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系統識別號 U0026-0812200911253312
論文名稱(中文) 多巴胺轉運器及第二亞型多巴胺接受器在魚藤精所誘發巴金森氏症大鼠模式中的表現
論文名稱(英文) The expression of dopamine transporter and D2 receptor in rotenone-induced Parkinsonian rat model
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 93
學期 1
出版年 94
研究生(中文) 林俊宏
研究生(英文) Chun-Hung Lin
電子信箱 c54871138@mail.bio.ncku.edu.tw
學號 s3691102
學位類別 碩士
語文別 英文
論文頁數 72頁
口試委員 指導教授-莊季瑛
召集委員-吳豐森
口試委員-黃阿敏
中文關鍵字 多巴胺接受器  多巴胺轉運器  巴金森氏症  魚藤精 
英文關鍵字 dopamine receptor  dopamine transporter  Parkinson's disease  rotenone 
學科別分類
中文摘要 巴金森氏症(Parkinson’s disease)為一種常見運動失調的神經退化性疾病。其病理上的主要特徵為黑質區多巴胺神經細胞大量流失以及有細胞質內涵物沉積現象,通稱為路易氏體,而其中最主要的成分為α突觸核素(alpha synuclein)。由死後病人的研究中指出,粒線體複合物的受損及多巴胺轉運器(dopamine transporter)的流失可能參與巴金森氏症的致病成因中。目前兩種粒線體抑制劑MPTP及魚藤精(rotenone)已廣泛應用在誘發多種動物產生類巴金森氏症。然而目前對於在巴金森氏症病人上所觀察到多巴胺轉運器的減少及多巴胺第二亞型接受器(dopamine D2 receptor)的增加,是否有參於造成多巴胺神經細胞流失的過程中,仍然尚不清楚。因此本實驗,想探討多巴胺轉運器及第二亞型多巴胺接受器在魚藤精及MPP+所誘發巴金森氏症動物模式中的表現。首先我們建立藉由皮下植入魚藤精去誘發類巴金森氏症的動物模式。在此動物模式中,我們觀察到由皮下植入魚藤精14天後,會造成動物的體重下降、自主活動力減緩以及黑質紋狀體多巴胺路徑(nigrostriatal dopaminergic)和正腎上腺神經細胞(noradrenergic)的受損。在此同時也發現魚藤精會造成多巴胺轉運器表現量下降及多巴胺第二亞型接受器和α突觸核素表現量明顯增加情形。我們更進一步證實退黑激素可以有效保護多巴胺神經細胞,並回復魚藤精毒性所造成的多巴胺轉運器表現量下降以及多巴胺第二亞型接受器和α突觸核素表現量增加的改變。為了更進一步去釐清多巴胺轉運器及多巴胺第二亞型接受器在多巴胺神經細胞流失過程中扮演的角色,我們探討給予個別專一性的抑制劑對魚藤精所誘發多巴胺神經細胞流失的影響。結果發現此兩種抑制劑皆無法顯著保護多巴胺神經細胞。另一方面,退黑激素也顯著避免由給予MPP+三天後所造成的紋狀體TH(tyrosine hydroxylase,多巴胺神經細胞的標記)蛋白表現量下降及多巴胺第二亞型接受器大量增加。綜合以上,我們的結果證實退黑激素可以避免由魚藤精所造成多巴胺神經細胞的死亡和存活神經細胞內α突觸核素的累積以及多巴胺轉運器表現下降和多巴胺第二亞型接受器增加的現象。
英文摘要 Parkinson’s disease (PD) is a common neurodegenerative disease with movement disorder. Pathological features include loss of dopaminergic neurons in the substantia nigra pars compacta and intracytoplasmic inclusions containing -synuclein, known as Lewy bodies. Human postmortem studies have suggested the involvement of mitochondrial complex I impairment and dopamine transporter (DAT) loss in the pathogenesis of PD. Two complex I inhibitors, rotenone and MPTP, had been used as popular tools for inducing a model of PD in many species of animals. However, it is unclear whether the loss of DAT and increase of dopamine D2 receptor (D2R) found in PD patients are involved in the pathogenesis of DA neuronal loss. In the present study, we investigate the role of DAT and D2R in rotenone or MPP+-treated rats. First of all, we had established a PD model by chronic exposure of rotenone subcutaneously. The toxicity of rotenone was confirmed by a significant loss of body weight and locomotor activity as well as nigrostriatal dopaminergic and noradrenergic degeneration 14 days after subcutaneous administration. We demonstrated not only down-regulation of DAT but also up-regulation of D2R and -synuclein induced by rotenone treatment. Furthermore, melatonin can effectively reverse the dopaminergic neuronal loss and the changes of DAT, D2R and -synuclein expression induced by rotenone. In order to clarify the role of DAT and D2R, we further evaluated the effect of specific antagonists in rotenone-treated rats. However, DAT or D2R antagonist had no significantly protective effect on dopaminergic neuron in rotenone-treated rats. In addition, melatonin significantly prevented the decrease of striatal TH immunoreactivity and D2R up-regulation 3 days after intra-striatal administration of MPP+. Our results demonstrated that melatonin provided protection against nigral dopaminergic degeneration and prevented aggregation of -synuclein in the survival nigral neuron and reversed the down-regulation of DAT and up-regulation of D2R in rotenone-treated animals.
論文目次 Table of Contents
Acknowledgments……………………………………………………... (i)
Table of Contents……………………………………………………… (ii)
Index to Figures and Tables.……………………………………………. (iv)
Abstract…………………………………………………………... ..........1
Chinese……………………………………………………….. .........1
English………………………………………………………... .........3
I. Introduction………………………………………………………........5
II. Materials and Methods……………………………………………..…10
(1) Animal surgery and treatment…………………………………....10
(2) Behavioral measurements—Locomotor activity………………...11
(3) Histochemical analyses……………………………………..........12
(4) Biochemical analyses…………………………....…………….…15
III. Results…………………………………………………………….…18
(1) A significant weight loss and locomotor deficit were observed in rotenone-treated animals….………………………………....…..18
(2) Rotenone induced nigrostriatal dopaminergic and noradrenergic degeneration..................................................................................18
(3) Melatonin prevented nigrostriatal dopaminergic degeneration
induced by rotenone treatment..………………….…………….…19
(4) Cytoplasmic inclusions were observed in SN of rotenone-treated rats………..…................................................................................20
(5) Melatonin prevented the down-regulation of DAT and up-regulation of D2R induced by rotenone treatment.…..........………………...20
(6) The blockage of D2R or DAT had no significantly protective effect against rotenone-induced DA neuron loss....................................21
(7) Melatonin prevented striatal TH decrease and D2R up-regulation
3 days after inta-striatal administration of MPP+…….………...…22
IV. Discussion………………………………………………...……..……50
V. References....……………………………………………………..……61
VI. Appendix……………………………………………………………68
VII. About the author……………………………………………….…..72
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