臺灣博碩士論文加值系統

研究背景：巴金森氏病為一種慢性神經系統退化疾病，主要為大腦黑質緻密部的多巴胺神經細胞退化所致，最近許多研究提出神經發炎反應在其病理上可能占有重要的角色，促發炎細胞激素在發炎反應中扮演著主要調控者，其中，腫瘤壞死因子─阿爾法被提到和多巴胺神經元死亡有關。在保守治療中，跑步機運動訓練已被證實可有效改善巴金森氏病患者及巴金森氏病大鼠模型之動作功能，最近研究已證實先前運動介入可減緩脂多醣造成的多巴胺神經元死亡並且改善動作表現。而大腦缺血大鼠模型研究發現，先前運動介入可以降低缺血後大腦的傷害程度以及減少腫瘤壞死因子接受器的表現。直至目前，針對巴金森氏病大鼠模型，先前運動介入對於神經發炎傷害的保護機制尚不清楚。研究目的：本研究利用六烴基多巴胺誘發之巴金森氏病模型大鼠，探討施打六烴基多巴胺對腫瘤壞死因子─阿爾法及其接受器表現的影響，以及先前跑步機運動介入對於疾病早期腫瘤壞死因子─阿爾法、腫瘤壞死因子接受器、多巴胺神經元和行為表現的影響。研究方法：本研究使用八周大雄性大鼠，隨機分配到三組，分別為對照組、無運動介入組和跑步機訓練組，對照組再分成兩個子組，分別為蛋白質分析組和行為分析組，無運動介入組和跑步機訓練組再分成三子組，分別為蛋白質分析組、免疫組織染色分析組以及行為分析組。跑步機訓練組給予為期三周，每周連續五天的介入，無運動介入組及對照組也會對應於跑步機訓練組的介入時間將大鼠放至跑步機上，但不啟動跑步機轉帶。運動介入三周後，利用立體定位儀將六烴基多巴胺或相同體積的生理食鹽水注射至大鼠右側的黑質緻密部，於藥物注射前一天、藥物注射後第一天和第七天進行蛋白質分析，於藥物注射後第七天進行免疫組織染色分析，並於跑步機訓練前、跑步機訓練後第一周、第二周、第三周、注射藥物後第一天以及第七天等六個時間點進行行為分析。免疫組織染色分析組以免疫組織化學法分析酪胺酸烴化酶在黑質緻密部的數量；蛋白質分析組以酵素連結免疫吸附法分析黑質區和紋狀體區中，腫瘤壞死因子─阿爾法和其接受器的蛋白質表現；行為分析組以滾輪測試評估大鼠動作功能表現。統計分析：本研究使用統計軟體SPSS 16.0版做統計分析。所有數值皆以平均值 ± 標準誤呈現。利用獨立t檢定比較施打六烴基多巴胺後對腫瘤壞死因子─阿爾法和其接受器的影響以及比較酪胺酸羥化酶細胞數目於跑步機訓練組和無運動介入組之間的差異；利用單因子變異數分析比較先前運動介入對於組內和組間的腫瘤壞死因子─阿爾法和其接受器的差異；利用雙因子重複性測量變異數分析來比較各時間點動作功能表現之結果。以圖基檢驗進行事後檢定。統計水準設定為0.05。研究結果：腫瘤壞死因子─阿爾法及其接受器的表現主要發生在黑質區。黑質區的腫瘤壞死因子─阿爾法表現量在施打六烴基多巴胺後第七天顯著提升，而腫瘤壞死因子第一型接受器則在第一天即顯著提升，腫瘤壞死因子第二型接受器並無影響。三周先前跑步機運動訓練可提升腫瘤壞死因子─阿爾法表現量，並且避免施打六烴基多巴胺後在黑質區及紋狀體區引起的表現量急遽上升，另外，黑質區的腫瘤壞死因子第二型接受器表現量在施打六烴基多巴胺後第一天和第七天皆有提升，紋狀體區則在第七天才有顯著提升。三周先前跑步機運動訓練可增加多巴胺神經元存活量並改善動作功能表現。討論與總結：施打六烴基多巴胺後可急遽提升腫瘤壞死因子─阿爾法和其第一型接受器表現量，而三周先前跑步機運動訓練可避免六烴基多巴胺所導致的腫瘤壞死因子─阿爾法表現量急遽提升，並且增加其第二型接受器的表現量、多巴胺神經元存活量並改善動作功能表現。先前跑步機運動訓練可避免罹患巴金森氏病後得到的傷害，可能是透過先前提升黑質區的腫瘤壞死因子─阿爾法以及增加腫瘤壞死因子第二型接受器的表現量。以預防醫學角度而言，平時保持適度運動，或許可避免罹病後所帶來的傷害。

Background: Parkinson’s disease (PD) is a neurodegenerative, slowly progressive disorder, mainly characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Recent studies suggest that neuroinflammation process appears to play a key role in dopamine (DA) neuron dysfunction and death in PD pathogenesis. Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) are key mediators of the inflammatory response. TNF-α level has been shown to correlate with the extent of DA neuronal death in SNpc. Previous studies have revealed that treadmill exercise improves motor function in patients and animal models with PD. Recently, pre-exercise treadmill training has shown the protection of dopaminergic neuron against lipopolysaccharide-induced neuronal loss in SNpc and improvement in behavioral performance. In cerebral ischemic rat model, exercise preconditioning reduced brain damage and inhibited TNF-α receptor expression after hypoxia/reoxygenation. Up to now, little studies focus on the effects of pre-exercise treadmill training on inflammatory response in PD. Purpose: The present study aims to examine the expression of TNF-α and TNF-α receptors on 6-hydrpxydopamine (6-OHDA) model of PD and to examine the effects of exercise preconditioning on TNF-α, TNF-α receptors, dopamine neuron and behavior in early stage of 6-OHDA-induced Parkinson’s rats. Methods: Adult male Sprague Dawley rats were randomly assigned to three groups: (1) sham, (2) non-exercised animals subjected to 6-OHDA, and (3) exercised animals subjected to 6-OHDA. Sham group was divided into two subgroups for protein and behavioral analysis. Non-exercised and exercised group were divided into three subgroups for immunohistochemistry, protein and behavioral analysis. Rats in exercised group subjected to 30 minutes of exercise on a treadmill each day for five consecutive days for 3 weeks. Then, they were induced by unilateral (right SNpc) intracranial administration of 6-OHDA or physiological saline. Spatial distribution of tyrosine hydroxylase (TH) cell was measured by immunoctochemistry at SNpc on day 7thafter 6-OHDA. Protein expression of TNF-α, TNF-α receptor-I and TNF-α receptor-II were measured by enzyme-linked immunoabsorbant assay at striatum and SN on the end of exercise and day 1st and day 7th after 6-OHDA. Behavioral testing was evaluated by rotarod for motor coordination on baseline, one week after exercise, two weeks after exercise and the end of exercise, day 1st and day 7th after 6-OHDA. Statistic analysis: Data were presented as mean ± standard error of mean. Independent t test was used to analyze the survival number of TH cells and the expression of TNF-α, TNF-α receptor-I and TNF-α receptor-II following 6-OHDA injection. One-way ANOVA was used to analyze protein expression among three groups. Two-way repeated measures ANOVA was used to analyze the motor performance. All analyses were followed by Tukey’s post hoc test. A p value of less than 0.05 is considered to be significant.
Results: The expressions of TNF-α and TNF receptors were prominent in SN. The expression of TNF-α was significantly increased in SN at day 7th after 6-OHDA injection. The expression of TNF-α receptor-I was elevated in SN at day 1st after 6-OHDA injection but no change in TNF-α receptor-II level. Expression of TNF-α in SN was increased after exercise for 3 weeks. The overexpression of TNF-α was not further elevated in 3-week exercised rats subjected to 6-OHDA injection in SN and striatum at day 1st and 7th, as compared to non-exercise rats. In SN, expression of TNF-α receptor-II was increased in exercised rats compared with non-exercised rats and sham group at day 1st and 7th. In striatum, expression of TNF-α receptor-II showed significantly increase in exercised rats compared with non-exercised rats and sham group at day 7th. Exercised 6-OHDA rats demonstrated a higher TH-positive cell ratio as compared to that in non-exercised 6-OHDA rats. Behavioral performance showed improvement after exercise at least two weeks.
Conclusion: Our results suggested that acutely elevated TNF-α and increase of TNF-α receptor-I in SN were found in early stage of 6-OHDA injection, with no change in TNF-α receptor-II level. Three-week treadmill preconditioning training induced pre-elevation of TNF-α, increased TNF-α receptor-II expression, protected dopaminergic neurons and improved motor performance in early stage of 6-OHDA-induced Parkinson’s rats. Our results supported benefits of exercise for preventing from suffering PD which might through pre- elevation TNF-α and increase the expression of TNF-α receptor-II in SN. Today, preventive medicine is advocated to protect human health. Our results supported benefits of regular exercise for preventing from suffering PD.

目錄
致謝 i
目錄 ii
圖目錄 v
中文摘要 vi
英文摘要 ix
第一章 簡介 1
第一節 研究背景與動機 1
第二節 研究目的 2
第三節 研究假設 2
第四節 研究重要性 3
第二章 文獻回顧 4
第一節 巴金森氏病 4
第二節 神經發炎反應 5
第三節 腫瘤壞死因子─阿爾法 7
一、腫瘤壞死因子─阿爾法路徑 8
二、腫瘤壞死因子─阿爾法對巴金森氏病的影響 9
第四節 巴金森氏病動物模型 10
第五節 跑步機先前運動訓練與巴金森氏病 12
第六節 跑步機先前運動訓練對發炎反應所造成的影響 12
第七節 總結及研究目的 13
第三章 研究方法 15
第一節 實驗動物 15
第二節 研究設計 15
第三節 跑步機運動訓練 16
第四節 動物模型 16
第五節 結果測量 17
一、蛋白質分析 17
二、免疫組織染色分析 17
三、行為分析 18
第六節 統計分析 18
第四章 研究結果 20
第一節 施打六烴基多巴胺對於腫瘤壞死因子─阿爾法及其接受器之影響 20
一、腫瘤壞死因子─阿爾法以及其接受器蛋白質表現量於黑質區之變化 20
二、腫瘤壞死因子─阿爾法以及其接受器蛋白質表現量於紋狀體區之變化 20
第二節 先前跑步機運動訓練對於腫瘤壞死因子─阿爾法及其接受器之影響 21
一、腫瘤壞死因子─阿爾法以及其接受器蛋白質表現量於黑質區之變化 21
二、腫瘤壞死因子─阿爾法以及其接受器蛋白質表現量於紋狀體區之變化 22
第三節 先前跑步機運動訓練對多巴胺神經元之影響 22
第四節 先前跑步機運動訓練對行為表現之影響 22
第五章 討論 24
第一節 施打六烴基多巴胺對於腫瘤壞死因子─阿爾法及其接受器之影響 24
一、施打六烴基多巴胺對於腫瘤壞死因子─阿爾法之影響 25
二、施打六烴基多巴胺對於腫瘤壞死因子接受器之影響 26
第二節、先前跑步機運動訓練對於腫瘤壞死因子─阿爾法及其接受器之影響 28
一、先前跑步機運動訓練對腫瘤壞死因子─阿爾法之影響 28
二、先前跑步機運動訓練對腫瘤壞死因子接受器之影響 29
第三節 先前跑步機訓練可增加多巴胺神經元存活量及改善行為表現 30
第四節 研究限制 32
第五節 臨床意義 33
第六章 結論 34
參考文獻 35

圖目錄
圖一、研究設計流程圖 42
圖二、測試時間點 43
圖三、施打六烴基多巴胺對於腫瘤壞死因子─阿爾法在黑質區之影響 44
圖四、施打六烴基多巴胺對於腫瘤壞死因子接受器在黑質區之影響 45
圖五、施打六烴基多巴胺對於腫瘤壞死因子─阿爾法在紋狀體區之影響 46
圖六、施打六烴基多巴胺對於腫瘤壞死因子接受器在紋狀體區的變化 47
圖七、先前跑步機運動訓練對於腫瘤壞死因子─阿爾法在黑質區之影響 48
圖八、先前跑步機運動訓練對於腫瘤壞死因子接受器在黑質區之影響 49
圖九、先前跑步機運動訓練對於腫瘤壞死因子─阿爾法在紋狀體區之影響 50
圖十、先前跑步機運動訓練對於腫瘤壞死因子接受器在紋狀體區之影響 51
圖十一、先前跑步機運動訓練對於多巴胺神經元存活比例之影響 52
圖十二、先前跑步機運動訓練對於行為表現之影響 53
附錄一、實驗動物照護及使用委員會同意書 54
附錄二、多巴胺神經元存活比例之組內重複性測量相關係數 55

1 Lees, A. J., Hardy, J. &; Revesz, T. Parkinson's disease. Lancet 373, 2055-2066 (2009).
2 Gelb, D. J., Oliver, E. &; Gilman, S. Diagnostic criteria for Parkinson disease. Archives of neurology 56, 33-39 (1999).
3 McGeer, P. L., Itagaki, S., Boyes, B. E. &; McGeer, E. G. Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains Neurology 38, 1285 (1988).
4 Mogi, M., Togari, A., Kondo, T., Mizuno, Y., Komure, O., Kuno, S., Ichinose, H. &; Nagatsu, T. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantia nigra from Parkinsonian brain. Journal of neural transmission 107, 335-341 (2000).
5 Nagatsu, T., Mogi, M., Ichinose, H. &; Togari, A. Changes in cytokines and neurotrophins in Parkinson’s disease. (2000).
6 Mogia, M., Haradaa, M., Kondob, T., Riedererd, P., Inagakic, H., Minamic, M. &; Nagatsu, T. Interleukin-1β, interleukin-6, epidermal growth factor and transforming growth factor-α are elevated in the brain from parkinsonian patients. Neuroscience letters 180, 147-150 (1994).
7 McCoy, M. K. &; Tansey, M. G. TNF signaling inhibition in the CNS: implications for normal brain function and neurodegenerative disease. Journal of neuroinflammation 5, 45 (2008).
8 Schober, A. Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP. Cell and tissue research 318, 215-224 (2004).
9 Engler, H., Doenlen, R., Riether, C., Engler, A., Niemi, M. B., Besedovsky, H. O., del Rey, A., Pacheco-Lopez, G., Feldon, J. &; Schedlowski, M. Time-dependent alterations of peripheral immune parameters after nigrostriatal dopamine depletion in a rat model of Parkinson's disease. Brain, behavior, and immunity 23, 518-526 (2009).
10 Wu, S. Y., Wang, T. F., Yu, L., Jen, C. J., Chuang, J. I., Wu, F. S., Wu, C. W. &; Kuo, Y. M. Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway. Brain, behavior, and immunity 25, 135-146 (2011).
11 Ding, Y. H., Young, C. N., Luan, X., Li, J., Rafols, J. A., Clark, J. C., McAllister, J. P., 2nd &; Ding, Y. Exercise preconditioning ameliorates inflammatory injury in ischemic rats during reperfusion. Acta neuropathologica 109, 237-246 (2005).
12 Ding, Y. H., Mrizek, M., Lai, Q., Wu, Y., Reyes, R., Jr., Li, J., Davis, W. W. &; Ding, Y. Exercise preconditioning reduces brain damage and inhibits TNF-alpha receptor expression after hypoxia/reoxygenation: an in vivo and in vitro study. Current neurovascular research 3, 263-271 (2006).
13 Parkinson, J. An Essay on the Shaking Palsy. (1817).
14 Beal, M. F. Experimental models of Parkinson's disease. Nature reviews. neuroscience. 2, 325-334 (2001).
15 Deumens, R., Blokland, A. &; Prickaerts, J. Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Experimental neurology 175, 303-317 (2002).
16 Gao, H. M. &; Hong, J. S. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends in immunology 29, 357-365 (2008).
17 Bartels, A. L. &; Leenders, K. L. Neuroinflammation in the pathophysiology of Parkinson's disease: evidence from animal models to human in vivo studies with [11C]-PK11195 PET. Movement disorders 22, 1852-1856 (2007).
18 Dauer, W. &; Przedborski, S. Parkinson’s disease: mechanisms and models. Neuron 39, 889-909 (2003).
19 Tansey, M. G. &; Goldberg, M. S. Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention. Neurobiology of disease 37, 510-518 (2010).
20 Hirsch, E. C. &; Hunot, S. Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet neurology 8, 382-397 (2009).
21 Dobbs, R. J., Charlett, A., Purkiss, A. G., Dobbs, S. M., Weller, C. &; Peterson, D. W. Association of circulating TNF-α and IL-6 with ageing and parkinsonism. Acta neurologica scandinavica 100, 34-41 (1999).
22 Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K &; T., N. Tumor necrosis factor-alpha (TNF-alpha) increases both in the brain and in the cerebrospinal fluid from parkinsonian patients. Neuroscience letters 165, 208-210 (1994).
23 Gagne, J. J. &; Power, M. C. Anti-inflammatory drugs and risk of Parkinson disease: A meta-analysis. Neurology 74, 995-1002 (2010).
24 He, Y., Appel, S. &; Le, W. Minocycline inhibits microglial activation and protects nigral cells after 6-hydroxydopamine injection into mouse striatum. Brain research 909, 187-193 (2001).
25 Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N. &; Williamson, B. An endotoxin-induced serum factor that causes necrosis of tumors. Proceedings of the national academy of sciences of the United States of America 72, 3666-3670 (1975).
26 Hanisch, U. K. Microglia as a source and target of cytokines. Glia 40, 140-155 (2002).
27 Liu, T., Clark, R. K., McDonnell, P. C., Young, P. R., White, R. F., Barone, F. C. &; Feuerstein, G. Z. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25, 1481-1488 (1994).
28 Lieberman, A. P., Pitha, P. M., Shint, H. S. &; M.L., S. Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proceedings of the national academy of sciences of the United States of America 86, 6348-6352 (1989).
29 Tartaglia, L. A., Rothe, M., Hu, Y. F. &; Goeddel, D. V. Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor. Cell 73, 213-216 (1993).
30 Montgomery, S. L. &; Bowers, W. J. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. Journal of neuroimmune pharmacology 7, 42-59 (2012).
31 Rauert, H., Wicovsky, A., Muller, N., Siegmund, D., Spindler, V., Waschke, J., Kneitz, C. &; Wajant, H. Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2). The journal of biological chemistry 285, 7394-7404 (2010).
32 Flood, P. M., Qian, L., Peterson, L. J., Zhang, F., Shi, J. S., Gao, H. M. &; Hong, J. S. Transcriptional Factor NF-kappaB as a Target for Therapy in Parkinson's Disease. Parkinson's disease 2011 (2011).
33 Sun, S. C. The noncanonical NF-kappaB pathway. Immunological reviews 246, 125-140 (2012).
34 Kim, J. Y., Morgan, M., Kim, D.-G., Lee, J.-Y., Bai, L., Lin, Y., Liu, Z.-g. &; Kim, Y.-S. TNF-α-induced noncanonical NF-κB activation is attenuated by RIP1 through stabilization of TRAF2. Journal of cell science 124, 647-656 (2011).
35 Marchetti, L., Klein, M., Schlett, K., Pfizenmaier, K. &; Eisel, U. L. Tumor necrosis factor (TNF)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by N-methyl-D-aspartate receptor activation. Essential role of a TNF receptor 2-mediated phosphatidylinositol 3-kinase-dependent NF-kappa B pathway. The journal of biological chemistry 279, 32869-32881 (2004).
36 Burow, M. E., Weldon, C. B., Melnik, L. I., Duong, B. N., Collins-Burow, B. M., Beckman, B. S. &; McLachlan, J. A. PI3-K/AKT regulation of NF-κB signaling events in suppression of TNF-induced apoptosis. Biochemical and biophysical research communications 271, 342-345 (2000).
37 Nishimura, M., Mizuta, I., Mizuta, E., Yamasaki, S., Ohta, M., Kaji, R. &; Kuno, S. Tumor necrosis factor gene polymorphisms in patients with sporadic Parkinson's disease. Neuroscience letters 311, 1-4 (2001).
38 Wu, Y. R., Feng, I. H., Lyu, R. K., Chang, K. H., Lin, Y. Y., Chan, H., Hu, F. J., Lee-Chen, G. J. &; Chen, C. M. Tumor necrosis factor-alpha promoter polymorphism is associated with the risk of Parkinson's disease. American journal of medical genetics part b (neuropsychiatric genetics) 144B, 300-304 (2007).
39 Boka, G., Anglade, P., Wallach, D., Javoy-Agid, F., Agid, Y. &; Hirsch, E. C. Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease. Neuroscience letters 172, 151-154 (1994).
40 Mladenović, A., Perović, M., Raičević, N., Kanazir, S., Rakić, L. &; Ruždijić, S. 6-Hydroxydopamine increases the level of TNFα and bax mRNA in the striatum and induces apoptosis of dopaminergic neurons in hemiparkinsonian rats. Brain research 996, 237-245 (2004).
41 McCoy, M. K., Martinez, T. N., Ruhn, K. A., Szymkowski, D. E., Smith, C. G., Botterman, B. R., Tansey, K. E. &; Tansey, M. G. Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease. The journal of neuroscience 26, 9365-9375 (2006).
42 Mogi, M., Kondo, T., Mizuno, Y. &; Nagatsu, T. p53 protein, interferon-γ, and NF-κB levels are elevated in the parkinsonian brain. Neuroscience letters 414, 94-97 (2007).
43 Hunot, S., Brugg, B., Ricard, D., Michel, P. P., Muriel, M. P., Ruberg, M., Faucheux, B. A., Agid, Y. &; Hirsch, E. C. Nuclear translocation of NF-κB is increased in dopaminergic neurons of patients with Parkinson disease. Proceedings of the national academy of sciences 94, 7531-7536 (1997).
44 Fischer, R., Maier, O., Siegemund, M., Wajant, H., Scheurich, P. &; Pfizenmaier, K. A TNF receptor 2 selective agonist rescues human neurons from oxidative stress-induced cell death. PLoS One 6, e27621 (2011).
45 Perese, D. A., Ulman, J., Viola, J., Ewing, S. E. &; Bankiewicz, K. S. A 6-hydroxydopamine-induced selective parkinsonian rat model. Brain research 494, 285-293 (1989).
46 Ungerstedt, U. Adipsia and aphagia after 6-hydroxydopamine induced degeneration of the nigro-striatal dopamine system. Acta physiologica scandinavica. supplementum 367, 95-122 (1971).
47 Blandini, F., Armentero, M. T. &; Martignoni, E. The 6-hydroxydopamine model: news from the past. Parkinsonism &; related disorders 14 Suppl 2, S124-129 (2008).
48 Jeon, B. S., Jackson-Lewis, V. &; Burke, R. E. 6-Hydroxydopamine lesion of the rat substantia nigra: time course and morphology of cell death. Neurodegeneration 4, 131-137 (1995).
49 Przedborski, S., Vernice Jackson-Lewis, Ali B. Naini, Michael Jakowec, Giselle Petzinger, Miller, R. &; Akram, M. The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a technical review of its utility and safety. Journal of neurochemistry 76, 1265-1274 (2001).
50 Cohen, A. D., Tillerson, J. L., Smith, A. D., Schallert, T. &; Zigmond, M. J. Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF. Journal of neurochemistry 85, 299-305 (2003).
51 Mabandla, M., Kellaway, L., St. Clair Gibson, A. &; Russell, V. A. Voluntary running provides neuroprotection in rats after 6-Hydroxydopamine injection into the medial forebrain bundle. Metabolic brain disease 19, 43-50 (2004).
52 Tillerson, J. Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson's disease. Neuroscience 119, 899-911 (2003).
53 Meredith, G. E. &; Kang, U. J. Behavioral models of Parkinson's disease in rodents: a new look at an old problem. Movement disorders 21, 1595-1606 (2006).
54 Rozas, G., Guerra, M. J. &; Labandeira-Garc´ıa, J. L. An automated rotarod method for quantitative drug-free evaluation of overall motor deficits in rat models of parkinsonism. Brain research protocols 2, 75-84 (1997).
55 Dekundy, A., Lundblad, M., Danysz, W. &; Cenci, M. A. Modulation of L-DOPA-induced abnormal involuntary movements by clinically tested compounds: further validation of the rat dyskinesia model. Behavioural brain research 179, 76-89 (2007).
56 Lee, E. Y., Lee, J. E., Park, J. H., Shin, I. C. &; Koh, H. C. Rosiglitazone, a PPAR-gamma agonist, protects against striatal dopaminergic neurodegeneration induced by 6-OHDA lesions in the substantia nigra of rats. Toxicology letters 213, 332-344 (2012).
57 Sriram, K., Matheson, J. M., Benkovic, S. A., Miller, D. B., Luster, M. I. &; O’Callaghan, J. P. Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: Implications for Parkinson's disease. The FASEB journal 16, 1474-1494 (2002).
58 Scalzo, P., Kummer, A., Cardoso, F. &; Teixeira, A. L. Increased serum levels of soluble tumor necrosis factor-alpha receptor-1 in patients with Parkinson's disease. Journal of neuroimmunology 216, 122-125 (2009).
59 Grassi-Oliveira, R., Brietzke, E., Pezzi, J. C., Lopes, R. P., Teixeira, A. L. &; Bauer, M. E. Increased soluble tumor necrosis factor-alpha receptors in patients with major depressive disorder. Psychiatry and clinical neurosciences 63, 202-208 (2009).
60 Engelmann, H., Novick, D. &; Wallach, D. Two Tumor Necrosis Factor-binding Proteins Purified from human urine. The journal of biological chemistry 265, 1531-1536 (1990).
61 Mogi, M., Togari, A., Tanaka, K.-i., Ogawa, N., Ichinose, H. &; Nagatsu, T. Increase in level of tumor necrosis factor (TNF)-a in 6-hydroxydopamine-lesioned striatum in rats without influence of systemic L-DOPA on the TNF-a induction. Neuroscience letters 268, 101-104 (1999).
62 Mogi, M., Togari, A., Tanaka, K.-i., Ogawa, N., Ichinose, H. &; Nagatsu, T. Increase in level of tumor necrosis factor-a in 6-hydroxydopaminelesioned striatum in rats is suppressed by immunosuppressant FK506. Neuroscience letters 289, 165-168 (2000).
63 McGuire, S. O., Ling, Z. D., Lipton, J. W., Sortwell, C. E., Collier, T. J. &; Carvey, P. M. Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons. Experimental neurology 169, 219-230 (2001).
64 McCoy, M. K., Ruhn, K. A., Martinez, T. N., McAlpine, F. E., Blesch, A. &; Tansey, M. G. Intranigral Lentiviral Delivery of Dominant-negative TNF Attenuates Neurodegeneration and Behavioral Deficits in Hemiparkinsonian rats. Molecular therapy 16, 1572-1579 (2008).
65 Ginis I, S. U., Brenner M, Liu J, Azzam N, Spatz M, Hallenbeck JM. TNF-alpha pretreatment prevents subsequent activation of cultured brain cells with TNF-alpha and hypoxia via ceramide. American journal of physiology 276, 1171-1183 (1999).
66 De Lella Ezcurra, A. L., Chertoff, M., Ferrari, C., Graciarena, M. &; Pitossi, F. Chronic expression of low levels of tumor necrosis factor-alpha in the substantia nigra elicits progressive neurodegeneration, delayed motor symptoms and microglia/macrophage activation. Neurobiology of disease 37, 630-640 (2010).
67 Bette, M., Kaut, O., Schafer, M. K. &; Weihe, E. Constitutive expression of p55TNFR mRNA and mitogen-specific up-regulation of TNF alpha and p75TNFR mRNA in mouse brain. The journal of comparative neurology 465, 417-430 (2003).
68 Veroni, C., Gabriele, L., Canini, I., Castiello, L., Coccia, E., Remoli, M. E., Columba-Cabezas, S., Arico, E., Aloisi, F. &; Agresti, C. Activation of TNF receptor 2 in microglia promotes induction of anti-inflammatory pathways. Molecular and cellular neurosciences 45, 234-244 (2010).
69 Xiao, B. G., Lu, C. Z. &; Link, H. Cell biology and clinical promise of G-CSF: immunomodulation and neuroprotection. Journal of cellular and molecular medicine 11, 1272-1290 (2007).
70 Delgado, M. &; Ganea, D. Anti-inflammatory neuropeptides: a new class of endogenous immunoregulatory agents. Brain, behavior, and immunity 22, 1146-1151 (2008).
71 Annemarie Ledeboer, John J. P. BreveÂ, Anne Wierinckx, Saskia van der Jagt, Adrian F. Bristow, JoseÂe E. Leysen, Fred J. H. Tilders &; Dam, A.-M. V. Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. European journal of neuroscience 16, 1175-1185 (2002).
72 Tajiri, N., Yasuhara, T., Shingo, T., Kondo, A., Yuan, W., Kadota, T., Wang, F., Baba, T., Tayra, J. T., Morimoto, T., Jing, M., Kikuchi, Y., Kuramoto, S., Agari, T., Miyoshi, Y., Fujino, H., Obata, F., Takeda, I., Furuta, T. &; Date, I. Exercise exerts neuroprotective effects on Parkinson's disease model of rats. Brain research 1310, 200-207 (2010).
73 Yoon, M. C., Shin, M. S., Kim, T. S., Kim, B. K., Ko, I. G., Sung, Y. H., Kim, S. E., Lee, H. H., Kim, Y. P. &; Kim, C. J. Treadmill exercise suppresses nigrostriatal dopaminergic neuronal loss in 6-hydroxydopamine-induced Parkinson's rats. Neuroscience letters 423, 12-17 (2007).
74 Sung, Y. H., Kim, S. C., Hong, H. P., Park, C. Y., Shin, M. S., Kim, C. J., Seo, J. H., Kim, D. Y., Kim, D. J. &; Cho, H. J. Treadmill exercise ameliorates dopaminergic neuronal loss through suppressing microglial activation in Parkinson's disease mice. Life sciences 91, 1309-1316 (2012).
75 Poulton, N. P. &; Muir, G. D. Treadmill training ameliorates dopamine loss but not behavioral deficits in hemi-parkinsonian rats. Experimental neurology 193, 181-197 (2005).
76 Petzinger, G. M., Walsh, J. P., Akopian, G., Hogg, E., Abernathy, A., Arevalo, P., Turnquist, P., Vuckovic, M., Fisher, B. E., Togasaki, D. M. &; Jakowec, M. W. Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. The journal of neuroscience 27, 5291-5300 (2007).