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系統識別號 U0026-0812200915285853
論文名稱(中文) 探討褪黑激素在永久局部腦缺血年老小白鼠模型中神經保護與神經重塑的效果
論文名稱(英文) Neuroprotective and Neuroplastic Effects of Melatonin in Aged Mice Subjected to Permanent 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 97
學期 2
出版年 98
研究生(中文) 曹智捷
研究生(英文) Zhi-jie Tsao
電子信箱 bluejay1031@gmail.com
學號 t9696102
學位類別 碩士
語文別 中文
論文頁數 85頁
口試委員 指導教授-司君一
指導教授-陳淑姿
指導教授-李宜堅
召集委員-陳鴻儀
中文關鍵字 缺血性腦中風  神經重塑  老化  神經保護  褪黑激素 
英文關鍵字 neuroprotection  melatonin  ischemic stroke  neuroplasticity  dendritic spine  dendritic arborization  aging 
學科別分類
中文摘要 根據先前的流行病學的統計指出臨床上腦中風好發於年老的個體上,且在個體年紀超過55歲時,罹患腦中風的機率會逐年大幅度地上升。此外,年老的病患在中風後的死亡率較高且恢復較差。顯示出老化對於腦中風而言是相當重要的危險因子之ㄧ。但目前針對腦中風研究的動物模型,大多採用年輕動物來進行實驗,因此無法合乎臨床上情況。若能夠將實驗動物改為年老動物是更有臨床上意義的。本研究係探討褪黑激素對於年老小白鼠缺血性腦中風之神經保護特性與神經重塑之相關表現。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褪黑激素在年老個體上於缺血性腦中風急性期(一天)下神經保護與神經重塑之潛能。
我們利用年輕與年老小白鼠進行中大腦動脈栓塞手術,並且於手術前給於有效劑量的褪黑激素(5mg/kg),並且在手術一天後,評估個別神經行為學功能恢復、評估缺血傷害情況以及利用Golgi-Cox stain評估中風誘發之神經元樹突傷害及神經重塑。由實驗結果證實褪黑激素在年老個體上於缺血性腦中風情況下,仍然能夠降低缺血傷害與增加神經行為學恢復。此外,藉由Golgi-cox stain的觀察結果得知,在同側(中大腦動脈栓塞側)缺血半影區內的腦皮質II-III層與腦皮質III-IV層以及同側腦皮質V-VI層褪黑激素治療組比控制組樹突小刺密度有較顯著的增加。而在同側缺血半影區內的腦皮質II-III層與腦皮質III-IV層褪黑激素治療組比控制組樹突分支有較顯著的複雜性。另外,在對側(大腦為傷害側)的腦皮質V-VI層褪黑激素褪黑激素治療組比控制組樹突小刺密度有較顯著的增加。
實驗結果支持褪黑激素於年老個體於缺血性腦中風下,具有神經保護效果,且可能具有神經重塑之潛力,並提供一有可能之神經保護前景,值得進一步的研究探討。
英文摘要 Stroke is an acute neurological injury caused by interruption of blood supply to the brain. Epidemiological studies show that age is an important determinant of the occurrence rate and the prognosis of stroke. Most of stroke models are performed on young animals and, therefore, the results are less applicable to what has happen to aged patients clinically. Therefore, studying on aged animals is more clinical application than young ones. Melatonin is a well-known potent free radical scavenger and an antioxidant. We have previously demonstrated that melatonin reduces infarction volume, enhances neurobehavioral and eletrophysiological recovery after transient cerebral ischemia. In this study, we evaluated whether melatonin has neuroprotective and neuroplastic effect in aged mice subjected to permanent focal cerebral ischemia. Young and aged ICR male mice receiving permanent middle cerebral artery occlusion (MCAo) were injected with melatonin (5 mg/kg) or vehicle (PEG-distilled water) before the surgery. At 24 hours after permanent MCAo surgery, animals’ neurobehavioral performance was examined and brain tissues were collected for biochemical analysis. Similar to our previous results from young animals melatonin failed to change core temperature and local cerebral blood flow in aged animals ,but was effective in reducing infarction volume and neuronal degeneration, increasing neuron survival and improving neurobehavioral recovery ,as compared to the vehicle-treated controls (P<0.05). Interestingly, melatonin treatment resulted in significantly higher dendritic spine density in the second-, third-order basilar dendrites of the pyramidal cells in the layer II-III and layer III-IV of the penumbra, the layer V-VI of the ispilateral (ischemic) cortex, and the layer V-VI in contralateral cortex, as compared to the vehicle-injected controls (p<0.05). Moreover, melatonin treatment led to better dendritic arborization in the pyramidal cells in the layer II-III and layer III-IV of the penumbra of the ipsilateral cortex as compared to the vehicle-injected control (P<0.05). Cumulatively, these results showed that melatonin protects neurons against ischemic injury and may have a beneficial role of neuroplasticity and the improved neurobehavioral recovery after melatonin treatment may be mediated by better preserved dendritic spine density and dendritic arborization in the ischemic hemisphere and upregulating the dendritic spine density non-ischemic contralateral hemisphere in aged mice.
論文目次 中文摘要 I
Abstract III
誌謝 V
目錄 VI
圖目錄 X
表目錄 XIII
第一章 緒論 1
1-1 腦中風 1
1-1-1 流行病學 1
1-1-2 缺血 (Ischemia)的傷害機制 2
1-2 老化(Aging) 5
1-2-1 老化與神經元細胞改變 5
1-2-2 Lipofuscin的累績(Lipofuscin accumulation) 7
1-3 老化與腦中風 8
1-4 大腦皮質 10
1-4-1 大腦皮質的分層 10
1-4-2 錐狀細胞與樹突小刺 11
1-5 褪黑激素(Melatonin) 13
1-5-1 生理調節 : 13
1-5-2 作用機轉 : 13
1-6 研究動機與目的 14
第二章 材料與方法 17
2-1 實驗流程 17
2-2 實驗方法 18
2-2-1 動物準備、麻醉與監控 18
2-2-2 實驗模型:中大腦動脈栓塞手術(Middle cerebral artery occlusion MCAo) 18
2-2-3核心體溫(Core temperature)監測 19
2-2-4 局部腦皮質血流量LCBF(Local cortical blood flow)監測 19
2-2-5 神經行為學評估與體重測量 20
2-2-6 動物犧牲、冷凍切片 22
2-2-7 Nissl stain染色法 23
2-2-8大腦灰質局部缺血傷害量化 23
2-2-9 Lipofuscin觀察與量化 25
2-2-10 組織化學雙染(Histochemical double stain) 25
2-2-11 Golgi-Cox染色法 26
2-2-12 樹突小刺密度(Dendritic spine density)分析 29
2-2-13 樹突分支(Dendritic arborization)分析 29
2-3 統計分析 30
第三章 結果 32
3-1 動物死亡率 32
3-2 Lipofuscin表現量 32
3-3 核心體溫之監控 32
3-4 局部腦皮質血流量之監測 33
3-5 體重改變量及神經行為評估系統之評量 33
3-5-1 體重改變 33
3-5-2 神經行為評估系統 33
3-6 大腦灰質局部缺血傷害 34
3-6-1 栓塞體積百分比與腦水腫百分比量化 34
3-6-2 皮質區與副皮質區栓塞體積量化 34
3-6-3 神經元細胞存活數計數 35
3-7 神經元細胞退化組織染色結果 35
3-8 樹突小刺密度的分析 35
3-8-1 同側半球缺血半影區皮質II-III層、缺血半影區皮質III-IV層與皮質V-VI層 36
3-8-2 對側半球皮質V-VI層 37
3-9 樹突分支的分析 38
3-9-1樹突分支總長(Total dendritic length) 38
3-9-2樹突分支總量(Total number of branch segments) 38
3-9-3 Centrifugal branch ordering 38
3-9-4 Sholl concentric sphere analysis 39
第四章 討論 41
4-1 死亡率、核心體溫與局部腦皮質血流量監控 41
4-2 褪黑激素與老化對神經行為的影響 42
4-3 褪黑激素的神經保護效果 43
4-4 褪黑激素與老化對神經重塑的影響 44
4-5 褪黑激素提升神經重塑的機制 46
第五章 結論與展望 48
5-1 結論 48
5-2 未來展望 48
第六章 參考文獻 50
第七章 統計圖表 64
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