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系統識別號 U0026-0812200914084199
論文名稱(中文) 神經膠細胞於情緒穩定劑丙戊酸神經保護作用中角色之探討
論文名稱(英文) Neuroprotective effects of the mood stabilizer valproate: role of glia
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 陳柏熹
研究生(英文) Po-see Chen
電子信箱 chenps@mail.ncku.edu.tw
學號 chenps
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-簡伯武
口試委員-曾淑芬
指導教授-洪昭雄
口試委員-顏茂雄
口試委員-藍先元
指導教授-陸汝斌
中文關鍵字 神經膠細胞  雙極性情感性精神病  情緒穩定劑  丙戊酸 
英文關鍵字 Valproate  glia  mood stabilizer  bipolar disorder 
學科別分類
中文摘要 腦可謂人體最精細複雜之器官。腦負責維持體內恆定並適應外界多變的環境。 過往多認為腦功能源於腦內的神經元。 而腦中含量約為神經元十倍的神經膠細胞在19世紀被發現後卻一直受到忽視,甚至有「只有十分之一的腦有功能」這樣的迷思。 自70年代開始有人認真思考神經膠細胞的角色後,人們始逐漸認識神經膠細胞對維持腦功能的重要性。 神經膠細胞中星狀神經膠細胞能提供神經元養分及氧氣並透過調節腦血管障壁維持腦內環境恆定。 寡樹突神經膠細胞可形成髓鞘。微神經膠細胞可摧毀病原體,並移除死亡的神經元。 除此之外,神經膠細胞可於腦發育早期導引神經元的遷移、分泌影響軸突及樹突生長的分子,並在突觸可塑性和突觸發生的過程中扮演關鍵角色。 近年的研究也逐漸推翻了神經膠細胞不參與腦部訊息傳導的想法。 其中星狀神經膠細胞被發現可藉由調節突觸間神經傳導物質的濃度而影響訊息的傳遞。 研究也發現神經膠細胞在神經病變性疼痛、癲癇、神經退化疾病以及精神病中皆可能扮演重要角色。 因此,神經膠細胞現今被視為腦病變藥物治療新的重要目標細胞。
雙極性情感性精神病又稱躁鬱症,是一種會造成病患情緒、驅力及功能大幅波動之腦部疾病。過往的腦照影以及腦組織研究都顯示病患會有腦細胞喪失以及腦萎縮的現象,而這樣的現象可能為腦細胞病變之結果。目前已有多種結構相異之情緒穩定劑可有效治療並預防此疾病之復發,但其於神經元直接作用之研究並未發現共同之分子作用標的可解釋其治療作用。然而在細胞或臨床試驗中均發現結構相異之情緒穩定劑具有共同的神經保護以及神經滋養作用。因為情緒穩定劑對神經膠細胞之直接作用幾乎未曾為人探討,加上近來情緒穩定劑中之丙戊酸被發現可藉由改變細胞核內組織蛋白尾端的乙烯化程度來調節外遺傳狀態影響細胞功能。 因此,本研究利用初代神經元神經膠細胞混和培養系統探討丙戊酸對神經膠細胞
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功能以及外遺傳特徵之直接影響,並探討此作用於丙戊酸神經保護作用中可能扮演之角色。
在目前的研究結果中發現丙戊酸可經由抑制微神經膠細胞釋放發炎因子並誘導活化之微神經膠細胞邁向凋亡來保護中腦多巴胺神經元免於腦內發炎性傷害。 此外研究結果顯示丙戊酸可誘導星狀神經膠細胞增加多種神經滋養因子之分泌,滋養中腦多巴胺神經元。 而這樣的作用都與丙戊酸增強神經膠細胞細胞核內特定組織蛋白尾端的乙烯化有關。此結果顯示神經膠細胞於丙戊酸神經保護作用中扮演重要角色 。此外,丙戊酸可藉由其於神經膠細胞之作用來調節中腦多巴胺神經元之功能。由此推論,神經膠細胞有可能是治療情感性精神病藥物丙戊酸重要的標的細胞,且丙戊酸可被視為神經膠細胞之外遺傳之調節物。 日後將進行系列實驗繼續探討神經膠細胞與外遺傳現象在雙極性情感性精神疾病治療與病理之細胞及分子層級機制中可能扮演之角色。 由此新研究領域著手,希望能讓人們對複雜精神疾病的致病機制與藥物作用機轉有新的認識。
英文摘要 The brain is the most intricate organ in the human body. The brain maintains internal homeostasis and adapt to the changing environment. Neurons are believed to underlie the function of the brain. Glial cells, including astrocytes, oligodendrocytes, and microglia, are estimated to outnumber neurons by about ten to one. Although glial cells constitute over 50% of brain cells, their involvement in normal brain function is poorly understood. An emerging alternative view holds that neuroglia coordinate brain function. Nowadays, astrocytes are known to provide nutrients, oxygen and maintain the homeostasis of the blood-brain barrier. Astrocytes have also been reported to play an active role in information transmission through the regulation of extrasynaptic neurotransmitter concentration. Oligodendrocytes make up the myelin sheath. Microglia can destroy foreign pathogens and remove dead neurons. In addition, glial cells can guide the migration of neurons in the early developmental stage of the brain and secrete factors to regulate the formation of neuritis. They also play a critical role in synaptogenesis and synaptic plasticity. Researchers also discovered that glial cells play important roles in the pathogenesis of neuropathic pain, epilepsy, neurodegenerative disorders, schizophrenia and affective disorders. Glial cells are now considered as important targets for pharmacological treatments of brain disorders.
Bipolar disorder, also known as manic-depressive illness, is a brain disorder that causes unusual shifts in a person's mood, energy, and ability to function. Previous structure and functional images for bipolar disorder showed the cell loss and brain atrophy in human suggested the consequence of cellular pathology. Nowadays there are structurally highly dissimilar mood stabilizers used to effectively treat and prevent the occurrence of bipolar disorder. Till now, there has been no consensus on direct neuronal mechanisms underlying the therapeutic actions. However, previous in vitro and clinical studies indicated they share the commonalities of neuroprotective and neurotrophic effects. Because the effects of mood stabilizers on glial cells have seldom been investigated plus that valproate, a
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mood stabilizer, is known to regulate the cellular epigenetic status through histone modifications, a series studies were performed to investigate the direct effect of valproate on glial cellular function and epigenetic status, and the indirect effects on neuroprotection using primary mixed neuron-glial culture systems.
The results showed that valproate can protect midbrain dopaminergic neurons from inflammatory injury by inhibiting the production of microglial inflammatory factors and inducing microglial apoptosis. More importantly, valproate could increase the astroglial production of neurotrophic factors. In turn, the increase in neurotrophic factors has trophic effects on midbrain dopaminergic neurons. All of these effects are mediated through the increase in specific glial histone protein acetylation that changes genes expression. The results suggest that glial cells play important roles in the neuroprotective effects of valproate. Besides, valproate could modulate the function of midbrain dopaminergic neurons through its direct effects on glial cells. These results suggested glial cells could be the important cellular therapeutic targets for valproate which may act as an epigenetic regulator. In the future, a series of studies would be proceeded to examine the role of glial cells and epigenetic phenomenon in the pathogenesis and treatment of bipolar disorder. Insights from these studies may advance our understanding of the pathogenesis of complex psychiatric diseases and also the development of epigenetic therapy.
論文目次 審查及口試合格證明 i
中文摘要 ii
Abstract v
Acknowledgement viii
Table of Contents ix
List of Tables xiii
List of Figures xiv
Glossary xvi
Chapter One:
Introduction 1
1.1 Bipolar disorder 2
1.2 Cellular pathophysiology of bipolar disorder 2
1.2.1 Structure neuroimage evidences 3
1.2.2 Postmortem study of bipolar disorder 3
1.3 Current drug treatments for bipolar disorder 3
1.3.1 Molecular targets for mood stabilizers 5
1.3.2 Commonalities signaling of mood stabilizers: neuroprotection 7
1.4 Glial cells 8
1.5 Hypothesis and research objective: Glia as targets for valproic acid 9
Chapter Two:
Material and methods 13
2.1. Reagents 14
2.2. Animals 14
2.3. Primary mesencephalic neuron–glia cultures 14
2.4. Rat mesencephalic neuron-enriched cultures 15
2.5. Enriched rat microglial culture 15
2.6. Primary cultures of rat cerebral cortical astrocytes 15
2.7. Rat C6 glioma cell culture 16
2.8. DA uptake assay 17
2.9. Immunostaining 17
2.10. TNFα and nitrite assays 17
2.11. Assay of intracellular ROS 18
2.12. Determination of microglia cell number 18
2.13. Cell viability 18
2.14. Annexin V staining 19
2.15. DNA fragmentation 19
2.16. TUNEL assay 20
2.17. Mitochondrial transmembrane potential measurement 20
2.18. Analysis of histone acetylation and cell cycle by flow cytometry 21
2.19. GDNF ELISA 21
2.20. GDNF antibody neutralization 21
2.21. RNA extraction and quantitative RT-PCR 22
2.22. GDNF promoter activity assay 22
2.23. Chromatin immunoprecipitation (ChIP) assay 23
2.24. Statistical analysis 24
Chapter Three:
Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia 25
3.1 Abstract 26
3.2 Introduction 26
3.3 Results 28
3.4 Discussion 30
Chapter Four:
Valproic Acid Induces Microglial Apoptosis and Attenuates Lipopolysaccharide-induced Dopaminergic Neurotoxicity 40
4.1 Abstract 41
4.2 Introduction 41
4.3 Results 42
4.4 Discussion 45
Chapter Five:
Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes 56
5.1 Abstract 57
5.2 Introduction 57
5.3 Results 58
5.4 Discussion 63
Chapter Six:
Histone Deacetylase Inhibitors Upregulate GDNF and BDNF Gene Transcription in Astrocytes and Protects Dopaminergic Neurons from Toxic Insult 72
6.1 Abstract 73
6.2 Introduction 73
6.3 Results 74
6.4 Discussion 77
Chapter Seven:
Conclusions and further directions 87
7.1 Glial cells as the therapeutic target for valproate 88
7.2 Valproate acid as an epigenetic modulator 89
7.3 Epigenetics and bipolar disorder 90
7.4 Conclusion and further directions 91
Significant references 93
Bibliography 110
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