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研究生：	徐志翔 Hsu,Chih-Hsiang
論文名稱：	傳統中醫藥緩解錳中毒的治療潛力 Therapeutic Potential of Traditional Chinese Medicine in Manganism
指導教授：	吳忠信 Wu, Chung-Hsin
學位類別：	博士 Doctor
系所名稱：	生命科學系 Department of Life Science
論文出版年：	2016
畢業學年度：	104
語文別：	英文
論文頁數：	84
中文關鍵詞：	錳中毒、類巴金森症候群、陰莖組織、多巴胺、大腦神經生長因子、一氧化氮合成酶、活性氧化物質、氧化壓力、發炎作用、細胞凋亡、草藥配方
英文關鍵詞：	Parkinsonism,, penile cavernous tissue, brain-derived, neurotrophic factor, herbal formula
DOI URL：	https://doi.org/10.6345/NTNU202204402
論文種類：	學術論文
相關次數：	點閱：75 下載：17
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本論文的主要研究目的為探討傳統中醫藥是否具有緩解錳中毒的治療潛力。過去文獻指出錳礦工人會因為吸入大量的錳而引起神經系統中毒以及勃起障礙的症狀，人體如果攝取過量的錳也會造成嚴重的神經系統疾病、行動障礙、心智和情緒的異常，嚴重的錳中毒甚至誘發類巴金森症候群。然而，臨床上利用西方藥物治療人體錳中毒的效果卻相當有限，如果選擇傳統中醫篩選緩解錳中毒的中草藥，則為錳中毒患者帶來替代治療的希望。為此，本研究選擇具有緩解發炎與氧化壓力的中藥配方B401，利用口服餵食錳毒處理的實驗雄鼠，探討中藥配方B401是否具備緩解錳中毒的治療潛力。本實驗選用的中藥配方B401，首先利用高效液相層析儀分析中藥各個配方的有效成分，再利用MTT分析檢視中藥配方B401的半抑制濃度；確定中藥配方B401的有效成分與半抑制濃度後，本實驗選用50隻ICR雄鼠，分為正常飲食(Sham)、錳毒處理(Mn)、餵食中藥配方B401 (B401)、以及餵食中藥配方B401加錳毒處理(B401+Mn)四組。實驗處理過程中，利用滾輪運動實驗檢視四組小鼠的運動與平衡能力，最後四組小鼠分別給予麻醉藥物處理後，採集小鼠血液，利用化學發光分析法檢視並且比較血液中活性氧化物質，同時利用多功能電化學偵測儀‎檢視並且比較陰莖組織一氧化氮的含量；隨後利用心臟灌流方式犧牲，採集四組小鼠的腦部與陰莖組織，再利用免疫組織化學染色以及西方轉漬方法檢視腦部與陰莖組織的相關蛋白質表現。實驗結果顯示ICR雄鼠給予錳毒處理後，會顯著增加血液中活性氧化物質(ROS)表現以及降低陰莖組織中一氧化氮(NO)的含量；從免疫組織化學染色以及西方轉漬方法的結果發現，ICR雄鼠給予錳毒處理後，會顯著降低腦部組織中多巴胺、多巴胺接受器、以及大腦神經生長因子(BDNF)的表現，以及降低陰莖組織中神經型一氧化氮合酶(nNOS)、内皮型一氧化氮合酶(eNOS)的表現；此外，ICR雄鼠給予錳毒處理後，對於腦部與陰莖組織均會增加氧化壓力、發炎反應以及細胞凋亡作用的標記蛋白表現。當ICR雄鼠預先餵食中藥配方B401，再給予錳毒處理，相較於單獨錳毒處理的ICR雄鼠，血液中ROS表現會顯著降低，陰莖組織中NO的含量則是改善增加；從免疫組織化學染色以及西方轉漬方法的結果發現，預先餵食中藥配方B401會使錳毒處理的ICR雄鼠腦部組織中多巴胺、多巴胺接受器、以及BDNF的表現會顯著回升；陰莖組織中nNOS、eNOS的表現也會顯著回升；此外，預先餵食中藥配方B401會使錳毒處理的ICR雄鼠腦部組織與陰莖組織的氧化壓力、發炎反應以及細胞凋亡作用的標記蛋白表現顯著下降。由以上實驗結果發現，ICR雄鼠口服中草藥配方B401可以透過促進腦部組織中多巴胺以及BDNF的表現，以及緩解腦部的氧化壓力、發炎作用與細胞凋亡反應來緩解錳毒引發的神經系統毒性；此外，ICR雄鼠口服中草藥配方B401可以透過增加陰莖組織中NO、nNOS、eNOS的表現，以及緩解陰莖組織的氧化壓力、發炎作用與細胞凋亡反應來緩解錳毒引發的陰莖毒性。因此，本論文結果認為中草藥配方B401應該具有緩解錳毒引起之神經毒性或是生殖毒性的醫療潛力。

The main purpose of my PhD dissertation is to explore whether the traditional Chinese medicine may have therapeutic potential on alleviation. From clinical case reports, welders often have problem with neurological symptoms and erectile dysfunction when they occupationally exposed to excess manganese (Mn) dust. These welders may cause brain, motor and reproductive defects that were known as manganism or Mn-induced parkinsonism. However, the clinical use of the western medicine in manganism alleviation is quite limited. It is possible that alternative therapy of traditional Chinese medicine may be useful in manganism alleviation. In this study, we investigated whether oral treatment of herbal formula B401 has therapeutic potential to alleviate manganism. We used high-performance liquid chromatography to analysis the active ingredients of the herbal formula B401. The half maximal inhibitory concentration (IC50) of the herbal formula B401 was evaluated by MTT assay. Total 50 male ICR mice were divided into four groups: normal diet (sham group), manganism treatment only (Mn group), herbal formula B401 treatment only (B401 group), as well as pretreatment of herbal formula B401 plus manganism treatment B401 (B401+Mn group). Motor coordination of these mice was compared in accelerating mode of rotarod test. Then reactive oxygen species (ROS) of the blood were examined to compare oxidative stress in these mice by using chemiluminescence. The nitric oxide (NO) of the penile cavernous tissue was also examined in these mice by using electrochemical detection instrument. Then these mice were sacrificed by using anesthesia and heart perfusion. We collected brain tissue and penile cavernous tissue from four groups of mice. By using immunohistochemistry staining and western blotting techniques, we examined different protein expressions from brain tissue and penile cavernous tissue in four groups of mice. Our results showed that those mice with Mn treatment showed brain and motor defects in comparison with those mice with sham treatment. As observed from immunohistochemical and western blotting, those mice with Mn treatment reduced dopaminergic and brain-derived neurotrophic factor (BDNF) expressions, while enhanced oxidative stress, inflammation and apoptosis related protein markers in their brain tissue. In addition, those mice with Mn treatment showed significantly decreased NO, neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) levels, while enhanced oxidative stress, inflammation and apoptosis related protein markers in their penile cavernous tissue, In comparison with those mice with Mn treatment only, those Mn treated mice with B401 pretreatment significantly improved their motor coordination, and enhanced dopaminergic and BDNF expressions, but alleviated oxidative stress, inflammation and apoptosis related protein markers in their brain tissue. Furthermore, these mice significantly enhanced NO, nNOS and eNOS levels, but alleviated oxidative stress, inflammation and apoptosis related protein markers in their penile cavernous tissue. Our findings provide evidences that oral B401 treatment may alleviate symptoms of Mn-induced neurotoxicity via enhancing dopaminergic and BDNF expressions, but suppressing oxidative stress, inflammation and apoptosis in their brain tissue. Also, oral B401 treatment may alleviate symptoms of Mn-induced reproductive toxicity via enhancing NO, nNOS and eNOS levels, but suppressing oxidative stress, inflammation and apoptosis in their penile cavernous tissue. Thus we suggest that the herbal formula B401 may have therapeutic potential for ameliorating Mn-induced neurotoxicity and reproductive toxicity

TABLE OF CONTENTS    I
LIST OF FIGURES    III
ABBREBIATION LIST    V
中文摘要    VII
ABSTRACT    IX
CHAPTER 1  INTRODUCTION    1
1.  What is manganism?    2
2.  Manganism-induced brain toxicology     2
3.  Manganism-induced reproductive toxicology    3
4. Therapeutic potential of herbal formula B401    4
5.  Aims of my study    5
CHAPTER 2  MATERIALS AND METHODS    7
1.  Chromatographic fingerprint analysis for the herbal formula B401    8
2.  Cell viability assay    8
3.  Experimental animal and treatments    9
4.  Motor performance    11
5.  Measurements of nitric oxide in penile tissue 11
6.  Reactive oxygen species (ROS) analysis in the blood 12
7.  Immunohistochemical (IHC) stain for protein expression    12
8.  Western blot analysis for protein expressions 13
9.  Statistical analysis    14
CHAPTER 3  RESULTS    15
1.  B401 treatment increases cell viability in glutamate-treated SH-SY5Y cells    16
2.  Effect of oral B401 treatment on motor coordination in Mn-treated mice    16
3.  Effect of oral B401 treatment on dopaminergic expressions in the brain tissue of Mn-treated mice    16
4.  Effect of oral B401 treatment on BDNF expressions in the brain tissue of Mn-treated mice    17
5.  Effect of oral B401 treatment on the blood ROS in Mn-treated mice    18
6.  Effect of oral B401 treatment on oxidative stress in the brain tissue
of Mn-treated mice    18
7.  Effect of oral B401 treatment on apoptosis in the brain tissue
of Mn-treated mice    19
8.  Effect of oral B401 treatment on nitric oxide and angiogenesis in the penile tissue of Mn-treated mice    21
9.  Effect of oral B401 treatment on oxidative stress and inflammation in the penile tissue of Mn-treated mice    22
10.Effect of oral B401 treatment on apoptosis in the penile tissue of Mn-treated mice    23
CHAPTER 4  DISCUSSION    25
1.  Oral treatment of the herbal formula B401 effectively alleviates Mn-induced brain toxicology    26
2.  Oral treatment of the herbal formula B401 effectively alleviates penile toxicity of Mn-treated mice    29
CHAPTER 5
CONCLUSION    33
REFERENCES    35
APPENDIX 1   Curriculum Vitae    i

LIST OF FIGURES
Figure 1. Chromatographic fingerprint analysis and cell viability assay of Chinese herbal formula B401    46
Figure 2. Motor coordination of Mn-treated mice was significantly enhance under oral B401 treatment    48
Figure 3. Expression levels of dopaminergic D1 receptors and dopamine in the brain tissue of Mn-treated mice were increased
significantly under oral B401 treatment    50
Figure 4. Expression levels of brain-derived neurotrophic factor (BDNF) in the brain tissue of Mn-treated mice were increased significantly under oral B401 treatment    52
Figure 5. Expression levels of ROS in the blood of Mn-treated mice was
significantly decreased under oral B401 treatment    54
Figure 6. Expression levels of anti-oxidative stress-related SOD2 in the brain tissue of Mn-treated mice were increased significantly under oral B401 treatment    56
Figure 7. Expression levels of oxidative stress-related 3-NT in the brain tissue of Mn-treated mice were decreased significantly under oral B401 treatment    58
Figure 8. The ratio of anti-apoptosis-related Bcl-2/Bax in the brain tissue of Mn-treated mice were increased significantly under oral B401 treatment    60
Figure 9. Expression levels of apoptosis-related caspase 3 in the brain tissue of Mn-treated mice were decreased significantly under oral B401 treatment    62
Figure 10. Cavernosal nitric oxide (NO) levels and H&E staining in Mn-treated mice with and without oral B401 treatment    64
Figure 11. Cavernosal levels of nitric oxide synthases between Mn-treated mice with and without oral B401 treatment    66
Figure 12. Cavernosal levels of VEGF, among Mn-treated mice with and without oral B401 treatment, and their sham mice    68
Figure 13. Cavernosal levels of catalase, and SOD2 among Mn-treated mice with and without oral B401 treatment, and their sham mice    70
Figure 14. Cavernosal levels of 4-HNE, an inducer of oxidative stress, between Mn-treated mice with and without oral B401 treatment    72
Figure 15. Cavernosal levels of TNF-α, a marker of inflammation, between Mn-treated mice with and without oral B401 treatment    74
Figure 16. Cavernosal levels of anti-apoptotic Bcl-2, and apoptotic inducers of c-PARP, Bax and Cyt-C between Mn-treated mice with and without oral B401 treatment    76
Figure 17. Cavernosal levels of apoptotic inducers of caspase 12 and caspase 3 among Mn-treated mice with and without oral B401 treatment, and their sham mice    78
Figure 18. The schematic diagram illustrates the possible protective pathways of B401 treatment in Mn-treated mice    80
Figure 19. The schematic diagram illustrates that oral B401 treatment may alleviate penile toxicity of excess Mn-treated mice in corpus cavernosum    82
                                

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