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研究生:鄒宜憲
研究生(外文):Yi-hsien Tsou
論文名稱:跑步運動訓練保護多巴胺神經元免於MPP+毒殺之機制:Nrf2抗氧化系統之角色
論文名稱(外文):Treadmill exercise prevents MPP+-induced oxidative insult and the down regulation of Nrf2-regulated antioxidant enzymes in rat nigrostriatal dopaminergic system
指導教授:莊季瑛莊季瑛引用關係
指導教授(外文):Jih-ing Chuang
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生理學研究所
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:英文
論文頁數:65
中文關鍵詞:多巴胺神經元運動訓練
外文關鍵詞:MPP+Nrf2GSHHO-1
相關次數:
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運動訓練能夠改善心血管方面的疾病以及降低神經退化性疾病發生的風險,例如:中風、阿茲海默症、帕金森氏症…等。雖然劇烈運動會造成氧化損傷,但適度的運動訓練誘發輕微的氧化壓力,卻可以活化內生性的抗氧化防禦機制。因為當面臨氧化壓力時,會活化轉錄因子 nuclear factor-erythroid 2 related factor 2 (Nrf2) 並調控上游具有抗氧化基因調節序列的抗氧化酵素表現,包括: ��-麩胺醯半胱胺酸合成酶和血紅素氧化酶-1。N-甲基-4-苯基啶離子 (MPP+) 是粒線體上電子傳遞鏈複合酶的抑制劑,會誘發氧化壓力,並使黑質區投射到紋狀體的多巴胺神經元大量死亡,因此被用來做為誘發帕金森氏症實驗模式的藥物。然而運動訓練對 MPP+ 的毒性及 Nrf2 抗氧化系統的表現之影響仍不清楚,因此我的研究目的為探討跑步運動訓練是否能透過活化 Nrf2所調控的抗氧化機制來保護由 MPP+ 所誘發的多巴胺神經元死亡。首先由酪胺酸羥化酶和多巴胺轉運器免疫組織染色的結果,得知四週跑步運動訓練可以避免由 MPP+ 造成的黑質區多巴胺神經元細胞數降低和紋狀體多巴胺轉運器表現下降,證明運動訓練可以保護多巴胺神經元免於 MPP+ 之毒殺。運動訓練可以避免 MPP+ 誘發的氧化壓力上升以及榖胱甘肽含量下降,並減緩 Nrf2和��-麩胺醯半胱胺酸合成酶表現量下降;相反的,MPP+ 誘發血紅素氧化酶-1表現量的增加,而此現象也可被運動訓練和抗氧化劑褪黑激素所抑制,顯示 MPP+ 所誘發的血紅素氧化酶-1表現量上升為對氧化壓力的代償現象。我的研究結果指出運動訓練可以避免 MPP+ 所誘發的氧化壓力、Nrf2和��-麩胺醯半胱胺酸合成酶的表現量降低,而達到保護多巴胺神經元的功能。
Benefits of regular exercise include improvement in cardiovascular health and decrease of risk for neurodegenerative diseases, such as stroke, Alzheimer’s disease, and Parkinson’s disease (PD). Although acute severe exercise causes oxidative insult, moderate exercise training induces mild oxidative stress which activates endogenous antioxidant defense system. In response to oxidative stress, transcription factor of nuclear factor-erythroid 2 related factor 2 (Nrf2), which binds to the antioxidant response element is activated to regulate the expression of antioxidant enzymes, such as �蛂Vglutamylcysteine synthetase (�脙CS) and heme oxygenase-1 (HO-1). 1-methyl-4-phenylpyridinium (MPP+), an inhibitor of mitochondria complex I, was extensively used to induce oxidative insult in nigrostriatal dopaminergic neurons and generate a model of PD. However, the effect of treadmill exercise on MPP+ neurotoxicity and Nrf2-antioxidant system is still unknown. Therefore, we hypothesized that treadmill exercise protects nigrostriatal dopaminergic (DA) neurons from MPP+ toxicity by upregulating Nrf2-antioxidant system. We found that treadmill exercise training prevented the MPP+-induced nigrostriatal DA neurodegeneration as indicated by the loss of tyrosine hydroxylase (TH)-positive neurons in substania nigra and expression of TH and dopamine transporter in the striatum. Exercise training also prevented MPP+-induced oxidative stress as shown in a high ratio of GSSG (oxidized glutathione):GSH (reduced glutathione) and decrease of GSH content, as well as the downregulation of Nrf2 and �脙CS in the striatum. On the contrary, HO-1 was upregulated 3 days after MPP+ injection and the phenomenon can be prevented by treadmill exercise and antioxidant of melatonin. The results suggested that HO-1 upregulation was a compensatory response to oxidative stress induced by MPP+. Our results also indicated that exercise training prevented MPP+-induced oxidative stress and Nrf2 and �脙CS downregulation may contribute to the effect of neuroprotection in nigrostriatal DA neurons.
Table of Contents - 8 -
Introduction - 10 -
Parkinson’s disease - 10 -
Animal models of Parkinson’s disease - 11 -
Oxidative stress and neurodegenerative diseases - 11 -
Antioxidant, glutathione in dopaminergic neurons - 12 -
Nrf2-regulated antioxidant defense system - 14 -
The role of Nrf2 in neurodegenerative diseases - 15 -
Beneficial effect of chronic exercise in neurodegenerative diseases - 16 -
Exercise, oxidative stress, and adaptation - 17 -
Research Rationales - 18 -
Materials and Methods - 20 -
Animals - 20 -
Exercise training protocol - 20 -
Surgery - 21 -
Citrate synthase assay - 22 -
Histological examination of brain - 22 -
Nissl stain - 23 -
Immunohistochemistry - 23 -
Preparation of nuclear and cytosolic extracts - 24 -
Measurement of protein concentration - 25 -
Western blot - 25 -
Antibodies for Western blot - 26 -
Total glutathione (GSH) and oxidized glutathione (GSSG) assay - 27 -
Statistical analysis - 27 -
Results - 29 -
Significant weight loss and increase activity of citrate synthase in soleus muscle were detected after treadmill exercise. - 29 -
Treadmill exercise prevented MPP+-induced neurodegeneration of nigrostriatal DA neurons. - 29 -
Treadmill exercise prevented MPP+-induced oxidative stress in the striatum. - 31 -
Treadmill exercise prevented MPP+-induced downregulation of expression of nuclear Nrf2 in the striatum. - 31 -
Treadmill exercise prevented MPP+-downregulated Nrf2-ARE binding activity. - 32 -
Treadmill exercise prevented MPP+-induced downregulation of �脙CS and upregulation of HO-1 in the striatum. - 33 -
Treadmill exercise prevented MPP+-induced upregulation of HO-1 in SNpc. - 33 -
Melatonin prevented MPP+-induced upregulation of HO-1 in the striatum. - 34 -
Discussion - 36 -
References - 43 -
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