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研究生:阮氏玉英
研究生(外文):THI NGOC ANH NGUYEN
論文名稱:利用斑馬魚神經行為學評估Donepezil暴露的潛在副作用
論文名稱(外文):Evaluation of potential side effects of Donepezil exposure in adult Zebrafish by multiple behavioral assessments
指導教授:蕭崇德
指導教授(外文):CHUNG DER-HSIAO
學位類別:碩士
校院名稱:中原大學
系所名稱:生物科技研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:英文
論文頁數:45
中文關鍵詞:DonepezilAcetylcholinesterase抑製劑癡呆斑馬魚斑馬魚行為
外文關鍵詞:Donepezilacetylcholinesterase inhibitordementiazebrafishzebrafish behavior
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Donepezil(DPZ)是一種acetylcholinesterase抑製劑,用於輕度認知障礙的臨床治療。但是,據報導DPZ具有不良反應,包括異常的心律,腹瀉,失眠,嘔吐,肌肉痙攣,疲倦和食慾不振。在動物模型中尚未仔細研究DPZ 可能引起的心理不良影響。在這裡,我們使用斑馬魚作為低等脊椎動物型,通過執行多種行為分析來測試DPZ對焦慮的潛在不利影響(新魚缸潛水測試),攻擊性(鏡像啄食測試),社群互動測試(社群互動測試和群游測試)。將年齡在6個月左右的成年斑馬魚隨機分為對照組和低劑量DPZ組和高劑量DPZ組(每組36隻動物)。此外,還比較了急性(4天)和慢性(14-21天)DPZ暴露之間的行為改變。最後,分離腦組織並進行ELISA以進行機理研究。急性和慢性暴露於低劑量的DPZ(1 ppm)都會引起斑馬魚的侵略性顯著提高。在進一步的觀察中,新魚缸潛水測試和群游測試揭示了多奈哌齊的抗焦慮作用,這歸因於在頂部區域的時間增加,進入頂部區域的次數增加甚至在群游測試中游泳範圍變鬆散。與低濃度(1 ppm)和對照組相比,高劑量(2.5 ppm)組的斑馬魚出現較低的運動表現與較高的變動性。生物標誌物測定顯示,多奈哌齊暴露有攻擊性增強和抗焦慮行為反應與應激激素皮質醇和九肽激素催產素的改變有關。肌肉組織中ROS水平和MDA水平的顯著增加,證明多奈哌齊暴露可引起肌肉損傷,虛弱和運動障礙。在這項研究中,我們仍然沒有發現多奈哌齊暴露引起的任何與神經遞質失調有關的行為反應。需要進一步研究潛在的神經元途徑,以了解行為反應與多奈哌齊暴露相關的精確機制。
Donepezil (DPZ) is an acetylcholinesterase inhibitor used for the clinical treatment of mild cognitive impairment. However, DPZ has been reported to have an adverse effect including abnormal cardiac rhythm, diarrhea, insomnia, nausea, vomiting, muscle cramps, tiredness and poor appetite. The possible induced-psychological adverse effect of DPZ has not been carefully addressed in animal models. Here we used zebrafish as a lower vertebrate model to prove this hypothesis by performing multiple behavioral assay on testing DPZ potential adverse effect on anxiety (novel tank diving test), aggressiveness (mirror biting test), social interaction (con-specific social interaction and shoaling tests) and fear (predator avoidance test). Adult zebrafish aged around 6-months old were randomly divided into control and low dose DPZ and high-dose DPZ groups (36 animals per group). In addition, the behavioral alteration between acute (4 days) and chronic (14-21 days) DPZ exposure were also compared. Finally, the brain tissues were isolated and subjected to Enzyme-linked immunosorbent assay for mechanistic studies. Both acute and chronic exposure to low-dose of DPZ (1 ppm) induced the significant increase in aggressiveness of zebrafish. During the response behavior observation, novel tank test and shoaling test revealing anxiolytic-like effect of donepezil due to robust behavior indicated by increasing time duration in top area and number of entries to top area even loosen in shoaling formation. Zebrafish locomotion displayed a higher reduction and variation in the high dose (2.5 ppm) group when compared to the low concentration (1 ppm) and the control group. Biomarker assays revealed that aggressiveness increase and anxiolytic behavior response after donepezil exposure associated with alterations of stress hormone cortisol and nonapeptide hormone oxytocin. The significant increase of ROS level and MDA level in muscle tissue as an evidence for muscle damage, weakness, and motor impairment effect of donepezil exposure. In this study, we still not find any neurotransmitter disorders-related behavior responses induced by donepezil exposure. Further investigations of potential neuronal pathways are needed to understand the more precise mechanisms underlying the behavior response relate to donepezil exposure.
CONTENTS
摘要 i
ABSTRACT ii
ACKNOWLEDGEMENTS iii
CONTENTS iv
LIST OF FIGURES vi
LIST OF TABLES vii
INTRODUCTION 1
Donepezil is an acetyl cholinesterase inhibitor used to fight dementia 1
Pharmaceutical effects of Donepezil done in higher vertebrates 2
Pharmaceutical effects of Donepezil done in lower vertebrates 3
Specific aim of this study is to study the pharmaceutical effects of Donepezil on behaviors by using zebrafish as an emerging lower vertebrate model. 3
MATERIAL AND METHOD 5
Animal Husbandry 5
Preparation of Donepezil HCl and Exposure 5
T-maze Test (Short-Term Memory Test) 5
Novel Tank Test 6
Aggressive Behavior Test 7
Predator Avoidance Assay 7
Social Interaction Test 7
Shoaling Test 7
Color Preferences Assay 8
Circadian Rhythm Locomotion Activity Test 8
Estimation of Neurotransmitter activity, Oxidative stress level, Antioxidant enzyme Stress hormone, neuropeptide in brain tissue 8
Determination of ATP, oxidative stress level and antioxidant enzyme activity in muscle tissues 9
Statistical Analysis 9
RESULT 10
Effect of Donepezil in T-maze (short-term memory test) in Zebrafish 10
Effects of Donepezil in Novel Tank Test for Zebrafish 11
Effects of Donepezil in Aggressive Behavior of Zebrafish 13
Effects of Donepezil in Predator Avoidance of Zebrafish 15
Effects of Donepezil in Social Interaction of Zebrafish 17
Effects of Donepezil in Shoaling of Zebrafish 19
Effects of Donepezil in Color Preference of Zebrafish 21
Effects of Donepezil in Circadian Rhythm Locomotion Activity of Zebrafish 22
Effect of Donepezil on antioxidant enzyme activity and stress marker level in the Brain and Muscle 23
Effect of Donepezil on the expression of neurotransmitter in the Brain 24
DISCUSSION 26
CONCLUSION 32
REFERENCES 34

LIST OF FIGURES
Figure 1. T-maze conditioning passive avoidance to test short-term memory of fish after chronic exposure with 2.5 ppm of donepezil. 11
Figure 2. Behavior endpoint of control and donepezil-exposed zebrafish in novel tank exploration test after 4 days of incubation. 12
Figure 3. Behavior endpoint of control and donepezil-exposed zebrafish in novel tank exploration test after 14 days of incubation. 13
Figure 4. Mirror biting behavior endpoint comparisons between the control group, 1 ppm, and 2.5 ppm donepezil-exposed zebrafish groups after 4 days of exposure. 14
Figure 5. Mirror biting behavior endpoint comparisons between the control group, 1 ppm, and 2.5 ppm donepezil-exposed zebrafish groups after 14 days of exposure. 15
Figure 6. Predator avoidance behavior endpoint comparisons between the control group, 1 ppm, and 2.5 ppm donepezil-exposed zebrafish groups after 4 days of exposure. 16
Figure 7. Predator avoidance behavior endpoint comparisons between the control group, 1 ppm, and 2.5 ppm donepezil-exposed zebrafish groups after 14 days of exposure. 17
Figure 8. Social interaction behavior endpoint comparisons between the control group, 1 ppm, and 2.5 ppm donepezil-exposed zebrafish groups after 4 days of exposure. 18
Figure 9. Social interaction behavior endpoint comparisons between the control group, 1 ppm, and 2.5 ppm donepezil-exposed zebrafish groups after 14 days of exposure. 19
Figure 10. Shoaling behavior endpoint comparisons between the control group, 1 ppm, and 2.5 ppm donepezil-exposed zebrafish groups after 4 days of exposure. 20
Figure 11. Shoaling behavior endpoint comparisons between the control group, 1 ppm, and 2.5 ppm donepezil-exposed zebrafish groups after 14 days of exposure. 21
Figure 12. Comparison of the color preference behavior between control and donepezil-exposed fish after chronic donepezil exposure. 22
Figure 13. Evaluation of the circadian rhythm through locomotion activity for control and chronic donepezil-exposed fish. 23
Figure 14. Summary of biochemical and behavioral changes in adult zebrafish after acute or chronic exposure to Donepezil. 32

LIST OF TABLES
Table 1. Comparison of biochemical levels in brain and muscle tissue between control fish and donepezil-exposed fish by enzyme-linked immunosorbent assay (ELISA). 26
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