進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-2601201703503300
論文名稱(中文) 利用離體與活體實驗探討厚朴酚與YC-1在缺血性中風的神經保護作用
論文名稱(英文) Neuroprotective effects of magnolol and YC-1 in ischemic stroke in vitro and in vivo
校院名稱 成功大學
系所名稱(中) 生物科技研究所
系所名稱(英) Institute of Biotechnology
學年度 105
學期 1
出版年 105
研究生(中文) 李威廷
研究生(英文) Wei-Ting Lee
學號 L68971045
學位類別 博士
語文別 中文
論文頁數 118頁
口試委員 指導教授-吳天賞
口試委員-李宜堅
口試委員-陳宗鷹
口試委員-蕭世裕
口試委員-陳鴻儀
中文關鍵字 中風  厚朴酚  YC-1  細胞內鈣離子  基質金屬蛋白酶  發炎反應 
英文關鍵字 ischemic stroke  magnolol  YC-1  intracellular calcium  matrix metalloproteinase, 
學科別分類
中文摘要 中風在世界上是相當重要的疾病,常會導致死亡及身體的失能。然而目前治療的方法僅能使用血栓溶解劑(tPA)與神經外科手術。因此需要發展更多的治療方式。這篇論文裡,我們的目的是評估厚朴酚與YC-1在中風後的神經保護效果。在缺血性損傷後利用劑量反應方式調查厚朴酚和YC-1的關鍵保護劑量,並探討厚朴酚和YC-1在中風傷害後的治療視窗。在厚朴酚與YC-1的神經保護能力研究,探討中風後後厚朴酚與YC-1是否可以抵抗麩胺酸所誘導的神經細胞死亡,腫脹以及細胞內鈣離子的增加。在YC-1的神經保護能力研究,我們也探討YC-1是否可以降低中風後所誘導NF-κB調控的發炎反應。我們的結果顯示,厚朴酚減少實驗動物中風後傷害程度並改善神經行為學表現直到中風後4小時使用厚朴酚進行治療仍具有保護作用。厚朴酚的神經保護能力可能是藉由減少麩胺酸以及N-甲基-D-天門冬胺酸誘導的神經毒性所達成。在YC-1的研究中顯示,YC-1對麩胺酸誘導的神經損傷和小鼠在暫時性局部腦缺血傷害中具有保護作用。所以它有治療的潛力,但必須在正確的治療時間使用是必要的。另外YC-1藉由抑制NF-κB的轉位及與DNA結合活性,有效減少中風後發炎反應並改善血腦壁障被破壞的程度。
英文摘要 Ischemic stroke is an important disease in the world and a leading cause of death and long-term disability. There remain only few treatment options, confined to thrombolysis (tPA) and neurosurgery. More widely applicable therapies are needed. In this thesis, we aimed to evaluate the neuroprotective efficacy of magnolol and YC-1 in vitro and in vivo. We investigated crucial neuroprotective effect in a dose-responsive manner of magnolol and YC-1 after ischemic injury. On the other hand, we also assessed the therapeutic window of magnolol and YC-1 after ischemic stroke. In addition, we evaluated the protective effects of both magnolol and YC-1 on cell injury, cell swelling and increased inflow of [Ca2+] (i) in cultured neurons after glutamate exposure. We also explored whether administration of YC-1 could reduce NF-κB-driven inflammatory response after ischemic stroke. In conclusion, magnolol has a therapeutic window up to 4 hrs after permanent focal cerebral ischemia. This neuroprotection may be by its ability to weaken the glutamate and NMDA-induced neurotoxicity. In addition, YC-1 offers neuroprotection against glutamate-induced neuronal damage and in mice received to transient focal cerebral ischemia. Although YC-1 provided potential for clinical therapy, but the right time for treatment was necessary. Moreover, YC-1 effectively reduced post-stroke inflammatory responses and ameliorated BBB permeability by inhibiting NF-κB binding activity and translocation against ischemic stroke.
論文目次 Table of Contents
Chinese Abstract (中文摘要).………………………………………………………… Ⅰ
Abstract........................................................................................................................... Ⅱ
Acknowledgements…………………………………………………………………… Ⅵ
Table of Contents………………………………………………………………….….. Ⅶ
Contents of Tables………………………………………………………………….…. Ⅹ
Contents of Figures…………………………………………………………………… ⅩⅠ
Abbreviation List…………….………………………………………………………... ⅩⅣ
Chapter 1 Research Background ……………………………………….....…….… 1
1-1 Pathophysiology and current status in treatment of ischemic stroke…..… 1
1-2 Mechanisms of cell death after ischemia…………….…………………... 3
1-3 Post-ischemic inflammation………………………………..…………….. 6
1-4 Magnolol is a potential neuroprotective agent for ischemic injuries….…. 10
1-5 YC-1 is a potential neuroprotective agent for ischemic injuries…………. 11
1-6 Thesis aims………………………………………………………….......... 12
Chapter 2 Materials and Methods……………………………..…………..………. 13
2-1 Primary cortical neuronal culture……………………….……………….. 13
2-2 Neurotoxicity of magnolol………………………………………………. 14
2-3 Neurotoxicity of YC-1…………………………………………………… 14
2-4 Glutamate- and N-methyl-D-aspartate (NMDA)-induced cell cytotoxicity 14
2-5 Oxygen and glucose deprivation (OGD)…………..…………..………..... 15
2-6 Cell swelling measurements………………………………...…..………... 15
2-7 Intracellular Ca2+ measurement………………………………………….. 16
2-8 Intracellular pH measurement…………………………………………..... 18
2-9 Electrophoretic mobility shift assay (EMSA)……………………............. 19
2-10 Gelatin zymography…………………………………………………….... 19
2-11 Western immunoblot assay………………………………………………. 20
2-12 Animal experimental model for Sprague-Dawley rats……………………. 21
2-13 Animal experimental model for C57 black (C57BL/B6) mice………........ 24
2-14 Immunofluorescence stain……………………………………………….. 27
2-15 Immunohistochemistry stain……………………………………………... 28
2-16 Measurement of blood brain barrier disruption…………………………... 28
2-17 Statistical analysis………………………………………………………... 29
Chapter 3 Magnolol reduces glutamate-induced neuronal excitotoxicity and protects against focal cerebral ischemia................................................. 30
3-1 Introduction................................................................................................. 30
3-2 Results......................................................................................................... 31
3-3 Discussion……………………………………………………………...… 35
3-4 Summary……………………………………………………………….… 38
Chapter 4 YC-1 reduces glutamate-induced neuronal excitotoxicity and
protects against focal cerebral ischemia…………………………….... 39
4-1 Introduction……………………………………………………………… 39
4-2 Results…………………………………………………………..….……. 41
4-3 Discussion................................................................................................... 44
4-4 Summary..................................................................................................... 49
Chapter 5 YC-1 reduces inflammatory responses after ischemic stroke……..... 50
5-1 Introduction……………………………………………………………… 50
5-2 Results…………………………………………………………….……... 53
5-3 Discussion................................................................................................... 56
5-4 Summary..................................................................................................... 58
Chapter 6 Conclusion………………………………………………………….…… 60
References....................................................................................................................... 62
Tables.............................................................................................................................. 77
Figures............................................................................................................................ 83
Related Paper Publications.......................................................................................... 119

Contents of Tables
Table 1. Physiologic parameters before (preocclusion) and after (postocclusion)
in rats subjected to permanent middle cerebral artery occlusion…………. 78
Table 2. The changes of core temperatures obtained in rats subjected to permanent
middle cerebral artery occlusion.................................................................. 79
Table 3. Neurobehavioral scores and body weight loss obtained in rats after
permanent middle cerebral artery occlusion in each pretreatment group.... 80
Table 4. Neurobehavioral scores and body weight loss obtained in rats after
permanent middle cerebral artery occlusion in each posttreatment group.. 81
Table 5. Neurobehavioral scores and body weight loss obtained in mice after
transient middle cerebral artery occlusion in each pretreatment group….. 82


Contents of Figures
Figure 1. Neurotoxicity of magnolol in primary cortical neuronal cultures………… 84
Figure 2. Magnolol achieved potent cytoprotection against glutamate-induced
neuronal damage………………………………………………………….. 85
Figure 3. Magnolol achieved potent cytoprotection against NMDA-induced
neuronal damage……………...……………………………………........... 87
Figure 4. Magnolol attenuated glutamate-induced rises in the intracellular calcium,
[Ca2+](i), inflow in cultured neurons……...……………………………… 89
Figure 5. Magnolol attenuated glutamate-induced cell swelling in cultured neurons. 91
Figure 6. Magnolol reduced brain infarction in rats subjected to permanent middle
cerebral artery (pMCAO) occlusion in pretreatment group…...…….......... 92
Figure 7. Therapeutic window for magnolol following rats subjected to permanent
middle cerebral artery (pMCAO) occlusion in posttreatment group……... 93
Figure 8. Neurotoxicity of YC-1 in primary cortical neuronal cultures…………….. 94
Figure 9. YC-1 achieved potent cytoprotection against glutamate-induced neuronal
damage......................................................................................................... 95
Figure 10. Therapeutic window for YC-1 in primary cortical neuronal cultures
exposed to glutamate-induced excitotoxicity……..…………………..….. 97
Figure 11. Delayed treatment YC-1 at 4 hrs attenuated glutamate-induced cell
swelling in cultured neurons……………………………………..…......... 99
Figure 12. YC-1 reduced ischemic brain infarction and edema in mice after transient
focal cerebral ischemia................................................................................. 100
Figure 13. Therapeutic window for YC-1 following mice subjected to transient
middle cerebral artery occlusion (MCAO)…………………………......... 101
Figure 14. YC-1 attenuated glutamate-induced rises in the intracellular calcium,
[Ca2+](i), inflow in cultured neurons………………………..…….……… 103
Figure 15. Immediately treatment with YC-1 after glutamate exposure caused intracellular pH drastic change………….………..……..……………...... 104
Figure 16. YC-1 decreased phosphorylation of IκB and nuclear factor-kappa B
translocation in cortical neuronal cultures................................................. 106
Figure 17. YC-1 decreased nuclear factor-kappa B binding activity in cortical
neuronal cultures........................................................................................ 107
Figure 18. YC-1 decreased phosphorylation of IκB and nuclear factor-kappa B
translocation in mice subjected to transient focal cerebral ischemia……. 108
Figure 19. YC-1 reduced iNOS positive cells in the ischemic brain.......................... 111
Figure 20. YC-1 reduced activated neutrophils infiltration in the ischemic brain...... 112
Figure 21. YC-1 reduced activated microglia/macrophages infiltration in the
ischemic brain............................................................................................ 113
Figure 22. YC-1 reduced MMP-9 activity in cortical neuronal cultures..................... 115
Figure 23. YC-1 reduced MMP-9 activity in mice after ischemic stroke.................... 115
Figure 24. YC-1 reduced MMP-9 expression in the ischemic brain........................... 117
Figure 25. YC-1 remarkably ameliorated blood-brain barrier disruption in mice
after ischemic stroke.................................................................................. 118
參考文獻 References
Abe, K., Aoki, M., Kawagoe, J., Yoshida, T., Hattori, A., Kogure, K., and Itoyama, Y. Ischemic delayed neuronal death. A mitochondrial hypothesis. Stroke; a Journal of Cerebral Circulation 26, 1478-1489, 1995.

Abeti, R., and Abramov, A. Y. Mitochondrial Ca(2+) in neurodegenerative disorders. Pharmacological Research 99, 377-381, 2015.

Allan, S. M., and Rothwell, N. J. Cytokines and acute neurodegeneration. Nature Reviews. Neuroscience 2, 734-744, 2001.

Araki, E., Forster, C., Dubinsky, J. M., Ross, M. E., and Iadecola, C. Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity. Stroke; a Journal of Cerebral Circulation 32, 2370-2375, 2001.

Arimoto, T., and Bing, G. Up-regulation of inducible nitric oxide synthase in the substantia nigra by lipopolysaccharide causes microglial activation and neurodegeneration. Neurobiology of Disease 12, 35-45, 2003.

Beckman, J. S. Oxidative damage and tyrosine nitration from peroxynitrite. Chemical Research in Toxicology 9, 836-844, 1996.

Bond, M., Chase, A. J., Baker, A. H., and Newby, A. C. Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cells. Cardiovascular Research 50, 556-565, 2001.

Burnstock, G. Purinergic signalling and disorders of the central nervous system. Nature Reviews. Drug Discovery 7, 575-590, 2008.

Busa, W. B., and Nuccitelli, R. Metabolic regulation via intracellular pH. The American Journal of Physiology 246, 409-438, 1984.

Carden, D. L., and Granger, D. N. Pathophysiology of ischaemia-reperfusion injury. The Journal of Pathology 190, 255-266, 2000.

Ceulemans, A. G., Zgavc, T., Kooijman, R., Hachimi-Idrissi, S., Sarre, S., and Michotte, Y. The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. Journal of Neuroinflammation 7, 74, 2010.

Chan, P. H. Reactive oxygen radicals in signaling and damage in the ischemic brain. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 21, 2-14, 2001.

Chang, C. C., Tien, C. H., Lee, E. J., Juan, W. S., Chen, Y. H., Hung, Y. C., Chen, T. Y., Chen, H. Y., and Wu, T. S. Melatonin inhibits matrix metalloproteinase-9 (MMP-9) activation in the lipopolysaccharide (LPS)-stimulated RAW 264.7 and BV2 cells and a mouse model of meningitis. Journal of Pineal Research 53, 188-197, 2012.

Chang, C. P., Hsu, Y. C., and Lin, M. T. Magnolol protects against cerebral ischaemic injury of rat heatstroke. Clinical and Experimental Pharmacology and Physiology 30, 387-392, 2003.

Chen, C., Ostrowski, R. P., Zhou, C., Tang, J., and Zhang, J. H. Suppression of hypoxia-inducible factor-1alpha and its downstream genes reduces acute hyperglycemia-enhanced hemorrhagic transformation in a rat model of cerebral ischemia. Journal of Neuroscience Research 88, 2046-2055, 2010.

Chen, H. Y., Hung, Y. C., Chen, T. Y., Huang, S. Y., Wang, Y. H., Lee, W. T., Wu, T. S., and Lee, E. J. Melatonin improves presynaptic protein, SNAP-25, expression and dendritic spine density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats. Journal of Pineal Research 47, 260-270, 2009.

Chen, H. Y., Hung, Y. C., Lee, E. J., Chen, T. Y., Chuang, I. C., and Wu, T. S. The protective efficacy of magnolol in hind limb ischemia-reperfusion injury. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology 16, 976-981, 2009.

Chen, T. Y., Lin, M. H., Lee, W. T., Huang, S. Y., Chen, Y. H., Lee, A. C., Lin, H. W., and Lee, E. J. Nicotinamide inhibits nuclear factor-kappa B translocation after transient focal cerebral ischemia. Critical Care Medicine 40, 532-537, 2012.

Chen, T. Y., Tai, S. H., Lee, E. J., Huang, C. C., Lee, A. C., Huang, S. Y., and Wu, T. S. Cinnamophilin offers prolonged neuroprotection against gray and white matter damage and improves functional and electrophysiological outcomes after transient focal cerebral ischemia. Critical Care Medicine 39, 1130-1137, 2011.

Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623-634, 1988.

Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijevic, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N., Smith, A. C., Eyassu, F., Shirley, R., Hu, C. H., Dare, A. J., James, A. M., Rogatti, S., Hartley, R. C., Eaton, S., Costa, A. S., Brookes, P. S., Davidson, S. M., Duchen, M. R., Saeb-Parsy, K., Shattock, M. J., Robinson, A. J., Work, L. M., Frezza, C., Krieg, T., and Murphy, M. P. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431-435, 2014.

Chun, Y. S., Yeo, E. J., Choi, E., Teng, C. M., Bae, J. M., Kim, M. S., and Park, J. W. Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochemical Pharmacology 61, 947-954, 2001.

Clemens, J. A. Cerebral ischemia: gene activation, neuronal injury, and the protective role of antioxidants. Free Radical Biology and Medicine 28, 1526-1531, 2000.

DeLorenzo, R. J., Sun, D. A., Blair, R. E., and Sombati, S. An in vitro model of stroke-induced epilepsy: elucidation of the roles of glutamate and calcium in the induction and maintenance of stroke-induced epileptogenesis. International Review of Neurobiology 81, 59-84, 2007.

Demaerschalk, B. M., and Yip, T. R. Economic benefit of increasing utilization of intravenous tissue plasminogen activator for acute ischemic stroke in the United States. Stroke; a Journal of Cerebral Circulation 36, 2500-2503, 2005.

DeNiro, M., Alsmadi, O., and Al-Mohanna, F. Modulating the hypoxia-inducible factor signaling pathway as a therapeutic modality to regulate retinal angiogenesis. Experimental Eye Research 89, 700-717, 2009.

Dubinsky, J. M. Intracellular calcium levels during the period of delayed excitotoxicity. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 13, 623-631, 1993.

Dziedzic, T. Systemic inflammation as a therapeutic target in acute ischemic stroke. Expert Review of Neurotherapeutics 15, 523-531, 2015.

Erecinska, M., and Silver, I. A. ATP and brain function. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 9, 2-19, 1989.

Fan, J., Vasuta, O. C., Zhang, L. Y., Wang, L., George, A., and Raymond, L. A. N-methyl-D-aspartate receptor subunit- and neuronal-type dependence of excitotoxic signaling through post-synaptic density 95. Journal of Neurochemistry 115, 1045-1056, 2010.

Fann, D. Y., Lee, S. Y., Manzanero, S., Chunduri, P., Sobey, C. G., and Arumugam, T. V. Pathogenesis of acute stroke and the role of inflammasomes. Ageing Research Reviews 12, 941-966, 2013.

Flynn, R. W., MacWalter, R. S., and Doney, A. S. The cost of cerebral ischaemia. Neuropharmacology 55, 250-256, 2008.

Forstermann, U., Boissel, J. P., and Kleinert, H. Expressional control of the 'constitutive' isoforms of nitric oxide synthase (NOS I and NOS III). FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 12, 773-790, 1998.

Friebe, A., and Koesling, D. Mechanism of YC-1-induced activation of soluble guanylyl cyclase. Molecular Pharmacology 53, 123-127, 1998.

Fukuyama, N., Takizawa, S., Ishida, H., Hoshiai, K., Shinohara, Y., and Nakazawa, H. Peroxynitrite formation in focal cerebral ischemia-reperfusion in rats occurs predominantly in the peri-infarct region. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 18, 123-129, 1998.

Garcia-Bonilla, L., Moore, J. M., Racchumi, G., Zhou, P., Butler, J. M., Iadecola, C., and Anrather, J. Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. Journal of Immunology 193, 2531-2537, 2014.

Gasche, Y., Copin, J. C., Sugawara, T., Fujimura, M., and Chan, P. H. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 21, 1393-1400, 2001.

Giorgio, V., von Stockum, S., Antoniel, M., Fabbro, A., Fogolari, F., Forte, M., Glick, G. D., Petronilli, V., Zoratti, M., Szabo, I., Lippe, G., and Bernardi, P. Dimers of mitochondrial ATP synthase form the permeability transition pore. Proceedings of the National Academy of Sciences of the United States of America 110, 5887-5892, 2013.

Gradia, S., Acharya, S., and Fishel, R. The role of mismatched nucleotides in activating the hMSH2-hMSH6 molecular switch. The Journal of Biological Chemistry 275, 3922-3930, 2000.

Grimm, S., and Baeuerle, P. A. The inducible transcription factor NF-kappa B: structure-function relationship of its protein subunits. The Biochemical Journal 290 ( Pt 2), 297-308, 1993.

Grynkiewicz, G., Poenie, M., and Tsien, R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. The Journal of Biological Chemistry 260, 3440-3450, 1985.

Hall, C. N., Reynell, C., Gesslein, B., Hamilton, N. B., Mishra, A., Sutherland, B. A., O'Farrell, F.M., Buchan, A. M., Lauritzen, M., and Attwell, D. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55-60, 2014.

Hamann, G. F., Okada, Y., Fitridge, R., and del Zoppo, G. J. Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke; a Journal of Cerebral Circulation 26, 2120-2126, 1995.

Haraguchi, H., Ishikawa, H., Shirataki, N., and Fukuda, A. Antiperoxidative activity of neolignans from Magnolia obovata. The Journal of Pharmacy and Pharmacology 49, 209-212, 1997.

Hatfield, R. H., Gill, R., and Brazell, C. The dose-response relationship and therapeutic window for dizocilpine (MK-801) in a rat focal ischaemia model. European Journal of Pharmacology 216, 1-7, 1992.

Hedrick, M. S., Fahlman, C. S., and Bickler, P. E. Intracellular calcium and survival of tadpole forebrain cells in anoxia. The Journal of Experimental Biology 208, 681-686, 2005.

Hsiao, G., Huang, H. Y., Fong, T. H., Shen, M. Y., Lin, C. H., Teng, C. M., and Sheu, J. R. Inhibitory mechanisms of YC-1 and PMC in the induction of iNOS expression by lipoteichoic acid in RAW 264.7 macrophages. Biochemical Pharmacology 67, 1411-1419, 2004.

Hsieh, M. T., Chueh, F. Y., and Lin, M. T. Magnolol decreases body temperature by reducing 5-hydroxytryptamine release in the rat hypothalamus. Clinical and Experimental Pharmacology and Physiology 25, 813-817, 1998.

Huang, J., Choudhri, T. F., Winfree, C. J., McTaggart, R. A., Kiss, S., Mocco, J., Kim, L. J., Protopsaltis, T. S., Zhang, Y., Pinsky, D. J., and Connolly, E. S., Jr. Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke. Stroke; a Journal of Cerebral Circulation 31, 3047-3053, 2000.

Huang, Y. T., Pan, S. L., Guh, J. H., Chang, Y. L., Lee, F. Y., Kuo, S. C., and Teng, C. M. YC-1 suppresses constitutive nuclear factor-kappaB activation and induces apoptosis in human prostate cancer cells. Molecular Cancer Therapeutics 4, 1628-1635, 2005.

Hung, Y. C., Chen, T. Y., Lee, E. J., Chen, W. L., Huang, S. Y., Lee, W. T., Lee, M. Y., Chen, H. Y., and Wu, T. S. Melatonin decreases matrix metalloproteinase-9 activation and expression and attenuates reperfusion-induced hemorrhage following transient focal cerebral ischemia in rats. Journal of Pineal Research 45, 459-467, 2008.

Hunot, S., Boissiere, F., Faucheux, B., Brugg, B., Mouatt-Prigent, A., Agid, Y., and Hirsch, E. C. Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience 72, 355-363, 1996.

Iadecola, C., and Alexander, M. Cerebral ischemia and inflammation. Current Opinion in Neurology 14, 89-94, 2001.

Iadecola, C., and Anrather, J. The immunology of stroke: from mechanisms to translation. Nature Medicine 17, 796-808, 2011.

Ito, H., Kanno, I., Ibaraki, M., Hatazawa, J., and Miura, S. Changes in human cerebral blood flow and cerebral blood volume during hypercapnia and hypocapnia measured by positron emission tomography. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 23, 665-670, 2003.

Jiang, N., Wu, J., Leng, T., Yang, T., Zhou, Y., Jiang, Q., Wang, B., Hu, Y., Ji, Y. H., Simon, R. P., Chu, X.P., Xiong, Z. G., and Zha, X. M. Region specific contribution of ASIC2 to acidosis-and ischemia-induced neuronal injury. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism pii: 0271678X16630558, 2016.

Kader, A., Brisman, M. H., Maraire, N., Huh, J. T., and Solomon, R. A. The effect of mild hypothermia on permanent focal ischemia in the rat. Neurosurgery 31, 1056-1060, 1992.

Kim, J. Y., Kawabori, M., and Yenari, M. A. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets. Current Medicinal Chemistry 21, 2076-2097, 2014.

Kreutzberg, G. W. Microglia: a sensor for pathological events in the CNS. Trends in Neurosciences 19, 312-318, 1996.

Le, W., Rowe, D., Xie, W., Ortiz, I., He, Y., and Appel, S. H. Microglial activation and dopaminergic cell injury: an in vitro model relevant to Parkinson's disease. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 21, 8447-8455, 2001.

Lee, E. J., Chen, H. Y., Hung, Y. C., Chen, T. Y., Lee, M. Y., Yu, S. C., Chen, Y. H., Chuang, I. C., and Wu, T. S. Therapeutic window for cinnamophilin following oxygen-glucose deprivation and transient focal cerebral ischemia. Experimental Neurology 217, 74-83, 2009.

Lee, E. J., Chen, H. Y., Lee, M. Y., Chen, T. Y., Hsu, Y. S., Hu, Y. L., Chang, G. L., and Wu, T. S. Cinnamophilin reduces oxidative damage and protects against transient focal cerebral ischemia in mice. Free Radical Biology and Medicine 39, 495-510, 2005.

Lee, E. J., Chen, H. Y., Wu, T. S., Chen, T. Y., Ayoub, I. A., and Maynard, K. I. Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats. Journal of Neuroscience Research 68, 636-645, 2002.

Lee, E. J., Hung, Y. C., Chen, H. Y., Wu, T. S., and Chen, T. Y. Delayed treatment with carboxy-PTIO permits a 4-h therapeutic window of opportunity and prevents against ischemia-induced energy depletion following permanent focal cerebral ischemia in mice. Neurochemical Research 34, 1157-1166, 2009.

Lee, M. M., Hseih, M. T., Kuo, J. S., Yeh, F. T., and Huang, H. M. Magnolol protects cortical neuronal cells from chemical hypoxia in rats. Neuroreport 9, 3451-3456, 1998.

Lee, W. T., Lin, M. H., Lee, E. J., Hung, Y. C., Tai, S. H., Chen, H. Y., Chen, T. Y., and Wu, T. S. Magnolol reduces glutamate-induced neuronal excitotoxicity and protects against permanent focal cerebral ischemia up to 4 hours. PLoS One 7, e39952, 2012.

Lemasters, J. J., Nieminen, A. L., Qian, T., Trost, L. C., and Herman, B. The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury. Molecular and Cellular Biochemistry 174, 159-165, 1997.

Li, M. H., Leng, T. D., Feng, X. C., Yang, T., Simon, R. P., and Xiong, Z. G. Modulation of Acid-sensing Ion Channel 1a by Intracellular pH and Its Role in Ischemic Stroke. The Journal of Biological Chemistry 291, 18370-18383, 2016.

Lin, S. P., Tsai, S. Y., Lee Chao, P. D., Chen, Y. C., and Hou, Y. C. Pharmacokinetics, bioavailability, and tissue distribution of magnolol following single and repeated dosing of magnolol to rats. Planta Medica 77, 1800-1805, 2011.

Lin, S. Y., Chang, Y. T., Liu, J. D., Yu, C. H., Ho, Y. S., Lee, Y. H., and Lee, W. S. Molecular mechanisms of apoptosis induced by magnolol in colon and liver cancer cells. Molecular Carcinogenesis 32, 73-83, 2001.

Lin, Y. R., Chen, H. H., Ko, C. H., and Chan, M. H. Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage. European Journal of Pharmacology 537, 64-69, 2006.

Lipton, P. Ischemic cell death in brain neurons. Physiological Reviews 79, 1431-1568, 1999.

Liu, B., and Hong, J. S. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. The Journal of Pharmacology and Experimental Therapeutics 304, 1-7, 2003.

Liu, Y. N., Pan, S. L., Peng, C. Y., Guh, J. H., Huang, D. M., Chang, Y. L., Lin, C. H., Pai, H. C., Kuo, S. C., Lee, F. Y., and Teng, C. M. YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole] inhibits neointima formation in balloon-injured rat carotid through suppression of expressions and activities of matrix metalloproteinases 2 and 9. The Journal of Pharmacology and Experimental Therapeutics 316, 35-41, 2006.

Lo, E. H., Moskowitz, M. A., and Jacobs, T. P. Exciting, radical, suicidal: how brain cells die after stroke. Stroke; a Journal of Cerebral Circulation 36, 189-192, 2005.

Lu, D. Y., Tang, C. H., Liou, H. C., Teng, C. M., Jeng, K. C., Kuo, S. C., Lee, F. Y., and Fu, W. M. YC-1 attenuates LPS-induced proinflammatory responses and activation of nuclear factor-kappaB in microglia. British Journal of Pharmacology 151, 396-405, 2007.

Maier, C. M., Ahern, K., Cheng, M. L., Lee, J. E., Yenari, M. A., and Steinberg, G. K. Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke; a Journal of Cerebral Circulation 29, 2171-2180, 1998.

Mari, Y., Katnik, C., and Cuevas, J. ASIC1a channels are activated by endogenous protons during ischemia and contribute to synergistic potentiation of intracellular Ca(2+) overload during ischemia and acidosis. Cell Calcium 48, 70-82, 2010.

Markgraf, C. G., Velayo, N. L., Johnson, M. P., McCarty, D. R., Medhi, S., Koehl, J. R., Chmielewski, P. A., and Linnik, M. D. Six-hour window of opportunity for calpain inhibition in focal cerebral ischemia in rats. Stroke; a Journal of Cerebral Circulation 29, 152-158, 1998.

McGeer, P. L., Itagaki, S., Boyes, B. E., and McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285-1291, 1988.

Minghetti, L. Role of COX-2 in inflammatory and degenerative brain diseases. Sub-Cellular Biochemistry 42, 127-141, 2007.

Minghetti, L., Walsh, D. T., Levi, G., and Perry, V.H. In vivo expression of cyclooxygenase-2 in rat brain following intraparenchymal injection of bacterial endotoxin and inflammatory cytokines. Journal of Neuropathology and Experimental Neurology 58, 1184-1191, 1999.

Moncada, S., Palmer, R. M., and Higgs, E. A. Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochemical Pharmacology 38, 1709-1715, 1989.

Musazzi, L., Racagni, G., and Popoli, M. Stress, glucocorticoids and glutamate release: effects of antidepressant drugs. Neurochemistry International 59, 138-149, 2011.

Mutch, W. A., and Hansen, A. J. Extracellular pH changes during spreading depression and cerebral ischemia: mechanisms of brain pH regulation. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 4, 17-27, 1984.

Nielsen, S., Nagelhus, E. A., Amiry-Moghaddam, M., Bourque, C., Agre, P., and Ottersen, O.P. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 17, 171-180, 1997.

O'Bryant, Z., Vann, K. T., and Xiong, Z. G. Translational strategies for neuroprotection in ischemic stroke--focusing on acid-sensing ion channel 1a. Translational Stroke Research 5, 59-68, 2014.

Oikonomidi, S., Kostikas, K., Tsilioni, I., Tanou, K., Gourgoulianis, K. I., and Kiropoulos, T.S. Matrix metalloproteinases in respiratory diseases: from pathogenesis to potential clinical implications. Current Medicinal Chemistry 16, 1214-1228, 2009.

Pan, S. L., Guh, J. H., Peng, C. Y., Chang, Y. L., Cheng, F. C., Chang, J. H., Kuo, S. C., Lee, F. Y., and Teng, C. M. A potential role of YC-1 on the inhibition of cytokine release in peripheral blood mononuclear leukocytes and endotoxemic mouse models. Thrombosis and Haemostasis 93, 940-948, 2005.

Papadia, S., Soriano, F. X., Leveille, F., Martel, M. A., Dakin, K. A., Hansen, H. H., Kaindl, A., Sifringer, M., Fowler, J., Stefovska, V., McKenzie, G., Craigon, M., Corriveau, R., Ghazal, P., Horsburgh, K., Yankner, B. A., Wyllie, D. J., Ikonomidou, C., and Hardingham, G. E. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nature Neuroscience 11, 476-487, 2008.

Papadia, S., Stevenson, P., Hardingham, N. R., Bading, H., and Hardingham, G. E. Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 25, 4279-4287, 2005.

Paschen, W. Role of calcium in neuronal cell injury: which subcellular compartment is involved? Brain Research Bulletin 53, 409-413, 2000.

Ramos, E., Patino, P., Reiter, R. J., Gil-Martin, E., Marco-Contelles, J., Parada, E., Los Rios, C., Romero, A., and Egea, J. Ischemic brain injury: New insights on the protective role of melatonin. Free Radical Biology and Medicine 104, 32-53, 2017.

Rash, J. E., Yasumura, T., Hudson, C. S., Agre, P., and Nielsen, S. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proceedings of the National Academy of Sciences of the United States of America 95, 11981-11986, 1998.

Reynolds, I. J., and Hastings, T. G. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 15, 3318-3327, 1995.

Ridder, D. A., and Schwaninger, M. NF-kappaB signaling in cerebral ischemia. Neuroscience 158, 995-1006, 2009.

Ridenour, T. R., Warner, D. S., Todd, M. M., and McAllister, A. C. Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats. Stroke; a Journal of Cerebral Circulation 23, 733-738, 1992.

Ritz, M. F., Curin, Y., Mendelowitsch, A., and Andriantsitohaina, R. Acute treatment with red wine polyphenols protects from ischemia-induced excitotoxicity, energy failure and oxidative stress in rats. Brain Research 1239, 226-234, 2008.

Rothman, S. M., and Olney, J. W. Glutamate and the pathophysiology of hypoxic--ischemic brain damage. Annals of Neurology 19, 105-111, 1986.

Savage, C. D., Lopez-Castejon, G., Denes, A., and Brough, D. NLRP3-Inflammasome Activating DAMPs Stimulate an Inflammatory Response in Glia in the Absence of Priming Which Contributes to Brain Inflammation after Injury. Frontiers in Immunology 3, 288, 2012.

Savman, K., Heyes, M. P., Svedin, P., and Karlsson, A. Microglia/macrophage-derived inflammatory mediators galectin-3 and quinolinic acid are elevated in cerebrospinal fluid from newborn infants after birth asphyxia. Translational Stroke Research 4, 228-235, 2013.

Sheldon, A. L., and Robinson, M. B. The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochemistry International 51, 333-355, 2007.

Shichita, T., Sugiyama, Y., Ooboshi, H., Sugimori, H., Nakagawa, R., Takada, I., Iwaki, T., Okada, Y., Iida, M., Cua, D. J., Iwakura, Y., and Yoshimura, A. Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury. Nature Medicine 15, 946-950, 2009.

Siesjo, B. K. Cell damage in the brain: a speculative synthesis. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 1, 155-185, 1981.

Siesjo, B. K. Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment. Journal of Neurosurgery 77, 337-354, 1992.

Singh, M. H., Brooke, S. M., Zemlyak, I., and Sapolsky, R. M. Evidence for caspase effects on release of cytochrome c and AIF in a model of ischemia in cortical neurons. Neuroscience Letters 469, 179-183, 2010.

Strbian, D., Karjalainen-Lindsberg, M. L., Tatlisumak, T., and Lindsberg, P. J. Cerebral mast cells regulate early ischemic brain swelling and neutrophil accumulation. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism 26, 605-612, 2006.

Sun, B. Z., Chen, L., Wu, Q., Wang, H. L., Wei, X. B., Xiang, Y. X., and Zhang, X. M. Suppression of inflammatory response by flurbiprofen following focal cerebral ischemia involves the NF-kappaB signaling pathway. International Journal of Clinical and Experimental Medicine 7, 3087-3095, 2014.

Sun, H. L., Liu, Y. N., Huang, Y. T., Pan, S. L., Huang, D. Y., Guh, J. H., Lee, F. Y., Kuo, S. C., and Teng, C. M. YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia. Oncogene 26, 3941-3951, 2007.

Szatkowski, M., and Attwell, D. Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends in Neurosciences 17, 359-365, 1994.

Tai, S. H., Chen, H. Y., Lee, E. J., Chen, T. Y., Lin, H. W., Hung, Y. C., Huang, S. Y., Chen, Y. H., Lee, W. T., and Wu, T. S. Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia. Journal of Pineal Research 49, 332-341, 2010.

Tai, S. H., Hung, Y. C., Lee, E. J., Lee, A. C., Chen, T. Y., Shen, C. C., Chen, H. Y., Lee, M. Y., Huang, S. Y., and Wu, T. S. Melatonin protects against transient focal cerebral ischemia in both reproductively active and estrogen-deficient female rats: the impact of circulating estrogen on its hormetic dose-response. Journal of Pineal Research 50, 292-303, 2011.

Tait, M. J., Saadoun, S., Bell, B. A., and Papadopoulos, M. C. Water movements in the brain: role of aquaporins. Trends in Neurosciences 31, 37-43, 2008.

Teng, C. M., Yu, S. M., Chen, C. C., Huang, Y. L., and Huang, T. F. EDRF-release and Ca+(+)-channel blockade by magnolol, an antiplatelet agent isolated from Chinese herb Magnolia officinalis, in rat thoracic aorta. Life Sciences 47, 1153-1161, 1990.

Trenholm, S., and Baldridge, W. H. The effect of aminosulfonate buffers on the light responses and intracellular pH of goldfish retinal horizontal cells. Journal of Neurochemistry 115, 102-111, 2010.

Vidale, S., Consoli, A., Arnaboldi, M., and Consoli, D. Postischemic Inflammation in Acute Stroke. Journal of Clinical Neurology 13, 1-9, 2017.

von Hanwehr, R., Smith, M. L., and Siesjo, B. K. Extra- and intracellular pH during near-complete forebrain ischemia in the rat. Journal of Neurochemistry 46, 331-339, 1986.

Wang, C. P., Li, J. L., Zhang, L. Z., Zhang, X. C., Yu, S., Liang, X. M., Ding, F., and Wang, Z. W. Isoquercetin protects cortical neurons from oxygen-glucose deprivation-reperfusion induced injury via suppression of TLR4-NF-small ka, CyrillicB signal pathway. Neurochemistry International 63, 741-749, 2013.

Wang, J. P., Chang, L. C., Raung, S. L., Hsu, M. F., Huang, L. J., and Kuo, S. C. Inhibition of superoxide anion generation by YC-1 in rat neutrophils through cyclic GMP-dependent and -independent mechanisms. Biochemical Pharmacology 63, 577-585, 2002.

Wang, Q., Tang, X. N., and Yenari, M. A. The inflammatory response in stroke. Journal of Neuroimmunology 184, 53-68, 2007.

Wang, W. Z., Chu, X. P., Li, M. H., Seeds, J., Simon, R. P., and Xiong, Z. G. Modulation of acid-sensing ion channel currents, acid-induced increase of intracellular Ca2+, and acidosis-mediated neuronal injury by intracellular pH. The Journal of Biological Chemistry 281, 29369-29378, 2006.

Watanabe, K., Watanabe, H., Goto, Y., Yamaguchi, M., Yamamoto, N., and Hagino, K. Pharmacological properties of magnolol and honokiol extracted from Magnolia officinalis: central depressant effects. Planta Medica 49, 103-108, 1983.

Williams, D. A., and Fay, F. S. Intracellular calibration of the fluorescent calcium indicator Fura-2. Cell Calcium 11, 75-83, 1990.

Wu, C. C., Ko, F. N., Kuo, S. C., Lee, F. Y., and Teng, C. M. YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase. British Journal of Pharmacology 116, 1973-1978, 1995.

Xiong, Z. G., Zhu, X. M., Chu, X. P., Minami, M., Hey, J., Wei, W. L., MacDonald, J. F., Wemmie, J. A., Price, M. P., Welsh, M. J., and Simon, R. P. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118, 687-698, 2004.

Yan, J., Zhou, B., Taheri, S., and Shi, H. Differential effects of HIF-1 inhibition by YC-1 on the overall outcome and blood-brain barrier damage in a rat model of ischemic stroke. PLoS One 6, e27798, 2011.

Yanamoto, H., Nagata, I., Niitsu, Y., Zhang, Z., Xue, J. H., Sakai, N., and Kikuchi, H. Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia. Stroke; a Journal of Cerebral Circulation 32, 232-239, 2001.

Yang, X., Wang, Y., Luo, J., Liu, S., and Yang, Z. Protective effects of YC-1 against glutamate induced PC12 cell apoptosis. Cellular and Molecular Neurobiology 31, 303-311, 2011.

Yuan, L. B., Dong, H. L., Zhang, H. P., Zhao, R. N., Gong, G., Chen, X. M., Zhang, L. N., and Xiong, L. Neuroprotective effect of orexin-A is mediated by an increase of hypoxia-inducible factor-1 activity in rat. Anesthesiology 114, 340-354, 2011.

Zador, Z., Stiver, S., Wang, V., and Manley, G. T. Role of aquaporin-4 in cerebral edema and stroke. Handbook of Experimental Pharmacology 190, 159-170, 2009.

Zhang, M., Xu, J. T., Zhu, X., Wang, Z., Zhao, X., Hua, Z., Tao, Y. X., and Xu, Y. Postsynaptic density-93 deficiency protects cultured cortical neurons from N-methyl-D-aspartate receptor-triggered neurotoxicity. Neuroscience 166, 1083-1090, 2010.

Zhang, Z., Yan, J., Taheri, S., Liu, K. J., and Shi, H. Hypoxia-inducible factor 1 contributes to N-acetylcysteine's protection in stroke. Free Radical Biology and Medicine 68, 8-21, 2014.

Zhou, W., and Jones, S. W. The effects of external pH on calcium channel currents in bullfrog sympathetic neurons. Biophysical Journal 70, 1326-1334, 1996.

Zivin, J. A., Fisher, M., DeGirolami, U., Hemenway, C. C., and Stashak, J. A. Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science 230, 1289-1292, 1985.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2021-01-26起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw