本文選題：神經(jīng)因子 + 脊髓損傷　； 參考：《南方醫(yī)科大學》2016年博士論文

【摘要】：背景：腦和脊髓共同構成神經(jīng)系統(tǒng)的主體部分中樞神經(jīng)系統(tǒng),主要負責信息的加工、傳遞和儲存。脊髓位于脊椎骨組成的椎管內(nèi)且被脊椎保護,是中樞神經(jīng)的低級延伸部分,同時也是人體簡單活動的初級反射中樞。交感神經(jīng)和一部分副交感神經(jīng)都起源于脊髓側角或者相當于側角的部位,主要功能是在周圍神經(jīng)與大腦之間傳遞信息。脊髓具有反射、傳導、運動和調節(jié)四大功能,來自四肢、軀干和大部分內(nèi)臟的各種感覺傳入神經(jīng)沖動,能夠通過脊髓的上行纖維束傳入到大腦中樞系統(tǒng),進行更加高級的綜合分析。由大腦發(fā)出的沖動,也必須通過脊髓白質的下行纖維束才能夠調節(jié)軀干、四肢骨骼肌和內(nèi)臟的生理活動。脊髓損傷(Spinal cord injury, SCI)作為一種常見的高致殘性、致死性神經(jīng)系統(tǒng)創(chuàng)傷,同時也是最嚴重的脊柱損傷并發(fā)癥。外傷、炎癥、腫瘤等導致椎體的移位或碎骨片突出于椎管內(nèi),導致脊髓或馬尾神經(jīng)出現(xiàn)不同程度的損傷,最終導致各種運動、感覺和括約肌功能障礙,肌張力及病理反射異常,會出現(xiàn)感覺障礙、運動障礙以及反射功能障礙等癥狀,還會導致許多器官功能障礙,其中以循環(huán)系統(tǒng)和呼吸系統(tǒng)的并發(fā)癥最為普遍且常見。隨著全球經(jīng)濟的快速發(fā)展,脊髓損傷的發(fā)生率呈現(xiàn)出上升趨勢。脊髓損傷按照病因學、病理學、損傷的嚴重程度和解剖部位不同可以分成不同的類型,疾病的演變進程呈現(xiàn)瀑布樣級聯(lián)反應,目前醫(yī)學界對脊髓損傷發(fā)病機制有待深入闡述。研究表明,脊髓損傷主要包括原發(fā)性損傷和繼發(fā)性損傷兩種損傷機制。其中,原發(fā)性損傷被動地發(fā)生在損傷后短時間內(nèi),是局限的、不可逆的。原發(fā)性損傷后的數(shù)分鐘到數(shù)天內(nèi)可逐漸形成可干預性的繼發(fā)損害。繼發(fā)性脊髓損傷的病理改變是由微循環(huán)障礙、興奮性氨基酸毒性、自由基損傷、一氧化氮機制、細胞凋亡與壞死、鈣超載、炎癥反應、神經(jīng)肽、內(nèi)皮素、前列腺素等等共同作用的結果。有資料顯示原發(fā)性損傷和繼發(fā)性損傷二者均對進行性的神經(jīng)組織功能喪失起到至關重要的作用。本病發(fā)病機制復雜,治療難度大,給患者本人帶來不可估量的身心傷害的同時,還給患者家庭和整個社會造成巨大的經(jīng)濟負擔。多種直接或間接致病因素均可造成不同程度的脊髓損傷,除了物理損傷以外,氧化應激也參與中樞神經(jīng)系統(tǒng)損傷機制的發(fā)生發(fā)展。機體在遭受任何形式的創(chuàng)傷時,神經(jīng)因子可以觸發(fā)固有干細胞作為信息傳導信號。脊髓組織含有豐富的脂類物質,易感于脂質過氧化反應。生理狀態(tài)下,內(nèi)源性氧化系統(tǒng)(包括超氧化物岐化酶(Superoxide dismutase,SOD)和過氧化氫酶(Catalase, CAT)等)為了維持人體內(nèi)各種細胞和亞細胞的結構完整性,可以有效地消除人體內(nèi)多余的自由基。脊髓損傷后,自由基生成增加與清除障礙,脊髓組織脂質過氧化產(chǎn)物蓄積,細胞膜的結構、流動性和通透性遭到破壞,同時抗氧化劑水平降低和Na+-K+-ATP酶系統(tǒng)受抑制,脊髓組織缺血、缺氧和細胞能量代謝失常,細胞內(nèi)鈣超載,使細胞線粒體電子傳遞鏈脫耦聯(lián),又產(chǎn)生和釋放大量氧自由基,最終導致神經(jīng)細胞及髓鞘的結構與功能受到損害。研究認為影響脊髓損傷治療與預后的因素主要是神經(jīng)修復與再生的困難性,因此,脊髓損傷治療的主要目的是通過各種治療措施為脊髓損傷的神經(jīng)再生提供一個有利的微環(huán)境,促進受損神經(jīng)軸突的再生以恢復其功能。目前醫(yī)療界尚缺乏有效的脊髓損傷的治愈手段,針對脊髓損傷的預防、治療和康復已成為全世界普遍面臨的一個大問題。脊髓損傷患者的臨床治療只能行脊髓減壓及脊椎穩(wěn)定術,無法根本性修復已經(jīng)損壞的脊髓組織。隨著神經(jīng)損傷分子病理學研究領域的不斷突破,人們發(fā)現(xiàn)機體產(chǎn)生的可溶性蛋白質分子——神經(jīng)營養(yǎng)因子(Neurotrophicfactors,NTFS),能夠促進神經(jīng)細胞存活、生長和分化,對于神經(jīng)系統(tǒng)的發(fā)育及營養(yǎng)具有重要意義。膠質細胞源性神經(jīng)營養(yǎng)因子(Glial derived neurotropic factor, GDNF)廣泛分布于神經(jīng)系統(tǒng)中,在神經(jīng)系統(tǒng)的發(fā)育、生長、損傷和修復的過程中均扮演著重要的角色,對多種神經(jīng)元具有營養(yǎng)作用,可以預防缺血性腦血管疾病和神經(jīng)系統(tǒng)變性性疾病。GDNF已經(jīng)成為當前生命科學領域的研究熱點之一。目的：理論研究部分旨在通過對文獻的深入研究挖掘,探討現(xiàn)代醫(yī)學與傳統(tǒng)醫(yī)學對脊髓損傷認識的異同及各自的特點,總結近年來脊髓損傷發(fā)病機理方面取得的成就,深入挖掘神經(jīng)營養(yǎng)因子治療髓損傷領域的當前研究現(xiàn)狀,以期為今后該領域的研究提供相關數(shù)據(jù)支持。實驗研究部分的主要目的是探討膠質細胞源性神經(jīng)營養(yǎng)因子在大鼠脊髓損傷模型中的抗氧化作用。方法：理論研究部分以PubMed為主要檢索工具,按照嚴格的納入排除標準,篩選出符合標準的神經(jīng)營養(yǎng)因子治療脊髓損傷的相關文獻,通過文獻計量分析方法總結脊髓損傷領域的研究現(xiàn)狀及熱點問題。實驗研究部分采用Wistar大鼠靜力性脊髓壓迫損傷模型。健康成年雌性Wistar大鼠60只,隨機分成5組：假手術組、手術對照組和給藥組Group Ⅰ、Group Ⅱ、Group Ⅲ (GDNF 5mg/kg, 10mg/kg,20mg/kg),每組12只,每天經(jīng)鼻飼給予GDNF 1次,連續(xù)給藥5天。評估血清總抗氧化狀態(tài)(Total oxidant status,TOS),檢測脊髓組織中ROS水平、脂質過氧化產(chǎn)物和蛋白質羰基含量等指標來評價GDNF對脊髓損傷大鼠氧化應激水平的影響：測定抗氧化物谷胱甘肽(Glutathione, GSH)水平,過氧化氫酶(CAT)、超氧化物歧化酶(SOD)、谷胱甘肽過氧化物酶(Glutathione peroxdiase,GPx)活性和谷胱甘肽-S轉移(Glutathione-S-transferase,GST)反應等指標來考察GDNF的抗氧化能力。結果：文獻計量學分析了從1990年至2015年25年間發(fā)表的關于神經(jīng)營養(yǎng)因子治療脊髓損傷的文獻,共計606篇。其中以實驗動物為研究對象的有408篇(占67.33%,408/606),以人為研究對象的是156篇(占25.74%,156/606)。神經(jīng)營養(yǎng)因子治療脊髓損傷的相關研究總體成上升趨勢,該領域仍是當前研究的熱點問題。截止至2015年神經(jīng)營養(yǎng)因子治療脊髓損傷相關研究最多的國家是美國,其次是中國,日本、加拿大、瑞典緊隨其后位列第3-5位。在相關文獻總發(fā)表量排名達到前10的期刊中,神經(jīng)科學相關專業(yè)的期刊有9種(占90%,9/10),但只有《journal of neuroscience》的影響因子在5以上。排名前10熱點關聯(lián)詞分別是神經(jīng)生長因子(Nerve Growth Factors, NGF)、功能恢復(Recovery of Function)、神經(jīng)營養(yǎng)因子受體結合(neurotrophin receptor binding)、神經(jīng)再生(Nerve Regeneration)、干細胞(Stem Cells)、神經(jīng)元可塑性(Neuronal Plasticity)、神經(jīng)營養(yǎng)素3(Neurotrophin 3,NT-3)、BDNF、trkB受體(Receptor, trkB)、谷胱甘肽調節(jié)鉀外排系統(tǒng)蛋白kefB (Glutathione-regulated potassium-efflux system protein kefB)。在GDNF抗脊髓損傷后氧化損傷的實驗研究中發(fā)現(xiàn),與模型組相比,GDNF(10mg/kg)能顯著降低血清TOS,減少脊髓組織中的ROS水平,同時,GDNF可顯著降低脂質過氧化和蛋白質羰基化,升高GSH、CAT、SOD、GPx、GST的水平,改善氧化應激。GDNF減少氧化應激,增加抗氧化水平,呈劑量依賴性。10mg/mL and 20mg/mL較對照組明顯改善,彼此之間無顯著差異。結論：本研究證實GDNF是通過減少氧化應激,增加抗氧化水平來實現(xiàn)對脊髓損傷大鼠模型的生物學作用。GDNF在抗脊髓損傷方面具有較好的生物學活性,值得深入探索和研究。
[Abstract]:Background: the central nervous system, the main part of the brain and spinal cord, is the main part of the nervous system, responsible for the processing, transmission and storage of information. The spinal cord is located in the spinal canal and is protected by the spine. It is the low-level extension of the central nervous system and the primary reflex center of the human body. The sympathetic nerve originates from the lateral horn of the spinal cord or the location of the lateral angle. The main function is to transmit information between the peripheral nerve and the brain. The spinal cord has four functions of reflex, conduction, motion, and regulation. The sensory afferent impulses from the limbs, trunk and most of the viscera can be afferent through the superior fiber bundle of the spinal cord to large The brain central system makes a more advanced comprehensive analysis. The impulses from the brain also have to be able to regulate the trunk, the skeletal muscles and the internal organs of the limbs through the descending fibers of the white matter of the spinal cord. Spinal cord injury (SCI) is a common high disability, fatal nervous system trauma, and also the most severe. Severe complications of spinal injury. Trauma, inflammation, and tumor, resulting in vertebral displacement or broken bone fragments out of the spinal canal, resulting in varying degrees of damage to the spinal cord or the cauda equina, resulting in various movements, sensory and sphincter dysfunction, muscular tension and pathological reflex, and the appearance of sensory disorders, dyskinesia, and reflex function. Disorders such as symptoms can also lead to many organ dysfunction, with complications most common and common in the circulatory system and the respiratory system. With the rapid development of the global economy, the incidence of spinal cord injury is on the rise. Spinal cord injury can be divided according to etiology, pathology, severity of injury and dissection of the anatomy. In the same type, the process of the evolution of the disease presents cascade cascade reaction, and the pathogenesis of spinal cord injury remains to be discussed in the medical field. The study shows that the spinal cord injury mainly includes two mechanisms of primary injury and secondary injury. The pathological changes in secondary spinal cord injury include microcirculation disorder, excitatory amino acid toxicity, free radical damage, nitric oxide, apoptosis and necrosis, calcium overload, inflammatory reaction, neuropeptides, endothelin, prostaglandins and other common effects on secondary spinal cord injury. Results. Data show that both primary and secondary injuries are of vital importance to the loss of progressive neurological function. The pathogenesis of this disease is complex, the treatment is difficult, it brings immeasurable physical and mental injury to the patient, and it also gives a huge economic burden to the patients' family and the society as a whole. Direct or indirect pathogenic factors can cause different degrees of spinal cord injury. In addition to physical damage, oxidative stress also participates in the development of the central nervous system damage mechanism. When the body suffers any form of trauma, the nerve factor can trigger the inherent stem cells as a signal transduction signal. The spinal cord contains rich lipids. Substances are susceptible to lipid peroxidation. Under physiological conditions, endogenous oxidative systems (including Superoxide dismutase, SOD) and catalase (Catalase, CAT), etc.) can effectively eliminate the excess free radicals in the human body in order to maintain the structural integrity of various cells and subcells in the human body. The lipid peroxidation product of the spinal cord, the accumulation of lipid peroxidation products in the spinal cord, the structure, the structure, the fluidity and permeability of the cell membrane were destroyed, and the level of antioxidant and the Na+-K+-ATP enzyme system were inhibited, the spinal cord ischemia, anoxia and cell energy metabolism disorder, the intracellular calcium overload, and the removal of the mitochondrial electron transfer chain. Coupled with a large number of oxygen free radicals produced and released, the structure and function of the nerve cells and myelin sheath were damaged. The study believed that the main factors affecting the treatment and prognosis of spinal cord injury were the difficulty of nerve repair and regeneration. Therefore, the main purpose of the treatment of spinal cord injury is to use various treatment measures to regenerate the nerve of spinal cord injury. It provides a favorable microenvironment to promote the regeneration of the damaged neurite to restore its function. There is still a lack of effective cure for spinal cord injury. The prevention of spinal cord injury, treatment and rehabilitation have become a major problem all over the world. The clinical treatment of spinal cord injury patients can only be treated with spinal cord decompression and spinal cord. Vertebral stabilization can not fundamentally repair the damaged spinal cord. With the continuous breakthrough in the field of molecular pathology, the soluble protein molecule Neurotrophicfactors (NTFS) produced by the body can promote the survival, growth and differentiation of nerve cells and the development of the nervous system. And nutrition is of great significance. Glial derived neurotropic factor (GDNF) is widely distributed in the nervous system and plays an important role in the development, growth, injury and repair of the nervous system. It is nutritious to a variety of neurons and can prevent ischemic cerebrovascular disease. .GDNF, a neurodegenerative disease, has become one of the hot topics in the field of life science. The purpose of this study is to explore the similarities and differences between modern medicine and traditional medicine on spinal cord injury and their respective characteristics through in-depth study of literature. In order to explore the current research status of neurotrophic factors in the field of spinal cord injury in order to provide data support for future research in this field, the main purpose of the experimental study is to explore the anti oxidative effect of glial cell derived neurotrophic factor in the rat model of spinal cord injury. Method: the theoretical research part is PubMed For the main retrieval tools, the relevant literature on the treatment of spinal cord injury with standard neurotrophic factors was selected according to the strict inclusion criteria, and the research status and hot issues in the field of spinal cord injury were summarized by bibliometric analysis. The experimental research part adopted the static spinal cord compression damage model of Wistar rats. 60 female Wistar rats were randomly divided into 5 groups: the sham operation group, the operation control group and the administration group Group I, the Group II, the Group III (GDNF 5mg/kg, 10mg/kg, 20mg/kg), 12 rats in each group, and were given GDNF 1 times by nasal feeding every day for 5 days. The serum total antioxidant status (Total oxidant status) was evaluated, and the levels of spinal cord tissue were detected and lipid levels were detected, lipids were detected, lipid levels detected in spinal cord tissue, lipid levels, lipids detected lipids levels, lipids detected in spinal tissue, lipids levels, lipids detected lipids levels, lipids detected levels, lipids in spinal tissue, lipids levels, lipids detected lipids levels, lipids detected levels, lipids levels detected spinal spinal tissue, lipid levels detected lipids levels, detected lipids in spinal tissue, lipid levels, lipids levels, lipids were detected The effects of peroxide product and protein carbonyl content on the level of oxidative stress in rats with spinal cord injury: the determination of the levels of glutathione (Glutathione, GSH), catalase (CAT), superoxide dismutase (SOD), glutathione enzyme (Glutathione peroxdiase, GPx), and glutathione -S transfer in rats with spinal cord injury (GDNF) (Glutathione-S-transferase, GST) reaction and other indicators to examine the antioxidant capacity of GDNF. Results: Bibliometrics analyzed the literature of neurotrophic factors for spinal cord injury published from 1990 to 2015, total of 606 articles. Among them, 408 (67.33%, 408/606) in experimental animals were studied for human studies. Like 156 articles (25.74%, 156/606). Neurotrophic factors in the treatment of spinal cord injury are generally on the rise, and this area is still a hot topic of current research. By the year 2015, the most research countries in the neurotrophic factor for spinal cord injury were the United States, which was followed by China, Japan, Canada and Sweden. Number 3-5. Among the first 10 journals, there were 9 journals (90%, 9/10) for neuroscience related majors, but only the factors of were more than 5. The top 10 hotspots were Nerve Growth Factors, NGF, and functional recovery (Recovery of Function). Neurotrophic factor receptor binding (neurotrophin receptor binding), nerve regeneration (Nerve Regeneration), Stem Cells, neuron plasticity (Neuronal Plasticity), neurotrophin 3 (Neurotrophin 3, NT-3), BDNF, glutathione regulated potassium excretion system Sium-efflux system protein kefB). In the experimental study of oxidative damage to GDNF after spinal cord injury, it was found that GDNF (10mg/kg) could significantly reduce serum TOS and reduce ROS levels in spinal cord tissue compared with the model group. Meanwhile, GDNF can significantly reduce lipid peroxidation and protein carbonylation and increase GSH, CAT, enrichment, and oxidation should be improved. .GDNF reduced oxidative stress and increased the level of antioxidant activity. The dose dependent.10mg/mL and 20mg/mL was significantly improved compared with the control group. There was no significant difference between each other. Conclusion: This study confirms that GDNF is a biological effect of.GDNF on spinal cord injury by reducing oxidative stress and increasing the level of antioxidant activity in the rat model of spinal cord injury. The mask has good biological activity and deserves further exploration and research.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R651.2

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4 呂衛(wèi)軍;;脊髓損傷康復的觀察[A];中國康復醫(yī)學會第五屆全國康復治療學術會議論文集[C];2006年

5 孫陽;呂政;高敏;李勝活;;脊髓損傷早期康復在我院開展現(xiàn)狀及開展早期康復理由[A];中華醫(yī)學會第九次全國物理醫(yī)學與康復學學術會議論文集[C];2007年

6 吳波;任先軍;郭樹章;;少突膠質前體細胞移植治療脊髓損傷[A];第八屆全國脊柱脊髓損傷學術會議論文匯編[C];2007年

7 蔡培強;湯遜;;脊髓損傷的移植治療研究現(xiàn)狀及進展[A];第八屆全國脊柱脊髓損傷學術會議論文匯編[C];2007年

8 白躍宏;;脊髓損傷的康復[A];中國康復醫(yī)學會第五次全國老年康復學術大會上海市康復醫(yī)學會成立20周年暨老年康復診療提高班論文匯編[C];2008年

9 萬里;史文博;廖利民;;夜間陰莖勃起測定系統(tǒng)對不同平面脊髓損傷者的觀測[A];中華醫(yī)學會男科學分會第十三次全國男科學術會議論文集[C];2012年

10 周謀望;;脊髓損傷康復進展[A];2013浙江省物理醫(yī)學與康復學學術年會暨第八屆浙江省康復醫(yī)學發(fā)展論壇論文集[C];2013年

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1 記者 于亞軍;首屆全國脊髓損傷外科治療與康復研討會在我市召開[N];呼和浩特日報(漢);2009年

2 ;北京：脊髓損傷發(fā)病率過高[N];健康時報;2003年

3 編譯 于娜;早期脊髓損傷有新療法[N];醫(yī)藥經(jīng)濟報;2009年

4 通訊員　陳亞偉　記者　徐丹鹿;我國每年脊髓損傷者數(shù)萬人[N];光明日報;2003年

5 上海楊浦 朱群邦;脊髓損傷患者的家居環(huán)境改進[N];上海中醫(yī)藥報;2012年

6 上海浦東 陸至順;脊髓損傷患者的心理特征[N];上海中醫(yī)藥報;2013年

7 ;脊髓損傷康復趕早[N];保健時報;2005年

8 鄭穎t，

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