transferrin Synthesis in Isolated Rat Hepatocyte Suspensions." The Biochemical journal, vol.146, no.1, 1975, pp. 141-155.
[30] Chadarevian R, Bruckert E, Leenhardt L, Giral P, Ankri A and Turpin G, "Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism." The Journal of clinical endocrinology and metabolism, vol.86, no.2, 2001, pp. 732-737.
[31] Li Y, Chen H, Tan J, Wang X, Liang H and Sun X, "Impaired release of tissue plasminogen activator from the endothelium in Graves'' disease - indicator of endothelial dysfunction and reduced fibrinolytic capacity." European journal of clinical investigation, vol.28, no.12, 1998, pp.1050-1054.
[32] N B Bennett, C M Ogston, and G M McAndrew, "The Thyroid and Fibrinolysis. "British Medical Journal, vol.4, no.5572, 1967, pp.147-148.
[33] Presti CF and Hart RG, "Thyrotoxicosis, atrial fibrillation, and embolism, revisited." American heart journal, vol.117, no.4, 1989, pp. 976-977.
[34] Polikar R, Burger AG, Scherrer U and Nicod P, "The thyroid and the heart." Circulation, vol.87, no. 5, 1993, pp.1435-1441.
[35] Miller LD, Park KS, Guo QM, Alkharouf NW, Malek RL, Lee NH, Liu ET and Cheng SY. " Silencing of Wnt signaling and activation of multiple metabolic pathways in response to thyroid hormone-stimulated cell proliferation." Molecular and cellular biology, vol. 21, No. 19 ,2001, pp.6626-6639.
[36] Dziegielewska KM, Saunders NR, Schejter EJ, Zakut H, Zevin-Sonkin D, Zisling R and Soreq H, "Synthesis of plasma proteins in fetal, adult, and neoplastic human brain tissue. " Developmental biology, vol.115, no. 1, 1986, pp.93-104.
[37] Shih CH, Chen SL, Yen CC, Huang YH, Chen CD, Lee YS and Lin KH ,"Thyroid Hormone Receptor-Dependent Transcriptional Regulation of Fibrinogen and Coagulation Proteins." Endocrinology, vol.145, no.6, 2004, pp. 2804–2814.
[38] K-H Lin, H-Y Lee, C-H Shih, C-C Yen, S-L Chen, R-C Yang1 and C-S Wang. "Plasma protein regulation by thyroid hormone. "Journal of Endocrinology, vol.179, no.3, 2003, pp. 367–377.
[39] Kensey KR, "The mechanistic relationships between hemorheo- logical characteristics and cardiovascular disease." Current medical research and opinion, vol.19, no. 7, 2003, pp.87-596.
[40] Baskurt OK, "Pathophysiological significance of blood rheology." Turkish Journal of Medical Sciences, vol.33,2003, pp.347-355.
[41] M.R. Hardeman, J.G.G. Dobbe and C. Ince, "The Laser-assisted Optical Rotational Cell Analyzer (LORCA) as red blood cell Aggregometer." Clinical Hemorheology and Microcirculation, vol.25, 2001, pp.1–11.
[42] W.G. Zijlstra, "Syllectometry, a new method for studying rouleaux formation of red blood cells.", Acta Phys. Pharm. Neerl, vol.7, 1958, pp.153–154.
[43] D.O. Gordon and M. D. Lowe: "Clinical Blood Rheology." ch. 3. vol.I, 1988.
[44] Chien S, Usami S, Dellenback RJ, Gregersen MI, Nanninga LB and Guest MM, "Blood viscosity: influence of erythrocyte aggregation." Science, vol.157, no. 3790 , 1967, pp. 829-831.
[45] Sowemimo-Coker SO, Yardin G and Meiselman HJ,"Effect of procaine hydrochloride on the aggregation behavior and suspension viscoelasticity of human red blood cells." Biorheology, vol.26, no.5, 1989, pp.951-972.
[46] Wells RE Jr, Gawronski TH, Cox PJ and Perera RD, "Influence of fibrinogen on flow properties of erythrocyte suspensions."American Journal of Physiology, vol.207,1964, pp.1035-1040.
[47] Bauduceau B, Renaudeau C, Mayaudon H, Helie C,Ducorps M, Sonnet E and Yvert J.P, "Blood rheological changes in microvascular complication of diabetes." Diabete and Metabolisme, vol.21, no.3, 1995, pp. 188-193.
[48] Rakow A, Simchon S, Sung LA and Chien S, "Aggregation of red cells with membrane altered by heat treatment." Biorheology, vol.18, no.1, 1981, pp. 3-8.
[49] Messmer K, Schmid-Schmid S-H, Chien S and Karger H. "Present stateof blood rheology in hemodilution." Theoretical Basis and Clinical Application, vol.1 , 1972 , pp.1–45.
[50] Mark F. Newman, MD; Hilary P. Grocott, FRCPC; Joseph P. Mathew, MD; William D. White, MPH; Kevin Landolfo, MD; Joseph G. Reves, MD; Daniel T. Laskowitz, MD; Daniel B. Mark, MD James A. Blumenthal, PhD for the Neurologic Outcome Research Group and the Cardiothoracic Anesthesia Research Endeavors (CARE) Investigators of the Duke Heart Center, "Report of subatudy assessing the impact of neurocognitive function on quality of life 5 years after cardic surgery." Stroke, vol.32, 2001, pp.2874-2881.
[51] Markus HS, "Cerebral perfusion and stroke." Journal of Neurology Neurosurgery and Psychiatry, vol.75, 2004 , pp.353-361.
[52] Kety SS, " Circulation and metabolism of the human brain in health and disease. " The American Journal of Medicine , vol.8 , no.2 , 1950, pp.205 - 217.
[53] Frank C Barone and Giora Z Feuerstein, " Inflammatory mediators and stroke: new opportunities for novel therapeutics." Journal of Cerebral Blood Flow & Metabolism, vol.19,1999, pp. 819–834.
[54] Choi DW, Lobner D and Dugan LL. "Glutumate receptor-mediated neuronal death in the ischemic brain. Ischemic stroke: from basic mechanisms to new drug development. " Basel: Karger, vol.16,1998, pp.1–13.
[55] Mody I. and MacDonald J.F., "NMDA receptor-dependent excitotoxicity. The role of intercellular Ca2+ release. " Trends in Pharmacological Sciences, vol.16, 1995 , pp. 356-359.
[56] Jesberger, J.A.and Richardson, J.S., "Oxygen free radicals and brain dysfunction. " The International journal of neuroscience, vol.57, 1991, pp.1 –17.
[57] Leach, M.J., Swan, J.H., Eisenthal, D., Dopson, M. and Nobbs, M., " BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage. " Stroke, vol.24, no.7, 1993, pp.1063– 1067.
[58] Robert OM. Nervous system disorders. In: Pathophysiology of Disease-An introduction to clinical medicine 4 th, International edition, Eds Stephen JM, Vishwanath RL, William FG. Lange Medical Books/McGraw-Hill Co,, Inc.,USA ,2003, pp. 170-187.
[59] Harman D, "Aging: a theory based on free radical and radiation chemistry."Journal of Gerontology, vol.11, no.3,1956, pp.298-300.
[60] Sweeney MI, Yager JY, Walz W, Juurlink BH, "Cellular mechanisms involved in brain ischemia." Canadian journal of physiology and pharmacology, vol.73, no.11, 1995, pp.1525-35.
[61] Hosseinzadeh H, Parvardeh S, Asl MN, Sadeghnia HR and Ziaee T, "Effect of thymoquinone and Nigella sativa seeds oil on lipid peroxidation level during global cerebral ischemia-reperfusion injury in rat hippocampus." Phytomedicine, vol.14, no.9, 2007, pp.621–627.
[62] Dubinsky, J.M., Kristal, B.S. and Elizondo-Fournier, M., "An obligate role for oxygen in the early stages of glutamate-induced, delayed neuronal death." The Journal of neuroscience : the official journal of the Society for Neuroscience, vol.15, no.11, 1995, pp.7071–7078.
[63] Patel, M., Day, B.J., Crapo, J.D., Fridovich, I. and McNamara, J.O., "Requirement for superoxide in excitotoxic cell death. " Neuron, vol.16, no.2,1996, pp.345–355.
[64] Cheeseman, K.H., "Mechanisms and effects of lipid peroxidation. " Molecular Aspects of Medicine, vol.14, no.3, 1993, pp.191–197.
[65] Serteser M, Ozben T, Gumuslu S, Balkan S and Balkan E, "The effects of NMDA receptor antagonist MK-801 on lipid peroxidation during focal cerebral ischemia in rats. " Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol.26, no.5, 2002, pp.871– 877.
[66] Al-Majed AA, Al-Omar FA and Nagi MN, "Neuroprotective effects of thymoquinone against transient forebrain ischemia in the rat hippocampus. " European Journal of Pharmacology, vol.543, 2006, pp.40–47.
[67] Chan Pak H, "Reactive Oxygen Radicals in Signaling and Damage in the Ischemic Brain. " Journal of Cerebral Blood Flow & Metabolism, vol.21, no.1, 2001, pp.2–14.
[68] Rosenzweig, M. R. ＆ Bennett, E. L.： Basic processes and modulatory influences in the stages of memory formation；In：Lynch , G.、McGaugh, J. L. ＆ Weinberger, N. M.；Neurobiology of learning and memory；The Guilford press , N. Y., 1984, pp.263-288.
[69] Morris, R. G., Garrud, P., Rawlins JN and O''Keefe J. ,"Place navigation impaired in rats with hippocampal lesions." Nature, vol.297, no.5868, 1982, pp.681-683.
[70] McDonald, R. J. and White, N. M. "A triple dissociation of memory systems：hippocampus, amygdala, and dorsal striatum." Behavioral Neuroscience, vol.107, no.1, 1993, pp.3-22.
[71] Gluck, M. A. and Myers, C. E. "Psychobiological models of hippocampal function in fearning and memory." Annual review of psychology, vol.48, 1997, pp. 481-514.
[72] Kandel, E. R. "The molecular biology of memory storage：A dialogue between genes and synapses." Science, vol. 294, no.5544, 2001, pp.1030-1038.
[73] Larry, RS and Stuart MZ. "Ischemic brain damage and memory impairment: a commentary."Hippocampus, vol.6, no.5, 1996, pp.546-52.
[74] Jocelyne, B and Martine, M. "Cerebral ischemia: are the memory deficits associated with hippocampal cell loss?" Hippocampus, vol.6, no.5, 1996, pp.553-60.
[75] Mishkin M. "Memory in monkeys severely impaired by combined but not by separate removal of amygdala and hippocampus." Nature, vol.273, 1978, pp.297-298.
[76] O''Keefe J and Conway DH. " Hippocampal place units in the freely moving rat: why they fire where they fire." Experimental brain research. vol.31, no.4, 1978, pp.573-590.
[77] Teyler TJ and DiScenna P. "The hippocampal memory indexing theory." Behavioral Neuroscience, vol.100, no.2 ,1986, pp.147-154.
[78] Ohno M and Watanabe S. "Ischemic tolerance to memory impairment associated with hippocampal neuronal damage after transient cerebral ischemia in rats." Brain research bulletin, vol.40, no.3, 1996, pp.229-236.
[79] Sliverman, A. P.：Animal behavior in the laboratory；Fist Published. London：Chapman Hall Ltd, 1978, pp.57-438.
[80] Morris R, "Developments of a water-maze procedure for studying spatial learning in the rat." Journal of neuroscience methods, vol.11, no.1, 1984, pp.47-60.
[81] Carr H and Purcell EM, "Effects of diffusion on free precession in NMR experiment." Physical Review, vol.94,1954, pp.630-638.
[82] Hahn EL, "Detection of sea-water motion by nuclear precession." Journal of geophysical research, vol.65, 1960, pp.776-777.
[83] Moran PR, "A flow velocity zeugmatographic interlace for NMR imaging in humans." Magnetic Resonance Imaging, vol.1, 1982, pp.197-203.
[84] Ozdemir S, Yücel R, Dariyerli N, Toplan S, Akyolcu MC, Yigit G and Hatemi H,"The Effects of Experimental Hyperthyroidism on Hemorheology and Plasma Fibrinogen Concentration." Endocrine, vol.30, no.2, 2006, pp.203–205.
[85] Morris RG, Anderson E, Lynch GS and Baudry M, "Selective impairment of learning and blockade of LTP by a NMDA receptor antagonist, AP5."Nature, vol. 319, 1986, pp.774-6.
[86] Mourad T, Min KL and Steghens JP, "Measurement of oxidized glutathione by enzymatic recycling coupled to bioluminescent detection." Analytical biochemistry, vol.283, 2000, pp.146-52.
[87] Nightingale S, Vitek PJ and Himsworth RL, " The Haematology of Hyperthyroidism." The Quarterly journal of medicine, vol.47, no. 185, 1978, pp. 35-47.
[88] Hershcovici T, Elishkevitz K, Rotstein R, Fusman R, Zeltser D, Shapira I, Arber N, Avitzour D, Berliner S and Beigel Y, " The Erythrocyte Adhesiveness/Aggregation Test to Reveal Real-Time Information of Rheological Relevance in Patients with Familial and Primary Hypercholesterolemia Before and Following Plasma Exchange. " Therapeutic Apheresis and Dialysis, vol.6, 2002, pp.140-144.
[89] Otto C, Geiss HC, Donner MG, Parhofer KG and Schwandt P, " Influence of Atorvastatin Versus Simvastatin on Fibrinogen and Other Hemorheological Parameters in Patients with Severe Hypercholesterolemia Treated with Regular Low-Density Lipoprotein Immunoadsorption Apheresis." Therapeutic Apheresis and Dialysis. vol.4 , 2000 ,pp. 244-248.
[90] Walzl M. "A promising approach to the treatment of multi-infarct dementia. " Neurobiol Aging, vol.21,no.2, 2000, pp.283-287.
[91] Shinichi Kimura, Hideya Saito, Masaru Minami, Hiroko Togashi, Nishio Nakamura, Masahiro Nemoto and Hasan S. Parvez,"Pathogenesis of vascular dementia in stroke-prone spontaneously hypertensive rats." Toxicology, vol.153, 2000, pp.167–178.
[92] Ajmani RS, Metter EJ, Jaykumar R, Ingram DK, Spangler EL, Abugo OO and Rifkind JM, "Hemodynamic changes during aging associated with cerebral blood flow and impaired cognitive function." Neurobiology of Aging, vol.21, 2000, pp.257–269.
[93] Elwood PC, Pickering J and Gallacher JE, "Cognitive function and blood rheology results from the Caerphilly cohort of older men." Age and Ageing, vol.30,2001, pp.135-139.
[94] Shin-ichi Satoh, Yoshinori Toshima, Asako Hitomi, Ichiro Ikegaki, Minoru Seto and Toshio Asano, "Wide therapeutic time window for Rho-kinase inhibition therapy in ischemic brain damage in a rat cerebral thrombosis model." Brain Research, vol.1193,2008, pp.102-108.
[95] Choy M, Ganesan V, Thomas DL, Thornton JS, Proctor E, King MD, van der Weerd L, Gadian DG and Lythgoe MF, "The chronic vascular and haemodynamic response after permanent bilateral common carotid occlusion in newborn and adult rats." Journal of Cerebral Blood Flow & Metabolism, vol.26,2006, pp.1066–1075.
[96] Siu FK, … et al. "Electroacupuncture reduces the extent of lipid peroxidation by increasing superoxide dismutase and glutathione peroxidase activities in ischemic-reperfused rat brains. " Neuroscience Letters. vol.354, no.2, 2004, pp.158-62.
[97] Khan M, Sekhon B, Jatana M, Giri S, Gilg AG, Sekhon C, Singh I and Singh AK, "Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. " Journal of neuroscience research, vol.76, no.4, 2004, pp.519-527.
[98] Nagasawa H and Kogure K, " Correlation between cerebral blood flow and
histologic changes in a new rat model of middle cerebral artery occlusion. " Stroke, vol.20, no.8, 1989, pp.1037-43.
[99] Davis HP, Tribuna J, Pulsinelli WA and Volpe BT, " Reference and working memory of rats following hippocampal damage induced by transient forebrain ischemia. " Physiology & behavior, vol.37, no.3, 1986, pp.387-92.
[100] Hong JT, Ryu SR, Kim HJ, Lee SH, Lee BM and Kim PY, " Involvement of cortical damage in the ischemia/reperfusion-induced memory impairment of Wistar rats. " Archives of pharmacal research, vol. 23, no.4, 2000, pp.413-7.
[101] Gabriel R. de Freitas GR, Devuyst G, van Melle G and Bogousslavsky J. , "Motor strokes sparing the leg: different lesions and causes." Archives of neurology, vol.57,2000, pp.513-518.
[102] Schäbitz WR, Berger C, Kollmar R, Seitz M, Tanay E, Kiessling M, Schwab S and Sommer C, "Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia." Stroke, vol.35, no.4,2004, pp.992-927.