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系統識別號 U0026-2906201011474400
論文名稱(中文) 探討低劑量內毒素前置處理保護幼鼠腦部對抗缺血缺氧性腦傷的機制
論文名稱(英文) The protective mechanism of low-dose lipopolysaccharide preconditioning against hypoxic-iscjemic brain injury in neonatal rats
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 98
學期 2
出版年 99
研究生(中文) 林相吟
研究生(英文) Hsiang-Yin Lin
學號 s5892154
學位類別 博士
語文別 英文
論文頁數 133頁
口試委員 指導教授-黃朝慶
口試委員-林以行
口試委員-張文粲
口試委員-曾淑芬
口試委員-陳慶鏗
口試委員-賴明宗
中文關鍵字 缺血缺氧性腦傷  內毒素前置處理  幼鼠腦部 
英文關鍵字 hypoxic-ischemic brain injury  LPS preconditioning  neonatal brain 
學科別分類
中文摘要 新生兒缺血、缺氧性腦病變是常見且嚴重的新生兒疾病,通常會造成癲癇、學習障礙、心智障礙、腦性麻痺、甚至是新生兒死亡等臨床病徵。目前針對這樣的腦傷尚未有良好的治療或預防措施。前置處理(preconditioning)是指在致死性傷害前給予組織或細胞非致死性刺激 (即前置處理)可以達到保護組織減緩傷害的現象。在動物實驗中有各種前置處理模式,例如缺氧性前置處理,已被證實可以改善成鼠腦中風的預後。而藉由了解各種前置處理的保護機制將有助於臨床對新生兒缺血、缺氧性腦病變的治療方法策略有所幫助。在我們的研究中成功的建立以低劑量的內毒素-脂多醣 (LPS 0.05mg/Kg)作為缺血、缺氧腦傷害(HI)之前置處理,可明顯的保護未成熟的腦部達到減緩缺血、缺氧性腦傷的動物模式,保護效果可改善缺血、缺氧性腦傷所導致的學習及記憶行為障礙。
LPS preconditioning明顯加強腦部神經細胞及血管內皮細胞內PI3K/Akt及eNOS的活化與表現 並且明顯減少 HI所引起的神經細胞及血管內皮細胞的死亡。
若以藥物抑制eNOS或PI3K/Akt的活化、或是以eNOS antisense 減少eNOS的表現,此時LPS preconditioning將無法保護腦部。由LPS preconditioning所活化的PI3K-Akt不僅與eNOS表現在相同的細胞中,也決定著eNOS活化及表現增加的情形。綜合上述結果,PI3K/Akt-eNOS是LPS preconditioning可以減少神經及血管內皮細胞死亡進而保護幼鼠腦部免於HI傷害的關鍵機制。以eNOS agonist(L-arginine)或帶有eNOS gene的adenovirus 增強幼鼠腦部表現eNOS,則可明顯降低幼鼠HI腦傷。另外,細胞實驗也證實eNOS表現的多寡關係著神經細胞及血管內皮細胞對HI刺激的抵抗性。因此,調節eNOS是臨床針對新生兒缺血、缺氧性腦病變可能的處理方式。
LPS preconditioning除增強PI3K/Akt-eNOS來形成保護外,也明顯減緩HI所引發之發炎反應、細胞凋亡及氧化壓力,甚至是減少HI導致幼鼠腦部GSK-3 beta 的活化。在各種細胞中,包括代謝、發炎、凋亡、甚至是細胞分裂等等的細胞訊息傳遞皆受GSK-3 beta 調控。暗示著LPS preconditioning的保護效應可能來自於減少HI引起GSK-3 beta 活化。的確,若以GSK-3 beta 抑制劑鋰鹽來降低HI導致GSK-3 beta 活化,不僅腦傷程度、也包括發炎反應、細胞凋亡等現象都明顯減緩了。間接證實,LPS preconditioning減少HI腦部GSK-3 beta 活化是保護效應的關鍵。綜合上述,藉由我們的研究成果可以推論”提升eNOS的表現”及”抑制GSK-3 beta活化”是臨床上針對新生兒缺血缺氧性腦傷可能的有效對策。
英文摘要 Hypoxic-ischemic encephalopathy (HIE) in newborn is a common and important neonatal disease. It always resulted in learning disability, mental retardation, cerebral palsy and even fetal death and there is no effective prevention or therapy for HIE. Based on the concept of preconditioning, which is a sub-lethal insult providing tissue or organs resistance to subsequent lethal insult, we established a low-dose lipopolysaccharide (LPS, 0.05mg/Kg) preconditioning against hypoxic-ischemic (HI) brain damage on both behavioral (learning and memory ability) and pathological levels (Brain weight reduction) in the neonatal rats. Delineating the underlying protective mechanisms of LPS preconditioning is the aim of this study. We found that LPS preconditioning-derived eNOS up-regulation and PI3K/Akt activation in cortical neuron and cerebral vessels are required for the neuroprotection. And the PI3k/Akt activation is responsible for the eNOS up-regulation. In vitro study showed that the expression level of eNOS is associated with the susceptibility to HI in neuronal cell and vascular endothelial cell. Low-dose LPS preconditioning-mediated PI3K/Akt-eNOS is suggested to contribute to neuro-vascular protection in the immature brain. It implicated that eNOS up-regulation is a potential approach for clinical prevention of HIE. We also got insight into how low-dose LPS preconditioning influences the pathogenetic cascades of HI brain injury including ROS accumulation, neuroinflammation, apoptotic cell death and apoptotic signaling cascades. Our findings revealed that low-dose LPS preconditioning reduced HI-induced inflammation, apoptosis and oxidative stress in the neonatal HI brain. And LPS preconditioning-mediated neuroprotective effects were correlated with LPS preconditioning-mediated GSK-3 beta inhibition after HI. Inhibition of GSK-3 beta by pretreatment of GSK-3 beta inhibitor ( lithium chloride) 30 minutes before HI can mimic LPS preconditioning-induced neuroprotective effects including anti-apoptotic and anti-inflammatory effects in the neonatal HI brain. It implicated that GSK-3 beta activation contributes to the pathogenesis of neonatal HI brain injury and inhibition of GSK-3 beta may be required for the acquisition of LPS preconditioning. Taken all together, we have demonstrated the protective mechanisms underlying low-dose LPS preconditioning against HI brain injury in neonatal rats. And it may be helpful for designing potential clinical therapy or prevention for HIE.
論文目次 中文摘要 3
Abstract 5
致謝 7
Contents 8
Figure lists 11
Introduction 15
Hypoxic-ischemic encephalopathy (HIE) and the animal model 15
Lipopolysaccharide (LPS) preconditioning 16
Pathogenesis of neonatal HI brain injury 18
Endothelial nitric oxide synthase (eNOS) 21
PI3K/Akt signaling 24
Glycogen synthase kinase 3β (GSK-3β) 26
Aims 30
Materials and Methods 33
Materials 33
Pharmacological Materials 33
Antibodies 34
Others 35
Animals 36
Animal Treatments 36
Animal model of LPS preconditioning in neonatal HI brain injury 36
Pharmacological Intervention 37
Nitric oxide synthase (NOS) inhibition-NOS inhibitor administration 37
eNOS up-regulation by eNOS agonist (L-arginine) administration 38
PI3k/Akt inhibition by PI3K inhibitor (Wortmannin) infusion 38
GSK-3β inhibition by GSK-3β inhibitor (LiCl) treatment 38
Genomic Manipulations 39
Outcome Assessments 41
Behavioral assessment-Morrris Water Maze (MWM) 41
Pathological Assessment-Brain Weight Reduction 43
TUNEL Stain 43
Immunoblotting 44
Immunohistochemistry 45
Immunofluorescence Staining 46
ROS Production 47
RNA Isolation and Semi-quantitative RT-PCR 48
Cell Culture and Oxygen-Glucose Deprivation (OGD) 49
In Vitro Genetic Manipulations 50
Adenoviral Cell Infection 50
shRNA Transfection 50
Statistics 50
Results 52
Effects of systemic LPS treatment on HI-mortality 52
Long-term outcome of LPS preconditioning in neonatal HI rats 52
Behavior assessment on P35 52
Pathological assessment on P42 53
Preconditioning-dose LPS different from sensitizing-dose LPS didn’t trigger inflammation. 54
Microglia activation 54
Pro-inflammatory cytokine (TNF-alpha) expression 54
Inducible Nitric oxide synthase (iNOS) expression 55
Protective Signaling Required for LPS Preconditioning 55
LPS Preconditioning selectively up-regulated eNOS 55
LPS preconditioning increased eNOS expression in cortical neurons and vascular endothelial cells 56
eNOS was required for the neuroprotection of LPS preconditioning 56
Pharmacological inhibition of eNOS 57
eNOS antisense OND infusion 57
Up-regulation of eNOS is sufficient for protecting immature brain from HI injury. 58
Pharmacologically enhanced eNOS 58
Adenoviral eNOS gene transfer 59
eNOS expression modulates the susceptibility of HI in vascular endothelial cell and neurons 59
LPS preconditioning activated PI3K/Akt in neurons and vascular endothelial cells 61
PI3K/Akt activation responsible for eNOS expression is required for LPS preconditioning 62
Neurorpotective effects of LPS preconditioning 62
LPS preconditioning attenuated HI-induced neuronal and vascular endothelial cell death 62
LPS preconditioning blocked the HI-induced ROS production 63
LPS preconditioning limited the HI-induced inflammation 64
Microglia activation 64
Pro-inflammatory cytokine (TNF-alpha) expression 64
LPS preconditioning attenuated the HI-induced apoptotic cell death. 65
LPS preconditioning reversed the HI-induced GSK-3β activation 66
Pretreatment of Lithium to limit GSK-3β activation was neuroprotective 67
Lithium pretreatment resembling LPS preconditioning attenuated the HI-induced apoptotic cell death 68
Lithium pretreatment resembling LPS preconditioning attenuated the HI-induced microglia activation 68
Figures and Figure legends 104
Conclusion 132
Publications 133
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