臺灣博碩士論文加值系統

中文摘要 本研究的目的在探討大白鼠前肢體感覺傳導徑路起源處及第二級接轉神經元處神經性結構在糖尿病初期、中期與晚期因糖尿病所引起的神經病變，以分析糖尿病對體知覺傳導系統的影響，並比較前肢與後肢足墊皮膚內糖尿病病變的差異。本研究以雄性大白鼠為材料，利用鏈狀致糖素(streptozotocin)，造成老鼠胰臟內b細胞的死亡而誘發type I糖尿病，經過一週到九個月不同的存活期後，再以含有2%三聚甲醛(paraformaldehyde)的PLP固定液進行灌流犧牲固定，取出老鼠之足墊皮膚、背根神經節、頸髓與腦幹楔狀神經核區狀，配合免疫細胞化學法以PGP9.5與substance P和CGRP抗體分別標誌足墊皮膚內的神經纖維，與背根神經節、頸髓節背角和楔狀神經核內上述免疫反應的變化，以觀察在糖尿病初期、中期與晚期周邊與中樞神經系統內的糖尿病神經病變。 研究結果顯示在糖尿病大白鼠前肢與後肢足墊內具PGP 9.5免疫反應的神經纖維有明顯的神經病變，且在不同的糖尿病病期有不同的增減變化。其中，具PGP 9.5免疫反應的真皮神經纖維(dermal fibers)有破碎的現象，晚期前肢的免疫反應量有顯著的增加。除此之外，表皮內的神經纖維(intraepithelial fibers)的邊界不清，且呈現不連續的現象，這種現象以糖尿病老鼠後肢的變化較為明顯。此外，中期時前肢者有顯著的減少，後肢有顯著的增加，初期與晚期則無明顯的差異。本研究首次發現在糖尿病的各個時期，PGP 9.5抗體標誌的Langerhans cells呈現較深的染色，且前肢在中期這些細胞數目也有顯著的增加，至中晚期則無明顯的差異；至於後肢在各個時期皆無明顯差異。利用可認識組織相容第二型抗原(major histocompatibility class II antigen, MHC class II antigen) OX6的免疫反應，標誌皮膚內所有的巨噬細胞(macrophage)，其中在在表皮者為Langerhans氏細胞，發現糖尿病大白鼠的前(與後)肢足墊皮膚內受OX6標誌的Langerhans氏細胞的數目在各個時期時大致相同，除了後肢者在糖尿病中期有明顯的減少，晚期有顯著的增加。因此糖尿病所引發皮膚中Langerhas氏細胞的PGP 9.5與OX6免疫反應有不同的表現。誘發糖尿病後，前、後肢足墊皮膚內有明顯具有PGP 9.5免疫反應的似Merkel氏細胞結構物(Merkel -cell-like structures)的出現，我們首度發現其數目會隨著糖尿病病期的加長而明顯的增加，且免疫反應也增強。 至於在頸段背根神經節、頸髓節背角與楔狀神經核免疫標誌的結果顯示，頸髓節背角的表層(superficial laminae)在糖尿病初期時，substance P免疫染色的表現有顯著的增加，而CGRP則沒有顯著的差異；至糖尿病中期與晚期時，substance P與CGRP的免疫反應並沒有顯著的變化。而頸段背根神經節與楔狀神經核中，substance P與CGRP的免疫染色表現在糖尿病的各個病程皆沒有顯著差異。糖尿病初期在脊髓背角表層substance P免疫反應的顯著增加是否即造成糖尿病初期所常見的感覺過敏現象之原因，這仍需要進一步的研究。 前肢與後肢足墊皮膚內的神經病變有程度輕重的差異，本研究認為適足以印證臨床上糖尿病患者下肢的病變常較上肢嚴重；另外，在體知覺傳導路徑中，足墊皮膚之神經纖維與標誌之細胞有顯著改變，反之在背根神經節、脊髓背角與楔狀神經核大多無顯著差異，因此我們認為糖尿病之周邊神經病變遠比中樞神經嚴重，至於其機制尚待詳細的研究與探討。

Abstract The present study aimed to investigate the neuropathic effects of the diabetes mellitus(DM) on the cells of the origin and the second order neurons in the somatosensory pathway of forelimbs, and we also compared these effects on forelimbs and hindlimbs. Young male Wistar rats were used. The DM rats were induced by streptozotocin which killed the b cell of pancreas. After different survival period from one weak to nine months, the rats were perfused with PLP fixative containing 2% paraformaldehyde. Parts of the peripheral and central sensory structures, i.e, footpads of forelimb and hindlimb, cervical dorsal root ganglia(DRG), spinal cords of C6-7, and lower medulla (cuneate region) were dissected out. Immunocytochemistry of PGP 9.5 (protein gene product 9.5) and OX6 on the skin of footpads and substance P and CGRP (calcitonin gene related peptide) on DRG, spinal cord and lower medulla were performed. The results showed the different change of PGP 9.5 immunoreactive(ir) fibers at different stages of diabetes in forelimb and hindlimb footpad. There are breakage of dermal fibers and increase of immunoreactivity in the skin of forelimb footpad at the chronic stage. Besides, there are discontinuity of intraepithelial fibers and decrease of immunoreactivity in skin of forelimb, but increase in the skin of hindlimb at intermediate stage. These changes was pronounced in the hindlimb footpad. We first found that there were significant increase of PGP 9.5 immunoreactivity in Langerhans cell, and the PGP 9.5-ir Langerhans cells in the skin of forelimb footpad increased at the intermediate stage. We used OX6, which can recognize major histocompatibility class II antigen (MHC class II antigen) to identify the all macrophages in footpads, and the macrophages in the epidermis was Langerhans cells. The results showed that there was no significant change in the footpad of forelimb at any stage but the number of OX6-ir Langerhans cells in the skin of hindlimb footpads decreased and increased at the intermediate and chronic stages respectively. These changes showed there were different expression of PGP 9.5 and OX6 immunoreactivity in diabetic rats. What may make these differences will be discussed in the discussion. Followed the induction of diabetes, there were increase in number of PGP-ir Merkel cell-like structures in forelimb and hindlimb footpad, and this increase were significant with the longer survival periods of diabetes. This is a novel finding. The immunoreactivity in DRG, dorsal horn of spinal cord and cuneate nucleus showed some change in immunoreactivity. At the acute stage of diabetes there was significant increase immunoreactivity of substance P but no significant change in CGRP immunoreactivity in dorsal horn. At the intermediate and chronic stage there was no significant change in substance P and CGRP immunoreactivity in dorsal horn. Besides, there was no significant change of substance P and CGRP immunoreactivity in DRG and cuneate nucleus at any stage of diabetes. Whether the significant increase in substance P immunoreactivity in dorsal horn may contribute the hyperalgesia at the acute stage of diabetes needs the advanced study. The difference of diabetic neuropathy between the footpads of forelimb and the ones of hindlimb can be explained clinically. The neuropathy of lower limbs of diabetic patients is more serious than the one of upper limbs. Besides, in the somatosensory pathway, there were more significant changes of PGP 9.5-ir fibers and cells in footpads, but fewer significant change in DRG, spinal dorsal horn and cuneate nucleus, which showed the more serious diabetic neuropathy in the peripheral nerve system. But the underlying mechanism is unknown and it needs more studies.

目 錄中文摘要‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧I英文摘要‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧IV緒論 ‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧1材料與方法 ‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧8結果‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧14討論‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧22參考文獻‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧32圖表與圖表說明‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧‧39

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