 |
| 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
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| 參考文獻 |
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