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研究生:吳承寯
研究生(外文):Cheng-Jiun Wu
論文名稱:運動對低壓缺氧所引起之神經細胞傷害的保護作用
論文名稱(外文):Protective effects of treadmill exercise on hypobarichypoxia induced neuronal damage
指導教授:林靜茹林靜茹引用關係
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:91
中文關鍵詞:缺氧運動神經元神經膠細胞
外文關鍵詞:hypobaric hypoxiaexerciseneuronglia cell
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缺氧,是全身或部分組織缺乏適當氧氣供應的現象,在日常生活中,身處於高海拔地區是正常人最容易碰到的缺氧情況之一。在臨床醫學研究中指出,在沒有經過適應的情況下,快速地暴露於高海拔地區時,便容易引起急性高山症(acute mountain sickness)的產生,嚴重的症狀則包括意識混淆、高海拔腦水腫( high altitude cerebral edema )、高海拔肺水腫( high altitude pulmonary edema )等,最終則可能出現昏迷及死亡。此外,缺氧也是引起許多神經系統疾病的重要病理因子,例如:中風(stroke)、腦部創傷(head trauma)、神經退化性疾病(neurodegenerative disease)等。
而過去研究發現,在缺血/缺氧傷害發生時,會導致一氧化氮生成酶(nitric oxide synthase)的表現上升,於回氧的階段時,會引起一氧化氮(NO)的大量形成;而且,在回氧階段時,容易產生ONOO-而引起細胞內的氧化壓力,造成細胞的死亡。另一方面,亦有研究證實缺氧會引起腦部神經膠細胞的活化而釋放出一些免疫發炎物質,當這些免疫發炎物質過度累積時,會造成細胞毒性而對神經元產生傷害。
運動,可以改善身體的體適能(physical fitness),幫助身體保持於健康、穩定的狀態。近來研究報導,運動可提升腦部大腦神經傳遞滋養物質(brain-derived neurotrophic factor,BDNF)與神經生長物質(nerve growth factor,NGF)的表現;這些神經滋養素被認為可以幫助腦部神經再生(Neurogenesis)、增強神經可塑性(neuroplasicity)、以及可以提高神經元的存活率及分化作用;此外,運動也被證實可以降低中風等腦部傷害的死亡率以及改善腦部傷害後的神經功能。然而,運動對保護低壓缺氧所引起的腦部傷害的研究卻相當缺乏。
因此,本研究以預防的角度出發,透過運動訓練的方式來觀察運動對大腦海馬迴低壓缺氧後所引起的神經毒性反應之影響;並期待經由運動訓練能達成減緩缺氧後的腦神經傷害,以達成對急性高山症預防之目的。
在研究方法上,本實驗的急性高山症缺氧模式以小型高度缺氧艙(altitude chamber)模擬海拔9000公尺之高度的氧分壓,相當於0.303大氣壓(氧分壓約48托耳)之情況。在進行低壓缺氧之前,5週大的雄性大鼠先進行四個禮拜的低強度或高強度跑步機運動訓練,每週訓練五天,每天持續20到50分鐘。運動訓練結束後至少休息兩天再進行低壓缺氧7個小時。低壓缺氧結束後,再分別立刻犧牲、4小時後犧牲、24小時後犧牲,犧牲後取腦部海馬迴區域做觀察。另有正常對照組及非運動合併缺氧處理組做為比較。
本實驗結果指出,低壓缺氧確實引起大鼠海馬迴內 HIF-1α、nNOS、iNOS、GFAP、procaspase-3的表現上升,另外,也影響了BDNF使之表現下降,特別在非運動組別尤其明顯。而運動訓練的效果可減緩因低壓缺氧所誘導的HIF-1α表現上升,改善缺氧程度;同時,也可以減緩因缺氧所誘導的nNOS、iNOS表現上升,改善缺氧後細胞內的氧化壓力;另一方面,運動也可以減緩神經膠細胞的活性,使局部組織表現GFAP及OX-42的細胞數下降;而在細胞凋亡方面,運動可減緩缺氧所誘導的procaspase-3的表現,降低細胞凋亡情況發生;最後,運動在神經保護作用上可減緩因缺氧所導致的BDNF表現下降,幫助BDNF表現恢復正常。
本實驗的結果大致上可說明運動對急性高山症有預防之功效,並可減緩因缺氧所引起的細胞內氧化壓力及細胞凋亡現象;然而,先前的研究中,運動在此急性高山症模式研究中的影響還未曾被做過探討,因此,仍有許多地方有待更深入的研究與確認。
Hypoxia is a pathological condition in which some tissue or general part of the body is deprived of adequate oxygen supply. Being in places of high altitude could be one of the most common situation when ordinary people would experience hypoxia. Previous clinical medical researches have highlighted that rapid exposure to areas of high altitude without well adaptation would precipitate the incidence of acute mountain sickness. In severe cases, some patients would experience consciousness disturbance, high altitude cerebral edema , high altitude pulmonary edema, and eventually coma or death . Hypoxia is also an important pathological factor of many neurological diseases, including stroke, head trauma and neurodegenerative disease.
Previous studies have pointed out that hypoxic/ischemic events would influence the homeostasis of intracellular calcium ions, leading to the overexpression of nitric oxide synthase, and subsequent mass production of nitric oxide during blood or oxygen reperfusion. In addition, over production of ONOO- induced intracellular oxidative stress, leading to cell apoptosis. Some researches also proved that hypoxia would activate glial cells in brain, thus release some immune-mediated inflammatory substances. When these substances accumulated excessively, they caused neuronal cytotoxicity.
Exercise has been shown to improve physical fitness, help body keeping in healthy and stable condition. Recent studies have shown that exercise could boosts the expression of brain-derived neurotrophic factor(BDNF)and nerve growth factor(NGF), which were beneficial for neurogenesis, neuroplasticity, neuronal survival and differentiation in the brain. The reported benefits of exercise induced decline of the mortality rate and better recovery of neurologic function after brain injuries like stroke. However, studies on whether exercise exerts protection effects on hypobaric hypoxia – induced neurotoxicity are scarce.
This research, from the prospective of disease prevention, inveatigated the influence of exercise training on ameliorating the neurotoxicity of hippocampus after hypoxia insult. We propose that exercise training would protect brain neurologic function against hypoxia induced neurotoxicity, thus to achieve the goal of preventing damage caused by acute mountain sickness.
The model of hypoxia representing acute mountain sickness was performed by a altitude chamber, simulating the condition of 9000 meters high, which equaled 0.303 atm. Before hypobaric hypoxia challenge, 5-week-old male rats underwent 4-week-long moderate or high intensity treadmill training, with twenty to fifty minutes once a day, five days a week. Rats would rest for more than two days before the 7-hour hypobaric hypoxia challenge was performed. Rats were then sacrificed at 0, 4, and 24 hours after hypoxia treatment. There were also groups of normal control and of sedentary combining hypoxia exposure for comparisons.
The result showed that hypobaric hypoxia increased the expression of HIF-1α, nNOS, iNOS, GFAP and procaspase-3 in the hippocampus of rats, while the levels of BDNF , especially in the sedentary were reduced. Exercise training reduced the elevation of HIF-1α and the drop of BDNF induced by hypoxia, attenuating the hypoxic injury. Intracellular oxidative stress decreased owing to less nNOS and iNOS expression. Exercise also reduced glial cells activation, indicated from down-regulating the expression of GFAP and OX-42.
This study result supported the preventing effect of exercise against, intracellular oxidative stress and apoptosis induced by hypobaric hypoxia which similar to AMS. However, the underlying mechanisms of how exercise works to protect the brain from injury of AMS has not been clearly researched and discussed in previous studies. The detail mechanisms need further research and confirmation.
第一章 前言
第一節 研究背景-------------------------------------------2
1. 缺氧(Hypoxia)------------------------------------------2
1-1 缺氧類型----------------------------------------------2
1-2 高海拔不適症(Altitude Illness)------------------------4
1-3 缺氧與神經元------------------------------------------5
1-3-1缺氧與缺氧誘導因子(Hypoxia Induce Factor)----------7
1-3-2 缺氧與一氧化氮(Nitric oxide ; NO)-------------------8
1-3-3 缺氧與氧化壓力(Oxidative stress)--------------------9
1-4 缺氧與神經膠細胞-------------------------------------10
1-5 缺氧與海馬迴( Hippocampus )--------------------------11
2 運動---------------------------------------------------12
2-1 運動對腦部的影響-------------------------------------13
2-2 運動對腦神經缺氧反應後的影響-------------------------15
第二節 研究目的------------------------------------------17
第三節 研究策略------------------------------------------17
第二章 材料與方法
第一節 實驗材料----------------------------------------------------19

第二節 實驗方法
1 實驗流程-----------------------------------------------19
2 實驗動物分組-------------------------------------------19
3 動物運動訓練-------------------------------------------20
4 動物低壓缺氧壓力模式-----------------------------------21
5 動物組織處理-------------------------------------------21
6 西方點墨法---------------------------------------------22
7免疫切片染色法(Immunohistochemistry)------------------25
8 細胞凋亡反應分析 (TUNEL assay)-----------------------29
第三節 統計分析------------------------------------------32
第三章 結果
第一節 西方點墨法實驗結果--------------------------------35
第二節 免疫切片染色結果----------------------------------39
第四章 討論
第一節 討論----------------------------------------------44
第二節 未來方向------------------------------------------52
圖表說明-------------------------------------------------53
參考文獻-------------------------------------------------78
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