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系統識別號 U0026-1808201715070100
論文名稱(中文) 褪黑激素於缺血性腦中風大鼠神經再塑與電生理官能連繫不良之研究
論文名稱(英文) Melatonin improves neuroplasticity and electrophysiological diaschisis recovery following transient focal cerebral ischemia in rats
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 105
學期 2
出版年 106
研究生(中文) 黃聖洋
研究生(英文) Sheng-Yang Huang
學號 P88961128
學位類別 博士
語文別 英文
論文頁數 93頁
口試委員 指導教授-張志涵
共同指導教授-李宜堅
召集委員-吳天賞
口試委員-陳宗鷹
口試委員-陳鴻儀
中文關鍵字 缺血性腦中風  神經再塑  突觸再塑  體感覺誘發電位  褪黑激素 
英文關鍵字 ischemic stroke  neuroplasticity  dendritic spine  GAP-43  SNAP-25  PSD-95  MMP-9 
學科別分類
中文摘要 本研究旨在研究褪黑激素Melatonin於缺血性中風後調控synaptosomal-associated protein 25kDa (SNAP-25)、growth-associated protein 43 (GAP-43)、NMDAR-postsynaptic density-95 (PSD95)、matrix metalloproteinases-9 (MMP-9)等蛋白的表現以增進缺血性腦中風後中長期神經再塑以及中風後改善電生理官能連繫不良以達神經保護之效果。跟據世界衛生組織統計,在全球人口十大死因中,腦中風排名在前三位居高不下,對於國家、社會醫療資源上都是非常沉重的負擔,因此開發有效的治療和預防藥物實為當務之急。
在腦中風治療的研究中,三種治療的方式被認為可有效提升中風後功能恢復。第一種形式需要一次治療針對在灰質、白質、皮質和皮質下的傷害,或者把在這一連串傷害內共同的特點作為調節目標,藉此減少缺血性傷害所導致各種細胞結構的損傷和功能的缺乏。第二種形式是去刺激或者提升損傷腦部之神經元的生長(Neuronal sprouting)、髓鞘再生(Myelin regeneration)、樹突的分支和突觸的重新連結(Synaptic rewiring)等來達到神經功能性的恢復。第三種則為幹細胞誘導重建治療。
腦中風發生後神經再塑對於大腦的功能恢復與調節相當重要,而提高樹突小棘密度是增進神經再塑及突觸重新連結的關鍵。先前的研究中指出,突觸前蛋白SNAP-25、synaptophysin在神經生長分化表現量明顯增加。SNAP-25是,主要的功能是神經傳遞物質的釋放與回收且被認為與觸突的功能與生長有關。
GAP-43是神經系統特有的蛋白,在神經元突起(Neurite)的形成、再生與再塑中扮演重要的角色。在神經元突起生長發育或是神經再生時,不論是中樞神經系統或是周邊神經系統都可以發現其大量分泌。因此我們可以知道SNAP-25、GAP-43對神經的生長或是再塑而言十分重要。
近年來,MMPs與PSD-95於中風後大腦重塑與突觸塑性的研究中被高度關注。於中風發生初期MMPs的過度表現雖然會使的腦組織細胞外基質(ECM)損傷及引起免疫細胞浸潤造成發炎時有毒物質進入腦組織造成損害,然而,在中風後中長期MMPs其調控蛋白水解是神經重塑及神經再生時,不可缺少的重要蛋白。PSD-95是突觸後結構中重要的支架蛋白,與NMDA受器結合被認為與突觸再塑與學習記憶有關,對於形成和維持突觸接合(synaptic junction)有重要的功能,當PSD-95s失去功能時,突觸的結構會被破壞而神經元之間的電訊號傳遞也會中斷而失去功能。先前研究發現在中風後,PSD-95能夠幫助建立神經突觸的架構,並且促成突觸其他部分結構的成熟。故MMPs與PSD-95對於神經再塑具有不可言喻之重要性。
Melatonin為神經科學研究的熱門話題,先前的研究中Melatonin於缺血性中風大鼠已有相當多優良的神經保護劑特性。包括在缺血性中風初期為強而有力之自由基清除劑以及抗氧化劑,保護灰質與白質在避免自由基與氧化壓力的傷害,降低因傷害造成的水腫,同時也有效的抑制缺血性傷害後所引起的發炎反應以及神經細胞凋亡等重要的保護效果。為進一步探討Melatonin於缺血性中風後電生理恢復以及神經再塑之機制。本研究分為兩個部分,在第一部分,建立一個月時程的體感覺誘發電位監測、Golgi-cox染色及神經行為學檢查之資料。觀察在中風後1、3、7、21、28天腦梗塞體積、臨床神經行為學分數的變化,體感覺誘發電位變化及官能連繫不良之現象,Golgi-cox 神經解剖學染色評估在缺血性中風後神經元樹突分枝數量和其上之樹突小刺之密度。經由這個部分的資料,更加瞭解在缺血性中風後急性期、亞急性期、中長期大鼠電生理與神經元上突觸之變化。第二部分,在缺血性中風後給予Melatonin,在第7天與第28天測量體感覺誘發電位,評估腦梗塞體積、神經行為學檢查並以Golgi-cox染色觀察神經元分枝數量樹突小刺密度,並以西方點墨法及免疫螢光染色分析相關蛋白如:SNAP-25、GAP-43、PSD-95,並以酶譜法測量MMPs在腦組織中活性。
本研究結果顯示,Melatonin於缺血性腦中風大鼠有效提供神經保護與神經再塑之效果並能有效改善中風後神經官能連繫不良之現象。我們不僅對於神經保護劑Melatonin有更深一層認識,並且對其調控機制也更清楚的瞭解。對於缺血性中風,一個致病率高且對國家社會帶來沉重負擔的疾病,在未來臨床上提供具有相當潛力之神經保護劑。
英文摘要 Melatonin improves neuroplasticity and the recovery of contralateral electrophysiological diaschisis by modulating synaptosomal-associated protein 25 kDa (SNAP-25), growth-associated protein 43 kDa (GAP-43), NMDAR-postsynaptic density protein 95 (PSD-95), and dendritic spine density following focal cerebral ischemia in rats.
Stroke is the third leading cause of death worldwide. There are three therapeutic modalities that have been proposed to improve functional outcome post-stroke. The first requires interventions targeted at common points of the injury cascades for various cytoarchitectural injuries (e.g., gray and white matter, cortical and subcortical structures, and the neurovascular unit), thereby decreasing the extent of direct damage to the partially injured (penumbral) brain tissues. The second option is to use specialized treatment modalities that enhance neuroplasticity (e.g., neuronal sprouting, myelin regeneration, dendritic spine density and arborization, and synaptic connections) during the sub-acute stage of brain injury. The third option is to introduce pluripotent stem cells from various organs or tissues into the ischemic brain and/or to enhance post-ischemic proliferation or the migration and differentiation of endogenous progenitor cells into the damaged brain, thereby restoring the neuronal, axonal, and synaptic functions via replenishment and rewiring of the damaged neural network. A great amount of progress has been achieved in the study of melatonin for use in the first therapeutic modality.
Neuroplasticity is important for the recovery of neural function. Recent studies have indicated that neuronal differentiation is accompanied by increased levels of SNAP-25 and synaptophysin (a calcium-binding protein found on presynaptic vesicle membranes) in neurons. In addition, dendritic spine density has been implicated in playing an essential role in neuronal plasticity. Growth Associated Protein 43 (GAP-43) is a nervous tissue-specific protein that is synthesized at a high rate during axonal growth in neuronal development and axonal regrowth during peripheral and central nervous system regeneration. GAP-43 therefore represents an important marker for axonal regeneration and sprouting. Accordingly, dendritic spine density and two presynaptic proteins, SNAP-25 and synaptophysin, as well as the postsynaptic protein PSD-95, were used as indices and outcome measures for neuronal plasticity in this study. Although the over-expression of matrix metalloproteinases (MMPs) poses damage to the extracellular matrix in the brain and causes infiltration of inflammatory cells during the acute stage of stroke, MMPs are also vital molecules for neuroplasticity in synapses and long-term nerve regeneration following stroke. Previous studies have indicated that PSD-95 is a crucial protein that may modulate the NMDAR-mediated pathway related to neuronal death in the cortex and hippocampus, facilitate the construction of neuronal synapses, and promote the maturation of other parts of the synapse. Together, MMPs and PSD-95 play a crucial role in the mechanisms of neuroplasticity.
Melatonin has strong potential to be used in the field of stroke and has been patented for such use. Previous studies have shown that melatonin exhibits potent antioxidant, radical-scavenging, and anti-inflammatory properties and reduces ischemic brain damage. In addition, previous studies have shown that melatonin may protect gray and white matter from damage caused by transient focal cerebral ischemia. To determine the effects of melatonin on neuroplasticity after ischemic cerebral stroke, this study used in vivo and in vitro models of transient ischemic cerebral stroke to estimate whether melatonin could achieve the effects of neuroplasticity through the modulation of growth-associated proteins in neurons or synapses.
In the first part of the study, somatosensory evoked potential (SSEP) recordings and Golgi-Cox analysis were performed in 28-day time course experiment. In the second part of the study, melatonin was administered 90 min following ischemia/reperfusion onset to determine its effect on ischemic stroke. After 7 or 28 days, SSEP was recorded and dendritic spines were quantified. The neuroplasticity associated proteins SNAP-25, synaptophysin, GAP-43, and PSD-95 were analyzed by Western blot. In addition, zymography was used to estimate the protein activity of MMP-9 or MMP-2 in vivo to investigate whether melatonin affects MMP-9 or MMP-2 at the sub-acute stage.
This study will provide insight as to whether melatonin provides long-term neuroprotective effects and demonstrate the benefits of neuroplasticity. Additionally, the results will identify potential neuroprotective agents that may be candidates for future clinical research.
論文目次 中文摘要 I
Abstract IV
Acknowledgements VII
Contents VIII
List of Tables X
List of Figures XI
Abbreviation List XIII
Chapter 1 Introduction 1
1.1 Background 1
1.2 Pathophysiology of ischemic stroke 1
1.3 Diaschisis in ischemic stroke 4
1.4 Neuroplasticity and associated protein SNAP-25, GAP-43, PSD-95, MMPs 5
1.5 Neuroprotectant - Melatonin 7
Chapter 2 Materials and methods 8
2.1 Primary cortical neuronal cultures 11
2.2 Glutamate-induced excitotoxicity and assay for dendritic aborizations 11
2.3 Animal preparation, anesthesia and monitoring 12
2.4 Experimental model and grouping 13
2.5 Somatosensory evoked potential recording (SSEP) 14
2.6 Neurobehavioral testing and body weight measurements 15
2.7 Quantification of ischemic damage 16
2.8 Golgi-Cox analysis 17
2.9 Gelatin zymography 17
2.10 Western Blot analysis 18
2.11 Statistical analysis 19
Chapter 3 Results 20
3.1 First series of experiments 20
3.1.1 Middle cerebral artery occlusion (MCAo) model 20
3.1.2 Histology and functional outcome during a 28-day recovery 27
3.1.3 Dendritic branches and dendritic spine density during a 28-day recovery 31
3.1.4 Electrophysiological outcome during a 28-day recovery 35
3.2 Second series of experiments 40
3.2.1 Melatonin improves dendritic abrizations and expression of the GAP-43 and PSD-95 proteins in cultured neurons 40
3.2.2 Melatonin reduced ischemic brain damage and improved neurobehavior outcome after a recovery period of 7 and 28 days 44
3.2.3 Melatonin improved the SNAP-25, GAP-43 and PSD-95 expression in the ischemic brain 52
3.2.4 Melatonin improved the activity of proMMP-9 and MMP-9 in the ischemic brain 61
3.2.5 Melatonin improves electrophysiological outcomes and diminished diaschisis after ischemic damage 66
3.2.6 Melatonin improved dendrite branches and density after brain ischemic damage 73
Chapter 4 Discussion 80
4.1 Discussion 80
4.2 Limitation 85
4.3 Future work 86
Chapter 5 Conclusion 87
Reference 88

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