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研究生:林清隆
研究生(外文):Lin, Ching-Lung
論文名稱:中草藥對於亨丁頓舞蹈症R6/2小鼠的心臟保護機制
論文名稱(外文):Cardiac protection of Chinese herbal medicine inthe R6/2 mouse model of Huntington’s Disease
指導教授:吳忠信吳忠信引用關係
指導教授(外文):Wu, Chung-Hsin
學位類別:博士
校院名稱:國立臺灣師範大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:105
中文關鍵詞:亨丁頓舞蹈症中草藥配方心臟保護作用氧化壓力發炎反應細胞凋亡基因轉殖小鼠模型
外文關鍵詞:Huntington’s diseaseChinese herbal formulacardioprotective effectoxidative stressinflammationapoptosistransgenic mouse model
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亨丁頓舞蹈症是一種遺傳性的神經退化疾病,其特徵在於認知和運動功能的障礙。亨丁頓舞蹈症被認為主要是一種神經退行性疾病;然而,心臟衰竭也是亨丁頓舞蹈症患者的主要死亡原因。許多發生在亨丁頓舞蹈症患者神經元當中的病症,如:粒線體功能障礙和代謝損傷,也會發生在亨丁頓舞蹈症患者的心肌細胞當中。然而,用於保護亨丁頓舞蹈症患者心臟功能的臨床藥物卻很少。在國內,有許多中草藥物可以透過刺激血液循環以及補充細胞能量來緩解心血管疾病;為此,這些中草藥應該可以應用於減輕亨丁頓舞蹈症患者的心臟衰竭。在台灣,中藥配方B307是保護心血管功能的知名保健漢方藥品。本論文探討口服中藥配方B307對於R6/2亨丁頓舞蹈症基因轉殖小鼠的心臟保護作用。R6/2小鼠每日口服中藥配方B307或媒介物,飲食治療兩週。然後,透過非侵入性的心臟超聲波影像和moor FLPI雷射都普勒成像儀器,檢視10週齡R6/2小鼠的心臟功能以及皮膚組織的微循環,接著我們利用免疫組織化學和西方轉漬分析,檢查R6/2小鼠心臟組織中特定蛋白質表現,本論文結果顯示,R6/2小鼠的心臟功能以及皮膚組織在服用中藥配方B307後均獲得顯著改善。並且,R6/2小鼠心臟組織的心肌發炎以及亨丁頓蛋白累積,在服用中藥配方B307後也獲得顯著改善。此外,R6/2小鼠服用中藥配方B307後,心臟組織的VEGF、eNOS、SOD2和Bcl-2的蛋白質表現會顯著增加,而TNF-α、3-NT、4-HNE、Bax、Calpain、Caspase 12、Caspase 9、Caspase 3的蛋白質表現則會顯著降低。由本論文研究發現口服中藥配方B307會有效減輕R6/2小鼠心臟組織的氧化壓力、發炎反應以及細胞凋亡的進程。因此,口服中藥配方B307應該可以通過這些保護機制而達到改善亨丁頓舞蹈症患者的心臟功能失調;因此中藥配方B307可能開發成為改善亨丁頓舞蹈症心臟衰竭的保健漢方藥品。
Huntington’s disease (HD) is considered as a irreversibly destructive genetic disease, characterized by cognitive impairment and motor dysfunction. Though HD has been considered as a neurodegenerative disease primarily, cardiac failure is also cause of death in HD patients. Some symptoms such as energetic dysfunction and metabolic injury that occur in HD neurons, and that also can be seen in failing cardiac myocytes of HD. Until now, the clinical drugs with profound cardioprotective effect in HD patients is quite rare. Some Chinese herbs have been claimed to relieve cardiovascular diseases by promoting blood circulation and supplementing vital energy. Thus, some specific Chinese herbs may be used as a potential therapeutic strategy for alleviating cardiac failure in HD patients. The herbal formula B307 is a well-known health supplement for enhancing cardiovascular function in Taiwan. Here we investigated the cardioprotective effects of oral B307 treatment in R6/2 HD mice. R6/2 HD mice were oral treated with B307 or with vehicle diet daily for two weeks. The level of cardiac performance and subcutaneous microcirculation of these R6/2 HD mice were measured at ten-weeks-old by non-invasive echocardiography and moorFLPI Laser Doppler imager respectively. Afterward, R6/2 HD mice and their wild type littermate controls (WT) were sacrificed. The heart tissues were examined by immunohistochemistry and western blotting. Our data showed that cardiac performance and subcutaneous microcirculation were ameliorated in R6/2 HD mice under oral treated with B307. We observed that myocarditis and aggregation of huntingtin protein in heart tissue of R6/2 HD mice were significantly enhanced than that of their WT, but were reduced under oral treated with B307. Proteins expression of VEGF, eNOS, SOD2 and Bcl-2 in heart tissue of R6/2 HD mice were reduced than that of their WT, but were enhanced under oral treated with B307. On the other hand, Proteins expression of 3-NT, 4-HNE, Bax, calpain, caspase-12, caspase-9, caspase-3, and TNF-α in heart tissue of R6/2 HD mice were enhanced than that of their WT, but were reduced under oral treated with B307. Base on our study, inflammation, oxidative stress and apoptosis in heart tissue were alleviated under oral treated with B307. We suggested that oral herbal formula B307 may be beneficial for cardiac protection in HD patients. It is possible that the herbal formula B307 can be developed as a health supplement for ameliorating cardiac failure of HD patients.
TABLE OF CONTENTS I
LIST OF FIGURES V
中文摘要 VIII
ABSTRACT IX
CHAPTER 1 INTRODUCTION 1
1.1 Huntington's disease 2
1.2 Cardiac failure in Huntington's disease 2
1.3 Effect of Chinese herbal medicine in cardiac failure 3
1.4 Research aims 4
CHAPTER 2 MATERIALS AND METHODS 7
2.1 Chromatographic fingerprint analysis for the Chinese herbal formula B307 8
2.2 MTT assay of the herbal formula B307 8
2.3 The R6/2 transgenic mouse model of Huntington’s disease 9
2.4 Oral B307 treatments in R6/2 HD mice 9
2.5 Lifespan in R6/2 HD mice 10
2.6 Body, heart, and brain weight in R6/2 HD mice 11
2.7 Motor activity analysis in R6/2 HD mice 11
2.8 Cardiovascular performance 12
2.9 Subcutaneous microcirculation measurement 13
2.10 Cardiac immunohistochemistry (IHC) analysis 13
2.11 Cardiac western blotting analysis 14
2.12 Statistical analysis 17
CHAPTER 3 RESULTS 19
3.1 Chromatographic fingerprint analysis for the Chinese herbal formula B307 20
3.2 The IC50 in SH-SY5Y cells of the herbal formula B307 20
3.3 Lifespan of R6/2 HD mice with oral B307 21
3.4 The body weight of R6/2 HD mice with oral B307 21
3.5 The brain weight of R6/2 HD mice with oral B307 22
3.6 The heart weight of R6/2 HD mice with oral B307 22
3.7 The motor ability of R6/2 HD mice with oral B307 23
3.8 The cardiac function of R6/2 HD mice with oral B307 24
3.9 T The subcutaneous microcirculation of R6/2 HD mice with oral B307 26
3.10 T The cardiac protein expression of VEGF in R6/2 HD mice with oral B307 27
3.11 The cardiac protein expression of eNOS in R6/2 HD mice with oral B307 27
3.12 The cardiac protein expression of mutant huntingtin in R6/2 HD mice with oral B307 28
3.13 The myocarditis in R6/2 HD mice with oral B307 29
3.14 The cardiac protein expression of 3-NT in R6/2 HD mice with oral B307 29
3.15 The cardiac protein expression of 4-HNE in R6/2 HD mice with oral B307 30
3.16 The cardiac protein expression of SOD2 in R6/2 HD mice with oral B307 30
3.17 The cardiac protein expression of TNF-α in R6/2 HD mice with oral B307 31
3.18 The cardiac protein expression of Cyto-c in R6/2 HD mice with oral B307 32
3.19 The cardiac protein expression of BAX in R6/2 HD mice with oral B307 32
3.20 The cardiac protein expression of Bcl-2 in R6/2 HD mice with oral B307 33
3.21 The cardiac protein expression ratio of Bcl-2 and BAX in R6/2 HD mice with oral B307 34
3.22 The cardiac protein expression of calpain in R6/2 HD mice with oral B307 34
3.23 The cardiac protein expression of caspase12 in R6/2 HD mice with oral B307 35
3.24 The cardiac protein expression of caspase9 in R6/2 HD mice with oral B307 35
3.25 The cardiac protein expression of caspase3 in R6/2 HD mice with oral B307 36
3.26 The cardiac protein expression ratio of full-form and cleaved-form of in R6/2 HD mice with oral B307
37
CHAPTER 4 DISCUSSION 39
4.1 Effect of oral B307 treatment on survival, body weight, motor performance, and cardiac performance of R6/2 HD mice 40
4.2 Effect of oral B307 treatment on myocarditis and cardiac failure of R6/2 HD mice 41
4.3 Effect of oral B307 treatment on oxidative damage of R6/2 HD mice 41
4.4 Effect of oral B307 treatment on inflammation of R6/2 HD mice 42
4.5 Effect of oral B307 treatment on apoptosis via ER-stress of R6/2 HD mice 43
4.6 Effect of oral B307 treatment on apoptosis via mitochondrial dysfunction of R6/2 HD mice 43
4.7 Effect of oral B307 treatment on apoptosis of R6/2 HD mice 44
CHAPTER 5 CONCLUSION 47
CHAPTER 6 REFERENCES 49
CHAPTER 7 FIGURES 57
APPENDIX 1: CV of Ching-Lung Lin i

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