系統識別號 U0026-1107201415434600
論文名稱(中文) 探討新生鼠缺血缺氧腦傷中神經血管性損傷的機制
論文名稱(英文) The mechanism of neurovascular damage in neonatal rat with hypoxic-ischemic brain injury
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 102
學期 2
出版年 103
研究生(中文) 許宜菁
研究生(英文) Yi-Ching Hsu
學號 s58941565
學位類別 博士
語文別 英文
論文頁數 76頁
口試委員 指導教授-黃朝慶
中文關鍵字 缺血缺氧性腦傷  神經血管性單元  腦血流  血管保護  一氧化氮合成酶 
英文關鍵字 hypoxia-ischemia brain injury  neurovascular unit  cerebral blood flow  vascular protection  nitric oxide synthase 
中文摘要 腦部細胞對氧氣的缺乏極為敏感,某些腦部細胞甚至在氧氣供應中斷的5分鐘後即開始死亡,因此腦缺氧足以快速的造成腦部傷害甚至腦細胞死亡。由於缺氧對腦部而言是一種緊急情況,越快給予醫療或重新供給氧氣,越能減少腦部的嚴重傷害或死亡。新生兒缺血缺氧性腦傷害為主要造成新生兒死亡與長期腦部失能的腦部病變,而目前已發展的神經保護藥物,用在中風病患上仍無法見效。過去研究已指出神經血管性單元在缺氧性壓力下,神經細胞與微小血管的反應一樣快速,因此血管保護可能可做為缺氧性腦傷的有效治療標的。我們利用出生後7天大的新生幼鼠做實驗模式,給予缺血缺氧處理,造成腦部的缺血缺氧性腦傷,探討其中傷害的機制。腦部血管病變是在急慢性腦部病變中相當常見的傷害,一旦缺乏血流供應,腦細胞迅速死亡,殘存的細胞將不足以維持正常功能。近年來在成鼠實驗模式中,神經血管性單元在腦部血液供應與腦部傷害之間的關連性逐漸被提及,尤其是缺血所造成的後續發炎反應、血管新生,在在影響腦傷的發展。因此本研究目標在於釐清新生兒缺血缺氧模式中血管性損傷是否是個早期事件,以及一氧化氮在血管性傷害中可能扮演的角色。結果指出在幼鼠模式中,早至缺血缺氧後一小時即可見到血管性病變與免疫球蛋白漏出血管外;3-硝基酪氨酸的表現量在缺氧後快速增加。而事先給予神經性一氧化氮合成酶(neuronal-NOS)及誘發性一氧化氮合成酶(inducible-NOS)的抑制劑分別有完全或部分的腦部保護效果。同時以缺血前置處理(ischemic preconditioning)做為已知的保護模式,比較其保護效果。僅在事先給予nNOS的抑制劑,或以缺血前置處理時,可維持腦部血液灌注,表示其可能是藉由血管保護進而達到腦部保護的效果。而缺血前置處理與血管內皮細胞之間是如何調控,因而對缺氧缺血性腦損傷有保護效果,則需進一步的研究。
英文摘要 Brain cells are extremely sensitive to oxygen deprivation. Some brain cells actually start dying just under five minutes after their oxygen supply is cut. As a result, brain hypoxia can kill brain cells and rapidly cause severe brain damage. This is an emergency, and the sooner medical attention is given and the oxygen supply restored, the lower the chances of severe brain damage or death. Neonatal hypoxic-ischemic (HI) stress can lead to HI encephalopathy. There is still no effective drug against neonatal HI brain injury. Most neuroprotective agents have not benefitted patients with stroke. Because researchers have reported that neurovascular units can be the targets of hypoxic stress and that both neurons and microvessels respond equally rapidly to the insult, it has been hypothesized that vascular protection would be more effective than neuroprotection against HI brain damage. To clarify the function of neurovascular unit in neonatal HI brain injury, a major cause of neonatal mortality and long-term disability, we used 7-day-old rat pups with an animal model of HI injury: one side carotid artery was permanently ligated and each rat pup was subjected to systemic hypoxia (8% O for 2 h) to induce ipsilateral cerebral HI injury. This study investigated whether neurovascular unit damage is an early event in HI neonatal brain damage and how nitric oxide contributes to HI-induced brain injury. The data show that IgG leakage and microvascular change were observed with transmission electron microscopy (TEM) as early as 1 h after HI insult. Nitrotyrosine was overexpressed immediately after reoxygenation. The hypothesis that “microvascular damage occurs soon after hypoxic-ischemia: neuronal nitric oxide synthase (nNOS) is activated and contributes to brain injury” was tested. Treating the rat pups with 7-nitroindazole (7-NI), an nNOS inhibitor, and aminoguanidine (AG), an inducible NOS (iNOS) inhibitor, before hypoxia provided complete and partial neuroprotection, respectively. I also use ischemic preconditioning (IP) as a complete brain protection model for comparison. Pretreatment with 7-NI and IP protected cerebral blood flow (CBF) from hypoxia-induced hypoperfusion that reduced the brain infarct area. In summary, nNOS-mediated vascular damage is an early event caused by hypoxic-ischemia and that vascular protection might be better than neuroprotection. However, how the IP is related to endothelial cells requires additional investigation.
論文目次 中文摘要...................................1
Figure contents............................8
Materials and methods.....................16
Figures and figure legends................45
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