臺灣博碩士論文加值系統

　　巴金森氏症病患早期藥物雖有治療效果，但長期藥物治療卻加重也已病變的多巴胺神經細胞工作負擔，導致對藥物產生耐藥性或強烈的副作用。本研究室以往曾報告移植胚胎中腦神經母細胞至巴金森動物可重建宿主多巴胺功能。因此本實驗的目的為探討移植成年周邊神經之可行性，以T2G異體移植於單側巴金氏症裸鼠紋狀體，觀察其功能性恢復和組織學再生之關係，並與以往移植胚胎中腦黑質組織比較。我們以經內視鏡切除之手汗症病患第二胸椎交感神經節（T2G）為移植材料。選用Fischer 344 裸鼠及Sprague-Dawley鼠為宿主。微量注射6-hydroxydopamine (6-OHDA)破壞動物單側黑質紋狀體多巴胺神經路徑。2-4週後，利用甲基安非他命引發之動物旋轉行為測量多巴胺神經破壞程度。之後，分別於破壞側紋狀體內植入人T2G、人T2纖維（T2F）、鼠上頸交感神經節，和鼠胚胎黑質組織。結果顯示在移植T2G後2週，動物旋轉行為有明顯改善。隨時間延長，動物旋轉行為逐漸回復至移植前的水平。免疫化學研究顯示，老鼠經6-OHDA單側破壞後在紋狀體區tyrosine hydroxylase (TH) 及glutamic acid decarboxylase (GAD) 的免疫組織化學活性皆減少。移植人T2G 2-4週後，移植區內有多數局限性TH(+)細胞和纖維存活。移植6-9週後，移植區內僅存非常少數的TH(+)細胞，但是卻有大量的TH(+)神經纖維增生。移植12週後，移植區內僅存非常少數的TH(+)細胞與TH(+)神經纖維。然而在T2G移植後移植區附近GAD(+)細胞之表現伴隨著存活TH(+)細胞的表現而有增量或減量調控的現象，此結果顯示存活的移植組織可與宿主產生功能性的交互作用。另外在移植人T2F或鼠上頸交感神經節則沒有TH(+)細胞存活，亦不能改善旋轉行為。因此移植T2G改善動物旋轉行為與TH(+)細胞與TH(+)神經纖維存活有關。移植鼠胚胎中腦腹側黑質組織則能較長期改善動物之旋轉行為，同時具較佳TH(+)細胞與TH(+)神經纖維存活。綜合上述結果得知，異體移植人T2G細胞可存活於單側巴金氏症裸鼠紋狀體，且可部份改善動物巴金氏症行為。

　　Parkinson's disease (PD) is a progressive neurodegenerative disorder, which involves destruction of nigrostrial dopaminergic pathway. Medical treatments using L-DOPA or other dopaminergic agonists often result in side effects and drug resistance. We and others previously found that transplantation of fetal nigral tissue to the parkinsonian rats restores DA functions. In this study, we investigate the functional recovery as determined by rotational behavior and anatomical restoration of tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD) as revealed by immunocytochemistry after xenografting of human second thoracic sympathetic ganglion (T2G.) Unilateral nigrostriatal deafferentation was performed by injection of 6-hydroxydopamine (6-OHDA) into left medial forebrain bundle of chloral hydrate anesthetized Sprague-Dawley rats and Fischer 344 nude rats. The effectiveness of lesioning was evaluated by measuring methamphetamine (MA) -induce rotation. Our data revealed that grafting human T2G partially reversed the MA-induced rotation by two weeks in the nude rats. The rotational behavior gradually returned to the pre-grafting level by three months. More importantly, this functional recovery was substantiated by the TH and GAD immunoreactivities. Similar to the behavioral response, two to four weeks after tansplantation, we found numerous TH positive neurons and fibers within the grafted striatum. Although we did not observe obvious TH positive cells six to nine weeks after grafting, we found a considerable TH positive cells six to nine weeks after grafting, we found a considerabe TH positive fiber sprouting in the grafting region. Three months after grafting, only a few TH ositive neurons and fibers was noted. Contrary to the human T2G grafting, both SCG grafting and T2 fiber grafting failed to improve the rotational behavior and to reveal any TH immunoreactivity. Fetal VM grafting resulted in amelioration the rotational behavior at three months out not two weeks after transplantation. Concomitantly, the profound TH positive cells and dense plexus of TH fibers in the grafting region is responsible for long term behavioral improvement. Meanwhile, the up- or down-regulation of GAD expression around the grafting region was modulated by the TH expression suggesting a functional interaction between the donor and host cells. Taken together, our data revealed that human T2G xenograft can survive in the hosts and partially reverse the rotational behavior.