臺灣博碩士論文加值系統

爲了探討酒精對於體內含硫胺基酸代謝的影響，以及是否會藉此而改變腦部神經傳導受器的表現，本研究共分為三部份進行，第一部份主要目的為觀察在短期以及連續酒精灌食下，大白鼠體內組織及血液中含硫胺基酸代謝是否受到影響。第二部份則探討在長期酒精攝取下，體內腦部、肝臟及血液中含硫胺基酸及NADH/NAD比值的變化，而在牛磺酸補充之下，酒精所造成的含硫胺基酸代謝異常是否可以獲得改善。最後利用腦部星狀細胞培養，觀察在高濃度酒精培養下是否會影響細胞神經傳遞受器的表現，並且進一步以牛磺酸取代酒精，模擬在酒精戒斷之情形下，牛磺酸的介入對於細胞神經傳遞受器的表現是否有改善作用以評估牛磺酸在酒精攝取下的可利用性。實驗結果發現，在短期酒精灌食下 (3 g/kg BW)，大白鼠體內組織的含硫胺基酸代謝會受到干擾，並顯著降低腦中SAM/SAH 之比值，此外甲硫胺酸、次牛磺酸 (hypotaurine)以及牛磺酸的含量也在連續酒精灌食七天後隨之降低。實驗二中則發現於飲水中添加酒精連續餵食一個月後，隨著血液中酒精濃度的上升，肝臟中NADH/NAD 比值亦隨之上升，而大白鼠腦部甲硫胺酸及SAM/SAH比值於第一週後的降低顯示出酒精抑制含硫胺基酸的轉甲基作用，降低的胱胺酸、牛磺酸及維生素B6則代表了轉硫作用受到了影響。牛磺酸的補充中則可顯著改善含硫胺基酸異常代謝之情形。在細胞實驗結果中則發現，星狀細胞在200 mM的酒精連續培養三天下，細胞內的GABAAα及NMDA第二型受器均受到顯著的影響，酒精抑制了GABAAα受器並同時促進了NMDA第二型受器的蛋白表現，並增加了牛磺酸於細胞內的滯留。此一結果與酒癮動物模式腦中受器表現之結果一致，而50至100 μM牛磺酸於第四天的置換則可有效改善酒精對神經傳遞受器所造成的影響。綜合以上所述，本研究證實了無論是短期或是長期酒精攝取均會影響實驗動物體內組織含硫胺基酸的代謝，此外也影響腦細胞中神經傳遞受器的表現，而添加含硫胺基酸代謝之中產物，牛磺酸，可以有效改善酒精所造成的影響，此結果可以支持牛磺酸於預防或輔助酒精戒斷方面之應用性。

The main purpose of the research was to clarify whether alcohol intake would affect body metabolism of sulfur containing amino acid (SCAA) and the supplementation of taurine could alter the changed expressions of NMDA and GABA A receptors brought by alcohol. The first study was to evaluate the effect of consecutively high alcohol administration on SCAA metabolism. Secondly, a chronic model of alcohol intake was applied to verify the effectiveness of taurine intervention on improving of SCAA metabolism. Finally, a study of brain astrocyte culture was conducted to verify the interference of ethanol on neurotransmission and related receptors, furthermore, evaluate the improvements and mechanisms of taurine treatment. Results showed that alcohol intake (3 g ethanol/g BW) interfered with brain SCAA metabolism in Sprague-Dawley rats, and lowered brain SAM/SAH ratio, methionine, hypotaurine, and taurine levels after 7 days of consecutive drinking. In the second study, rats with long-term alcohol drinking had different pattern of SCAA profiles. The transmethylation index, SAM/SAH ratio, decreased with methionine in brain. Moreover, liver NADH/NAD ratio also increased with alcohol drinking. However, taurine supplementation improved the increasing NADH/NAD ratio in the end of the experiment. As to the cell culture study, the expression of NMDA2A, NMDA2B and GABAAα4, GABAAα5 receptors altered and taurine depleted under three-day 200 mM alcohol administration, 100 μM of taurine treatment in day 4 till day 6 normalized such imbalanced receptor expression caused by ethanol. In conclusion, ethanol intake interfered in the SCAA metabolism thus affect taurine metabolism in brain and taurine supplementation could alter the neuronal changes caused by alcohol drinking in rats. The mechanism might involve in the regulation of taurine on brain GABAAα and NMDA receptors expression.

Table of contents
Acknowledgements Ⅰ
Abstract Ⅲ
中文摘要 Ⅴ
List of tables Ⅶ
List of figures Ⅷ
Abbreviations XI
Table of contents 1
Chapter 1. Introduction 5
Chapter 2. Literature review 7
Epidemiology of alcohol abuse and dependence 7
Medications used for alcohol dependence 9
Effects of alcohol on neurotransmission in central system 12
Taurine metabolism in human body 14
Transmethylation and transsulfuration 15
Alcohol and SCAA metabolism 16
Taurine and SCAA on neurotransmission 17
Taurine application on alcohol abuse and craving 19
The role of astrocytes on CNS and recent applied cell line used for astrocyte study. 21
Chapter 3. Main purpose 23
Chapter 4. Scheme of the research 24
Chapter 5. Evaluate the short term alcohol drinking effect on SCAA metabolism. 25
Abstract 25
Introduction 27
Experimental design 28
Materials 28
Animal protocol 28
Biochemical analysis 30
Statistical analysis 33
Results 34
Changes in SCAA levels in tissues with consecutive alcohol administration 34
Concentrations of plasma SCAA, glutathione, and pyridoxal phosphate levels with alcohol administration 38
Discussion 41
Chapter 6. Effects of taurine supplementation on SCAA metabolism under 4 weeks alcohol exposure. 46
Abstract 46
Introduction 48
Experimental design 49
Materials 49
Animal and treatment 49
Biochemical analysis 51
Statistical analysis 56
Results 57
Intake of alcohol and taurine 57
Plasma alcohol concentration and hepatic NADH/NAD ratio 58
Transmethylaton in brain and liver 60
SCAAs attenuated in brain, liver and plasma 62
Changes of pyridoxal –5’ –phosphate (PLP) in tissues 67
Discussion 69
Chapter 7. Improvements of taurine administration on different neuronal receptors in brain cells. 74
Abstract 74
Introduction 76
Experimental design 77
Materials 77
Study design 80
Immunocytochemistry of cultured cells 82
Analysis of cell viability 83
Observation & analysis 84
Statistical analysis 86
Results 87
Viability of cell cultures during the experiment 87
Effects of alcohol on various neurotransmitter expression on astrocyte 89
Effects of taurine administration during the alcohol abstinence on astrocyte 97
Discussion 115
Chapter 8. Summary of conclusions 120
References 121
Published Articles 130

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