進階搜尋


 
系統識別號 U0026-0812200913594329
論文名稱(中文) 探討褪黑激素在短暫局部腦缺血大白鼠模型中神經重塑的效果
論文名稱(英文) Neuroplasticity Effects of Melatonin in Rats Subjected to Transient Focal Cerebral Ischemia
校院名稱 成功大學
系所名稱(中) 細胞生物及解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 95
學期 2
出版年 96
研究生(中文) 王憶華
研究生(英文) Yi-Hua Wang
學號 t9694102
學位類別 碩士
語文別 中文
論文頁數 72頁
口試委員 召集委員-陳鴻儀
指導教授-李宜堅
指導教授-陳淑姿
中文關鍵字 神經重塑  褪黑激素  神經保護  缺血性腦中風 
英文關鍵字 ischemic stroke  neuroplasticity  neuroprotection  dendritic spine  melatonin 
學科別分類
中文摘要 本研究係探討褪黑激素對於實驗鼠缺血性腦中風之神經保護特性與神經重塑之相關表現。近年來褪黑激素為神經科學之一熱門話題。過去研究發現褪黑激素是一種強而有效之自然抗氧化劑與自由基截取劑,另外有潛力降低缺血後能量流失、梗塞體積,增強受傷神經存活、行為能力及電生理回復。本實驗將進一步擴展研究褪黑激素在缺血性腦中風於急性期(一天)、亞急性期(七天)及長期(二十八天)神經重塑之潛能。
我們利用大白鼠進行可逆轉之中大腦動脈縫線栓塞,並於靜脈給予有效劑量每公斤5毫克的褪黑激素,評估其栓塞後個別腦血流、神經感覺運動功能與體重回復,另外利用 Golgi-Cox 染色法加以評估中風誘發之神經元樹突傷害及神經重塑。經由實驗,證明褪黑激素於可逆轉之中大腦動脈縫線栓塞後至少60分鐘仍具有效神經保護作用,且並無明顯不當之副作用。藉由 Golgi-Cox 染色法之結果觀察得知,在右側(中大腦動脈栓塞側)的缺血中心、缺血半影區及腦皮質V-VI層之區域,褪黑激素治療組比控制組之樹突小刺密度有顯著性的增加,表示褪黑激素有不錯的神經保護效果。此外,在左側(大腦未傷害側)的腦皮質V-VI層之區域,以及,比較兩側大腦皮質一天、七天與二十八天的結果發現,褪黑激素治療組有促進樹突小刺密度生長的潛能,表示褪黑激素在神經重塑上扮演一有益之角色。
此研究成果更支持褪黑激素於腦局部缺血損傷後治療有短期至長期的神經保護效果,且有促進神經重塑之潛力,並提供一有可能之神經保護前景,值得進一步的研究探討。
關鍵詞: 神經保護、缺血性腦中風、褪黑激素、神經重塑
英文摘要 Melatonin (N-aceyl-5-methoxytryptamine) is a well-known, potent free radical scavenger and an antioxidant. It is known that melatonin reduces infarct volumes and enhances neurobehavioral and electrophysiological recoveries following transient middle cerebral artery (MCA) occlusion and reperfusion in rats. In this study, we examined the melatonin’s potential for neuroplasticity at 1, 7 and 28 days after reperfusion in rats subjected to MCA occlusion for 1 hour. Melatonin (5 mg/kg) or vehicle was given intravenous injection at the commencement of reperfusion. Brain was sectioned and stained using the Golgi-Cox procedure, and spines density was quantified in second-, third-order basilar dendrites of pyramidal neurons in ischemic core (layer II-III), penumbra (layer III-IV), and layer V-VI of forelimb and hindlimb areas. Our data indicate that melatonin did not affect core temperature, local cerebral blood flow or other physiological parameters. Melatonin treatment, however, significantly enhanced dendritic spines density in the second-, third-order basilar dendrites of the pyramidal cells in the ischemic core, penumbra, and layer V-VI of the ispilateral and the contalateral cortices, as compared to the vehicle-treated controls. In addition, melatonin improves neurobehavioral outcome at various time points measured following transient focal cerebral ischemia. The results suggest that the melatonin has the potential to improve neurobehavioral outcome after stroke via upregulating the dendritic spine density in the residual cortical neurons in the ischemic hemisphere as well as in the non-injured, intact brain. The findings support melatonin’s potential for decreasing ischemic brain injury in the territory at risk of ischemia and also suggest that it may have a beneficial role of neuroplasticity for the brain in the filed of ischemic stroke.
Keywords:neuroprotection, melatonin, ischemic stroke, neuroplasticity, dendritic spine
論文目次 目錄
中文摘要 I
英文摘要(Abstract) III
目錄......................................................................................VI
表目錄 VIII
圖目錄 IX
第一章緒論 1
1-1 腦中風 2
1-1-1 流行病學 2
1-1-2 缺血-再灌流所造成的傷害機制 3
1-2 大腦皮質 4
1-2-1 大腦皮質的分層 5
1-2-2 錐狀細胞與樹突小刺 6
1-3 腦中風後之功能恢復與神經重塑的關係 9
1-4 褪黑激素 11
1-4-1 生理調節 11
1-4-2 作用機轉 12
1-4-3 生理功能及其臨床上之可能應用 13
1-5 研究動機與目的....................................................................................14
第二章材料與方法 17
2-1 實驗流程 18
2-2 實驗方法 19
2-2-1 動物準備,麻醉和監控 19
2-2-2 實驗模型 19
2-2-3 LCBF監測 21
2-2-4 神經行為測試及體重測量 22
2-2-5 Golgi-Cox染色法 25
2-2-6 樹突小刺密度分析.................................................................................28
2-3 統計分析..............................................................................................30
第三章結果 31
3-1 核心體溫之監控 32
3-2 局部腦皮質血流量之監測 32
3-3 體重改變量及神經行為評估系統之評量 33
3-4 樹突小刺密度的分析 33
第四章討論 38
4-1 褪黑激素對核心體溫及局部腦血流的影響 39
4-2 褪黑激素對神經行為的影響 40
4-3 褪黑激素對神經重塑的影響 41
4-4 褪黑激素提升神經重塑的機制………………………………………43
第五章結論與展望 45
5-1 結論 46
5-2 未來展望 46
第六章 統計圖表 48
第七章 參考文獻 60
表目錄
表1 感覺神經行為檢查評估表 23
表2 運動神經行為檢查評估表 23
表3 28點分數的臨床等級評估量表 24
表4 於再灌流後體重喪失與神經學評估系統之測量結果 53
表5 大腦皮質各部位之小刺密度統計表………………………………...58



圖目錄
圖1-1 大腦皮質的分層 6
圖1-2 大腦皮質第三層之錐狀細胞形態 7
圖1-3 突觸的結構 8
圖1-4 Melatonin (N-acetyl-5-methoxytryptamine)之分子結構 11
圖2-1 實驗流程圖 18
圖2-2 以尼龍縫線延伸經內頸動脈至中大腦動脈阻塞之示意圖 20
圖2-3 神經行為測試及體重量測之時間表示圖 23
圖2-4 典型大白鼠中大腦動脈栓塞冠狀切片示意圖 29
圖2-5 計算區域示意圖 29
圖3-1 各組核心體溫與時間關係圖 49
圖3-2 同側半球SⅡ區域局部腦皮質血流監測圖 50
圖3-3 同側半球SⅠ區域局部腦皮質血流量監測圖 51
圖3-4 對側半球SⅡ區域局部腦皮質血流量監測圖 52
圖3-5 再灌流後第七天,大腦皮質第三層錐狀細胞之顯微照片 54
圖3-6 缺血中心區錐狀細胞樹突第二段之小刺密度統計圖 55
圖3-7 缺血中心區錐狀細胞樹突第三段之小刺密度統計圖 55
圖3-8 缺血半影區錐狀細胞樹突第二q之小刺密度統計圖 56
圖3-9 缺血半影區錐狀細胞樹突第三段之小刺密度統計圖 56
圖3-10 同側半球Layer V-VI錐狀細胞樹突第二段之小刺密度統計圖 57
圖3-11 同側半球Layer V-VI錐狀細胞樹突第三段之小刺密度統計圖 57
圖3-12 對側半球Layer V-VI錐狀細胞樹突第二段之小刺密度統計圖 58
圖3-13 對側半球Layer V-VI錐狀細胞樹突第三段之小刺密度統計圖 58
參考文獻 參考文獻
1. Newman MF, Grocott HP, Mathew JP, et al. Report of subatudy assessing the impact of neurocognitive function on quality of life 5 years after cardic surgery. Stroke. 2001; 17:927-938.
2.衛生統計資訊網(民96)‧95年國人十大死因‧行政院衛生署統計室。
3. Mayo NE, Wood-Dauphinee S, Ahmed S, Gordon C, Higgins J, McEwen S, Salbach N. Disablement following stroke. Disabil. Rehabil. 1999; 21:258-268.
4.朱復禮(民81)‧臨床神經醫學‧臺北:合記。
5. Martin RL, Lloyd HG, Cowan AI. The early events of oxygen and glucose deprivation :setting the scene for neuronal death ? Trends Neurosci. 1994;17: 251-257.
6. Katsura K, Kristian T, Siesjo BK. Energy metabolism, ion homeostasis, and cell damage in the brain. Biochem Soc Trans. 1994; 22:991-996.
7. Centonze D, Marfia G.A, Pisani A, Picconi B, Giacomini P, Bernardi G., Calabresi P. Ionic
mechanisms underlying differential vulnerability to ischemia in striatal neurons, Prog Neurobiol. 2001; 63:687-696.
8. Larsen GA, Skjellegrind HK, Berg-Johnsen J, Moe MC, Vinje ML. Depolarization of
mitochondria in isolated CA1 neurons during hypoxia, glucose deprivation and glutamate
excitotoxicity. Brain Res. 2006; 1077:153-160.
9. Hagemann G., Redecker C, Neumann-Haefelin T, Freund H.J, Witte OW. Increased
long-term potentiation in the surround of experimentally induced focal cortical infarction. Ann Neurol. 1998; 44:255-258.
10. Jiang ZG., Lu XC, Nelson V, Yang X, Pan W, Chen RW, Lebowitz MS, Almassian B, Tortella FC, Brady RO, Ghanbari HA. A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia. PNAS. 2006; 103:1581-1586.
11. Calabresi P, Centonze D, Pisani A, Cupini L, Bernardi G. Synaptic plasticity in the
ischaemic brain. Lancet Neurol. 2003; 2:622-629.
12. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003; 4:399-415.
13. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke : an integrated view. Trends Neurosci 1999; 22:391-7.
14. Hickenbottom SL, Grotta J. Neuroprotective therapy. Semin Neurol 1998;18:485-92.
15. Steiner T, Hacke W. Combination therapy with neuroprotectants and thrombolytics in
acute ischemic stroke. Eur Neurol. 1998; 40:1-8.
16. 盧孟佑 (民81)‧神經解剖學‧臺北:合記。
17. Quoted from http://www.users.globalnet.co.uk/~lka/conz3a.htm
18. Kolb Bryan, Gorny Grazyna, Li Yilin, Samaha Anne-Noël, Robinson Terry E.
Amphetamine or cocaine limits the ability of later experience to promote structural
plasticity in the neocortex and nucleus accumbens. PNAS. 2003; 100(18):10523-10528.
19. Cajal SR, Histologie du systeme nerveux de homme et des vertrbres, Paris: Maloine 1991.
20. Michele P., Marsha CB, Varda G, Menahem S. Morphological analysis of dendritic spine
development in primary cultures of hippocampal neurons. J. Neurosci. 1995; 15(1):1-11.
21. Gordon MS. The dendritic spine: a multifunctional integrative unit. J. Neurophysiol.
1996; 75:2197-2210.
22. Larkman AU. Dendritic morphology of pyramidal neurons of the visual cortex of the rat: III. Spine distribution. J. Comp. Neurol. 1991; 306:332-343.
23. Harris KM, Stevens JK. Dendritic spines of CA1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics. J. Neurosci. 1989; 9:2982-2997.
24. Amaral DG., Ishizuka N, Claiborne BJ. Neurons, numbers and the hippocampal network. Brain Res. 1990; 83:1-11.
25. Harris KM and Kater SB. Dendritic spines: cellular imparting both stability and flexibility to synaptic function. Neuroscience 1994; 17:341-371.
26. Quoted from http://www.mult-sclerosis.org/dendrite.html
27. Andersen P, Blackstad T, Hulleberg G, Trommald M, Vaaland JL. Dimensions of dendritic spines of rat dentate granule cells during long-term potentiation. Journal of Physiology 1987; 390:264.
28. Andersen P, Blackstad T, Hulleberg G, Trommald M, Vaaland JL. Changes in spine morphology associated with LTP in rat dentate granule cells. Proceeds of the Physiological Society 1987; 288.
29. Chang FLF, Greenough WT. Transient and enduring morphological correlates of synaptic activity and efficacy change in the rat hippocampal slice. Brain Research 1984; 309:35-46.
30. Moser MB, Trommald M, Egel T, Andersen P. Spatial training in a complex environment and isolation alter the spine distribution differently in rat CA1 pyramidal cells. Journal of Comparative Neurology 1997; 380:373-381.
31. Trommald M, Vaaland JL, Blackstad T, Andersen P. Dendritic spine changes in rat dentate granule cells associated with long-term potentiation. In: A. Guidotti, Editor, Neurotoxicity of Excitatory Amino Acids. Raven Press 1990; 163-174.
32. Trommald M, Hulleberg G, Andersen P. Long-term potentiation is associated with new excitatory spine synapses on rat dentate granule cells. Learning and Memory 1996; 3:218-228.
33. Grutzendler J, Kasthuri N, Gan WB () Long-term dendritic spine stability in the adult cortex. Nature 2002; 420:812-816.
34. Trachtenberg JT, Chen BE, Knott GW, Feng G, Sanes JR, Welker E, Svoboda K. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 2002; 420:788-794.
35. Kirov SA, Harris KM. Dendrites are more spiny on mature hippocampal neurons when synapses are inactivated. Nat Neurosci. 1999; 2:878-883.
36. Majewska A, Sur M. Motility of dendritic spines in visual cortex in vivo: changes during the critical period and effects of visual deprivation. PNAS. 2003; 100:16024-16029.
37. Kleim JA, Hogg TM, VandenBerg PM, Cooper NR, Bruneau R, Remple M. Cortical synaptogenesis and motor map reorganization occur during late, but not early, phase of motor skill learning. J Neurosci 2004; 24:628-633.
38. Mizrahi A, Crowley JC, Shtoyerman E, Katz LC. High-resolution in vivo imaging of hippocampal dendrites and spines. J Neurosci. 2004; 24:3147-3151.
39. Rensing N, Ouyang Y, Yang XF, Yamada KA, Rothman SM, Wong M. In vivo imaging of dendritic spines during electrographic seizures. Ann Neurol. 2005; 58:888-898.
40. Zuo Y, Yang G, Kwon E, Gan WB. Long-term sensory deprivation prevents dendritic spine loss in primary somatosensory cortex. Nature 2005; 436:261-265.
41. Holtmaat A, Wilbrecht L, Knott GW, Welker E, Svoboda K. Experience-dependent and cell-type-specific spine growth in the neocortex. Nature 2006; 441:979–983.
42. Gonzalez CL, Kolb B. A comparison of different models of stroke on behaviour and brain morphology. Eur J Neurosci. 2003; 18:1950-1962.
43. Corbett D, Giles T, Evans S, McLean J, Biernaskie J. Dynamic changes in CA1 dendritic spines associated with ischemic tolerance. Exp Neurol. 2006; 202:133–138.
44. Kelley M. Harmona, Cara L. Wellman. Differential effects of cholinergic lesions on dendritic spines in frontal cortex of young adult and aging rats. Brain Research 2003; 992:60-68.
45. Dijkhuizen RM, Singhal AB, Mandeville JB, Wu O, Halpern EF, Finklestein SP, Rosen BR, Lo EH. Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study, J. Neurosci. 2003; 23: 510-517.
46. Corbett D, Giles T, Evans S, McLean J, Biernaskie J () Dynamic changes in CA1 dendritic spines associated with ischemic tolerance. Exp Neurol. 2006: 202:133-138
47. Carmichael ST. Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann Neurol. 2006; 59:735-742.
48. Cramer SC, Chopp M. Recovery recapitulates ontogeny. Trends Neurosci. 2000; 23:265-271.
49. Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996; 272:1791-1794
50. Dijkhuizen RM, Ren J, Mandeville JB, Wu O, Ozdag FM, Moskowitz MA, Rosen BR, Finklestein SP. Functional magnetic resonance imaging of reorganization in rat brain after stroke. PNAS. 2001; 98:12766-12771.
51. Wei L, Erinjeri JP, Rovainen CM, Woolsey TA. Collateral growth and angiogenesis around cortical stroke. Stroke 2001; 32:2179-2184.
52. Jaillard A, Martin CD, Garambois K, Lebas JF, Hommel M. Vicarious function within the human primary motor cortex? A longitudinal fMRI stroke study. Brain 2005; 128:1122-1138.
53. Rosenzweig MR, Bennett EL. Psychobiology of plasticity: effects of training and experience on brain and behavior. Behavioral Brain Research 1996; 78:57-65.
54. Kelley M. Harmona and Cara L. Wellman. Differential effects of cholinergic lesions on dendritic spines in frontal cortex of young adult and aging rats. Brain Research 2003; 992:60-68.
55. Quoted from http://en.wikipedia.org/wiki/Neuroplasticity
56. Traversa R, Cicinelli P, Bassi A, Rossini PM, Bernardi G.. Mapping of motor cortical reorganization after stroke. A brain stimulation study with focal magnetic pulses. Stroke 1997; 28(1):110-117.
57. Cramer SC, Bastings EP. Mapping clinically relevant plasticity after stroke. Neuropharmacology 2000; 39(5):842-851.
58. Hallett M. Plasticity of the human motor cortex and recovery from stroke. Brain Res. 2001; 36(2-3):169-174.
59. Nudo RJ, Plautz EJ, Frost SB. Role of adaptive plasticity in recovery of function after damage to motor cortex. Muscle Nerve 2001; 24(8):1000-1019.
60. Nudo RJ. Adaptive plasticity in motor cortex: implications for rehabilitation after brain injury. J. Rehabil. Med. 2003; 41:7-10.
61. Hallett M. Plasticity of the human motor cortex and recovery from stroke. Brain Res. Rev. 2001; 36:169-174.
62. Johansson BB. Brain plasticity and stroke rehabilitation. Stroke 2000; 31:223-230.
63. Lee RG, Donkelaar van P. Mechanisms underlying functional recovery following stroke. Can. J. Neurol. Sci. 1995; 22:257-263.
64. Nelles G.. Cortical reorganization-effects of intensive therapy. Restor. Neurol. Neurosci. 2004; 22:239-244.
65. Seil FJ, Recovery and repair issues after stroke from the scientific perspective. Curr. Opin. Neurol. 1997; 10:49-51.
66. Steinberg BA, Augustine JR. Behavioral, anatomical, and physiological aspects of recovery of motor function following stroke. Brain Res. Brain Res. Rev. 1997; 5:125-132.
67. Abo M, Chen Z, Lai LJ, Reese T, Bjelke B. Functional recovery after brain lesion-contralateral neuromodulation: an fMRI study, NeuroReport 2001; 12:1543-1547.
68. Dijkhuizen RM, Ren J, Mandeville JB, Wu O, Ozdag FM, Moskowitz MA, Rosen BR, Finklestein SP. Functional magnetic resonance imaging of reorganization in rat brain after stroke. PNAS. 2001; 98:12766-12771.
69. Dijkhuizen RM, Singhal AB, Mandeville JB, Wu O, Halpern EF, Finklestein SP, Rosen BR, Lo EH. Correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study. J. Neurosci. 2003; 23:510-517.
70. Cuadrado ML, Egido JA, Gonzalez-Gutierrez JL, Varela-De-Seijas E. Bihemispheric contribution to motor recovery after stroke: a longitudinal study with transcranial doppler ultrasonography. Cerebrovasc Dis. 1999; 9:337-344.
71. Marshall RS, Perera GM, Lazar RM, Krakauer JW, Constantine RC, DeLaPaz RL. Evolution of cortical activation during recovery from corticospinal tract infarction. Stroke 2000; 31:656-661.
72. Nelles G., Spiekermann G., Jueptner M, Leonhardt G, Müller S, Gerhard H, Diener C. Reorganization of sensory and motor systems in hemiplegic stroke patients. A positron emission tomography study. Stroke 1999; 30:1510-1516.
73. Biernaskie J, Corbett D. Enriched rehabilitative training promotes forelimb motor function and enhanced dendritic growth after focal ischemic injury. J. Neurosci. 2001; 21:5272-5280.
74. Biernaskie J, Chernenko G., Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J. Neurosci. 2004; 24:1245-1254.
75. Luke LM, Allred RP, Jones TA. Unilateral ischemic sensorimotor cortical damage induces contralesional synaptogenesis and enhances skilled reaching with the ipsilateral forelimb in adult male rats. Synapse 2004; 54:87-199.
76. Jones TA, Schallert T, Use-dependent growth of pyramidal neurons after neocortical damage, J. Neurosci. 1994; 14:2140-2152.
77. Gonzalez Claudia LR, Gharbawie A. Omar, Kolb Bryan. Chronic low-dose administration of nicotine facilitates recovery and synaptic change after focal ischemia in rats. Neuropharmacology 2006; 50:777-787.
78. Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996; 272:1791-1794.
79. Taub E, Miller NE, Novack TA, Cook EW, Fleming WC, Nepomuceno CS, Connell JS, Crago JE. Technique to improve chronic motor deficit after stroke. Arch Phys Med Rehabil. 1993; 74:347-354.
80. Kunkel A, Kopp B, Miller G, Villringer K, Villringer A, Taub E, Flor H. Constraint-induced movement therapy for motor recovery in chronic stroke patients. Arch Phys Med Rehabil. 1999; 80:624-628.
81. Liepert J, Bauder H, Miltner WHR, Taub E, Weitller C. Treatment-induced cortical reorganization after stroke in humans. Stroke 2000; 31:1210-1216.
82. Gonzalez Claudia LR, Gharbawie A. Omar, Kolb Bryan. Chronic low-dose administration of nicotine facilitates recovery and synaptic change after focal ischemia in rats. Neuropharmacology 2006; 50:777-787.
83. Crisostomo EA, Duncan PW, Propst M, Dawson DV, Davis JN. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann. Neurol. 1988; 23:94-97.
84. Feeney DM. From laboratory to clinic: noradrenergic enhancement of physical therapy for stroke or trauma patients. Adv. Neurol. 1997; 73:383-394.
85. Lee EH, Ma YL. Amphetamine enhances memory retention and facilitates norepinephrine release from the hippocampus in rats. Brain Res. Bull. 1995; 37:411-416.
86. Soetens E, Casaer S, Hooge Dn’R, Hueting JE. Effect of amphetamine on long-term retention of verbal material. Psychopharmacology 1995; 119:155-162.
87. Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R. Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence. Stroke 1995; 26:2254-2259.
88. Quoted from http://en.wikipedia.org/wiki/Melatonin#_note-Caniato2003
89. Quoted from http://www.vghks.gov.tw/meta/melatoni.htm
90. Arlene Goldman. Melatonin: A Review. British Journal of Clinical Pharmacology 1995;
19:258-260.
91. Boutin J, Audinot V, Ferry G, Delagrange P. Molecular tools to study melatonin pathways and actions. Trends Pharmacol Sci 2005; 26(8):412-9.
92. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 2005; 27(2):119-30.
93. Tan D, Manchester L, Reiter R, Qi W, Karbownik M, Calvo J. Significance of melatonin in anti oxidative defense system: reactions and products. Biol Signals Recept 2000; 9(3-4):137-59.
94. Karbownik M, Reiter R, Cabrera J, Garcia J. Comparison of the protective effect of melatonin with other antioxidants in the hamster kidney model of estradiol-induced DNA damage. Mutat Res 2001; 474(1-2):87-92.
95. Carrillo-Vico A, Guerrero J, Lardone P, Reiter R. A review of the multiple actions of melatonin on the immune system. Endocrine 2005; 27(2):189-200.
96. Lewis, Alan. Melatonin and the Biological Clock. McGraw-Hill 1999; 23.
97. Sessa Ben. Can psychedelics have a role in psychiatry once again? The British Journal of Psychiatry 2005; 457-458.
98. Sessa Ben. Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine. Med Hypotheses 2005; 5 (64): 930-7.
99. Bellipanni G, DI Marzo F, Blasi F, Di Marzo A. Effects of melatonin in perimenopausal and menopausal women: our personal experience. Ann N Y Acad Sci 2005; 1057: 393-402.
100. Lee EJ, Lee MY, Chang GL, Chen LH, Hu YL, Chen TY, Wu TS. Delayed treatment with magnesium reduces brain infarction and improves electrophysiological recovery following transient focal cerebral ischemia in rats. J Neurosurg. 2005; 102:1085-93
101. Maestroni G. Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer. Adv Exp Med Biol. 1999; 467: 217-26.
102. Ravindra T, Lakshmi NK, Ahuja YR.Melatonin in pathogenesis and therapy of cancer.Indian. J Med Sci. 2006; 60(12):523-35.
103. Lee EJ, Chen HY, Wu TS, Chen TY, Ayoub IA, Maynard, K.I. Acute administration of Ginkgo biloba extract(EGb 761)affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats. J. Neurosci. Res. 2002; 68:636-645.
104. Lee EJ, Wu TS, Lee MY, Chen TY, Tsai YY, Chuang JI, Chang G.L. Delayed treatment with melatonin enhances electrophysiological recovery following transient focal cerebral ischemia in rats. J. Pineal Res. 2004; 36:33-42.
105. Lee EJ, Ayoub IA, Harris FB, Hassan M, Ogilvy CS, Maynard KI. Mexiletine and magnesium independently, but not combined, protect against permanent focal cerebral ischemia in Wistar rats. J. Neurosci. Res. 1999; 58(3): 442-448.
106. Lee EJ, Lee MY, Chen HY, Hsu YS, Wu TS, Chen ST, Chang G.L. Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia. J. Pineal Res. 2005; 38:42-52.
107. SiesjÖ BK. Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. J Neurosurg 1992; 77:337-354.
108. Traystman RJ, Kirsch JR, Koehler RC. Oxygen radical mechanisms of brain injury following ischemia and reperfusion. J Appl Physiol. 1991; 71:1185-1195.
109. Kuroda S, SiesjÖ BK. Reperfusion damage following focal ischemia: pathophysiology and therapeutic windows. Clin Neurosci. 1997; 4:199-212.
110. Chen JH, Wu CC, George H, Yen MH. Magnolol induces apoptosis vascular smooth muscle. Naunyn-Schmiedberg's Arch Pharmacology 2003;368:127-133.
111. Zhang L, Zhang ZG, Zhang RL, et al. Postischemic(6-Hour)treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia. Stroke 2001; 32:2926-2931.
112. Maeda M, Furuichi Y, Ueyama N, et al. A combined treatment with tacrolimus (FK506) and recombinant tissue plasminogen activator for thrombotic focal cerebral ischemia in rats: increased neuroprotective efficacy and extended therapeutic time window. J Cereb Blood Flow Metab 2002; 22:1205-1211.
113. Fisher M. Characterizing the target of acute stroke therapy. Stroke 1997; 28:866-872.
114. Wang YF, Tsirka SE, Strickland S, et al. Tissue plasminogen activator(t-PA)increases neuronal damage after focal cerebral ischemia in wild-type and t-PA-deficient mice. Nat Med 1998; 4:228-231.
115. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator(Alteplase)for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999; 282:2019-2026.
116. Asahi M, Asahi K, Wang X, et al. Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2000; 20:452-457.
117. Lee EJ, Chen HY, Lee MY, Chen TY, Hsu YS, Hu YL, Chang GL, Wu TS. Cinnamophilin reduces oxidative damage and protects against transient focal cerebral ischemia in mice. Free Radic Biol Med. 2005; 39(4): 495-510.
118. Li Y, Jiang N, Powers C, Chopp M. Neuronal damage and plasticity identified by microtubule-associated protein 2, growth-associated protein 43, and cyclin D1 immunoreactivity after focal cerebral ischemia in rats. Stroke 1998; 29:1972-1981.
119. Stroemer RP, Kent TA, Hulsebosch CE. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 1998; 29:2381-2395.
120. Skaper SD, Floreani M, Ceccon M, et al. Excitotoxicity, oxidative stress, and the neuroprotective potential of melatonin. Ann N Y Acad Sci. 1999; 890:107-118.
121. Cheung RT. The utility of melatonin in reducing cerebral damage resulting from ischemia and reperfusion. J Pineal Res. 2003; 34:153-160.
122. Tan DX, Chen LD, Poeggeler B, et al. Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J. 1993; 1:57-60.
123. Reiter RJ, Tan DX, Manchester LC, et al. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys 2001; 34:237-256.
124. Tan DX, Reiter RJ, Manchester LC, et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem. 2002; 2:181-197.
125. Onuki J, Almeida EA, Medeiros MH, et al. Inhibition of 5-aminolevulinic acid-induced DNA damage by melatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, quercetin or resveratrol. J Pineal Res. 2005; 38:107-115.
126. Guenther AL, Schmidt SI, Laatsch H, et al. Reactions of the melatonin metabolite AMK (N1-acetyl-5-methoxykynuramine) with reactive nitrogen species: formation of novel compounds, 3-acetamidomethyl-6-methoxycinnolinone and 3-nitro-AMK. J Pineal Res. 2005; 39:251-260.
127. Rosen J, Than NN, Koch D, et al. Interactions of melatonin and its metabolites with the ABTS cation radical: extension of the radical scavenger cascade and formation of a novel class of oxidation products, C2-substituted 3-indolinones. J Pineal Res. 2006; 41:374-381.
128. Yeleswaram K, McLaughlin LG, Knipe JO, Schabdach D. Pharmacokinetics and oral bioavailability of exogenous melatonin in preclinical animal models and clinical implications. J Pineal Res. 1997; 22:45-51.
129. Pixinos G, Watson C. The rat brain in stereotaxic coordinates. Academic Press, New York, 1982.
130. Nagasawa H, Kogure K. Correlation between cerebral blood flow and histologic changes in a new rat model of middle cerebral artery occlusion. Stroke 1989; 20:1037-1043.
131. Memezawa H, Minamisawa H, Smith ML, et al. Ischemic penumbra in a model of reversible middle cerebral artery occlusion in the rat. Exp Brain Res. 1992; 89:67-78.
132. Belayev L, Alonso OF, Busto R, Zhao, Ginsberg MD. Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 1996; 27:1616-1623.
133. Clark WM, Rinker LG, Lessov NS, Hazel K, Hill JK, Stenzel-Poore M, Eckenstein F. Lack of interleukin-6 expression is not protective against focal central nervous system ischemia. Stroke 2000; 31(7):1715-1720.
134. Glaser EM, Van der Loos H. Analysis of thick brain sections by obverse–reverse computer microscopy: application of a new, high clarity Golgi–Nissl stain. J. Neurosci. Methods 1981; 4:117-125.
135. Paxinos G., Watson C. The Rat Brain in Stereoataxic Coordinates (Compact 3rd ed.), Academic Press, San Diego. 1997.
136. Gibb R, Kolb B. A method for vibratome sectioning of Golgi–Cox stained whole rat brain, J. Neurosci. Methods 1998; 79:1-4.
137. Krause DN, Barrios VE, Duckles SP. Melatonin receptors mediate potentiation of contractile responses to adrenergic nerve stimulation in rat caudal artery. Eur J Pharmacol 1995; 276:207–213.
138. Regrigny O, Delagrange P, Scalbert E et al. Melatonin improves cerebral circulation security margin in rats. Am J Physiol. 1998; 275:H139-H144.
139. Bolay H, Dalkara T. Mechanisms of motor dysfunction after transient MCA occlusion: persistent transmission failure in cortical synapses is a major determinant. Stroke 1998; 29:1988-1994.
140. Whishaw IQ, O'Connor WT, Dunnett SB. The contributions of motor cortex, nigrostriatal dopamine and caudate-putamen to skilled forelimb use in the rat. Brain 1986; 109:805-843.
141. Cuzzocrea S, Costantino G, Gitto E, Mazzon E, Fulia F, Serraino I, Cordaro S, Barberi I, De Sarro A, Caputi AP. Protective effects of melatonin in ischemic brain injury. J Pineal Res. 2000; 29:217-227.
142. Skaper SD, Floreani M, Ceccon M, Facci L, Giusti P. Excitotoxicity, oxidative stress, and the neuroprotective potential of melatonin. Ann N Y Acad Sci. 1999; 890:107-118.
143. Pei Z, Fung PC, Cheung RT. Melatonin reduces nitric oxide level during ischemia but not blood-brain barrier breakdown during reperfusion in a rat middle cerebral artery occlusion stroke model. J Pineal Res. 2003; 34:110-118.
144. Adkins DL,. Voorhies AC, Jones AT. Behavioral and neuroplastic effects of focal endothelin-1 induced sensorimotor cortex lesions. Neuroscience 2004; 128:473-486.
145. Biernaskie J, Corbett D. Enriched rehabilitative training promotes forelimb motor function and enhanced dendritic growth after focal ischemic injury. J. Neurosci. 2001; 21:5272-5280.
146. Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J. Neurosci. 2004; 24:1245-1254.
147. Biernaskie J, Szymanska A, Windle V, Corbett D. Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats. Eur. J. Neurosci. 2005; 21:989-999.
148. Ito U, Kuroiwa T, Nagasao J, Kawakami E, Oyanagi K. Temporal profiles of axon terminals, synapses and spines in the ischemic penumbra of the cerebral cortex: ultrastructure of neuronal remodeling. Stroke 2006; 37:2134-2139.
149. Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke1995; 26:2135-2144.
150. Mervis RF, Pope D, Lewis R, Dvorak RM, Williams LR. Exogenous nerve growth f actor reverses age-related structural changes in neocortical neurons in the aging rat. A quantitative Golgi study. Ann. N. Y. Acad. Sci. 1991; 640:95-101.
151. Kolb B, Cote S. A. Ribeiro-da-Silva and C. Cuello, Nerve growth factor treatment prevents dendritic atrophy and promotes recovery of function after cortical injury. Neuroscience 1996; 76:1139-1151.
152. Tolwani RJ, Buckmaster PS, Varma S, Cosgaya JM, Wu Y, Suri C, Shooter EM. BDNF overexpression increases dendrite complexity in hippocampal dentate gyrus. Neuroscience 2002; 114:795-805.
153. Papadopoulos CM, Tsai SY, Cheatwood JL, Bollnow MR, Kolb BE, Schwab ME, Kartje G.L. Dendritic plasticity in the adult rat following middle cerebral artery occlusion and Nogo-a neutralization. Cereb. Cortex 2006; 16:529-536.
154. Kawamata T, Ren J, Chan TC, Charette M, Finklestein SP. Intracisternal osteogenic protein-1 enhances functional recovery following focal stroke. NeuroReport 1998; 9:1441-1445.
155. Adkins DL, Jones AT. d-Amphetamine enhances skilled reaching after ischemic cortical lesions in rats. Neurosci. Lett. 2005; 380:214-218.
156. Zhao CS, Puurunen K, Schallert T, Sivenius J, Jolkkonen J. Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury. Behav. Brain Res. 2005; 158:211-220.
157. 吳進安 (民85)‧基礎神經學‧臺北:合記。
158. Dudek S, Bear MF. Homosynaptic long term depression in area CA1 of the hippocampus and effects of NMDA receptor blockade. PNAS. 1992; 89:4363-4367.
159. Pei Z, Pang SF, Cheung RT. Pretreatment with melatonin reduces volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model. J Pineal Res. 2002; 32:168-172.
160. Pei Z, Pang SF, Cheung RT. Administration of melatonin after onset of ischemia reduces the volume of cerebral infarction in a rat middle cerebral artery occlusion stroke model. Stroke 2003; 34:770-775.
161. Sinha K, Degaonkar MN, Jagannathan NR, Gupta YK. Effect of melatonin on ischemia reperfusion injury induced by middle cerebral artery occlusion in rats. Eur J. Pharmacol 2001; 428:185-192.
162. Mattson MP. Modification of ion homeostasis by lipid peroxidation: roles in neuronal degeneration and adaptive plasticity. Trends Neurosci. 1998; 21:53-57.
163. Almaguer-Melian W, Cruz-Aguado R, Bergado JA. Synaptic plasticity is impaired in rats with a low glutathione content. Synapse 2000; 38:369-374.
164. Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 2005; 27(2):119-30.
165. Escames G., León J, López LC, Acuña-Castroviejo D. Mechanisms of N-methyl-d-Aspartate Receptor Inhibition by Melatonin In the Rat Striatum. Journal of Neuroendocrinology 2004; 16(11): 929-935.
166. Laque JM, Puig N, Martinez JM, Gonzalez-Garcia C, Cene V. Glutamate N-methyl-D-aspartate receptor blockade prevents induction of GAP-43 after focal ischemia in rats. Neurosci Lett 2001; 305:87-90.
167. Vickers Catherine A, Stephens Benjamin, Bowen Julian, Gordon W. Arbuthnott,Seth G.N. Grant, Cali A. Ingham.Neurone specific regulation of dendritic spines in vivo by post synaptic density 95 protein (PSD-95). Brain Res. 2006; 1090(1):89-98.
168. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Hoxter G, Mahagne MH, Hennerici M, for the ECASS Study Group. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995; 274:1017-1025.
169. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999; 282:2019-2026.
170. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II): Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998; 352: 245-1251.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2010-08-28起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2012-08-28起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw