研究目的：脊髓損傷是中樞神經系統的嚴重創傷，致殘率高。脊髓損傷後的再生修復一直是當前醫學的難題。迄今為止，脊髓損傷依然缺乏一種有效地治療方法。既往研究證明，胰島素樣生長因子-1對鼠和兔脊髓損傷有保護作用，為了進一步把這些發現應用到臨床方面，我們採用與人類生理更相近的豬只作為實驗動物，構建與臨床相似的脊髓損傷動物模型，并以此為基礎，系統性研究胰島素樣生長因子-1的脊髓保護作用，評估該治療的功效。 / 研究方法：以運動誘發電位為指導，通過直接壓迫和牽拉造成脊髓損傷。18頭猪只隨機分為3組：胰島素樣生長因子-1治療組、生長激素治療組及生理鹽水對照組。脊髓損傷后1小時、24小時及48小時經鞘內注射給藥。于術後第1天、第3天及第21天收集腦脊液檢測胰島素樣生長因子-1和生長激素濃度。連續21天使用修正的 Tarlov 評分標準對動物的運動功能進行評估。第21天處死動物並取材，檢測脊髓中NeuN, GFAP, caspase-3 的活性，并通過TUNEL染色觀察細胞凋亡情況，比較各組之間有無差別。 / 研究結果：通過這種方法建立的脊髓損傷動物模型穩定可靠，各組之間無明顯差異。鞘內給藥24小時及48小時后，腦脊液中胰島素樣生長因子-1和生長激素濃度明顯升高，術後21天檢測，其濃度恢復至基礎值。胰島素樣生長因子-1治療組的運動功能的恢復優於其它各組。與生理鹽水對照組比較，胰島素樣生長因子-1治療組可以明顯提高脊髓損傷后神經元的存活數量，抑制星形膠質細胞增生，減少細胞凋亡。而生長激素治療組僅抑制星形膠質細胞增生，其它方面與生理鹽水對照組無明顯差別。 / 結論：胰島素樣生長因子-1通過提高神經元存活數量，抑制星形膠質細胞增生，以及減少細胞凋亡促進脊髓損傷的恢復。 / Objective: Spinal cord injury is a devastating condition that leads to long-term disabilities. Currently, there is no effective treatment that minimizes spinal cord damage or enhances neurological recovery. Recent studies in rats or rabbits suggested that neurologic recovery after spinal cord injury could be improved with the administration of neurotropic hormones, such as insulin-like growth factor-1 (IGF-1). In order to apply such bench-side discovery to clinical practice, we conducted a study in a higher animal model, akin to human physiology, to evaluate the effectiveness of intrathecal injections of IGF-1to improve neurological recovery in a porcine model of acute traumatic spinal cord injury. / Methods: Traumatic spinal cord injury model was produced by controlled compression and distraction of the exposed T12 segment of the spinal cord. Eighteen pigs were randomly assigned to receive intrathecal injections of either IGF-1, growth hormone or saline at 1, 24 and 48 hours after spinal cord injury. Locomotor function was assessed daily using the validated modified Tarlov’s scale for 21 days. Spinal cord segments were then harvested and the survival of neurons, reactive astrogliosis and apoptosis were determined using neuronal-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), cleaved caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assays. / Results: Intrathecal injections of IGF-1 and growth hormone significantly increase the concentrations of the neurotropic hormones in the cerebrospinal fluid after injury (p < 0.01). These concentrations returned to baseline by 21 days after drug delivery. Motor deficits on the first day after injury were comparable between animals in the treatment and control groups. By the end of the third week, neurologic recovery was better in animals receiving IGF-1 treatment (p < 0.05). Immunohistological and western blot studies of the injured segments of spinal cord showed that treatment with both IGF-1 and growth hormone prevented reactive astrogliosis (p < 0.05) while only IGF-1 improved the survival of mature neurons (p < 0.05). IGF-1 also inhibited apoptosis after spinal cord injury (p < 0.05). / Conclusions: In our clinically relevant model of traumatic spinal cord injury in pigs, intrathecal injection of IGF-1 demonstrated beneficial effects on neurological and histological recovery. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wang, Qinzhou. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 105-122). / Abstract also in Chinese. / Declaration of origination --- p.I / Abstract --- p.II / Acknowledgements --- p.VI / Table of Contents --- p.VIII / List of Tables --- p.XII / List of Figures --- p.XIII / Abbreviations --- p.XVIII / Chapter Part 1 --- Spinal Cord Injury: A Review --- p.1 / Chapter Chapter 1-1 --- Acute Spinal Cord Injury: Epidemiology, Socioeconomic Impact --- p.2 / Chapter 1.1.1 --- Epidemiology of Spinal Cord Injury --- p.2 / Chapter 1.1.2 --- Socioeconomic Impact of Acute Spinal Cord Injury --- p.5 / Chapter Chapter 1-2 --- Mechanisms of Spinal Cord Injury --- p.6 / Chapter Chapter 1-3 --- Putative Treatments for Spinal Cord Injury --- p.8 / Chapter 1.3.1 --- Methylprednisolone --- p.8 / Chapter 1.3.2 --- Stem Cell Therapy --- p.11 / Chapter 1.3.3 --- Riluzole --- p.11 / Chapter 1.3.4 --- Other Pharmacological Therapies for Spinal Cord Injury --- p.12 / Chapter Chapter 1-4 --- Insulin-like Growth Factor-1 for the Treatment of Spinal Cord Injury --- p.13 / Chapter Chapter 1-5 --- Summary --- p.17 / Chapter Part 2 --- Insulin-like Growth Factor-1 and Growth Hormone for Spinal Cord Injury --- p.18 / Chapter Chapter 2-1 --- Hypothesis and Objectives --- p.19 / Chapter Chapter 2-2 --- Establishment of Animal Models for Acute Spinal Cord Injury --- p.22 / Chapter 2.2.1 --- Introduction --- p.22 / Chapter 2.2.2 --- Experimental Animals --- p.22 / Chapter 2.2.3 --- Anesthesia --- p.23 / Chapter 2.2.4 --- Transcranial Electrical Motor Evoked Potential --- p.26 / Chapter 2.2.5 --- Surgery --- p.28 / Chapter 2.2.6 --- Statistics --- p.34 / Chapter 2.2.7 --- Results --- p.34 / Chapter 2.2.8 --- Discussion --- p.38 / Chapter Chapter 2-3 --- Optimal Stimulation Protocols for Transcranial Electrical Motor Evoked Potential. --- p.42 / Chapter 2.3.1 --- Introduction --- p.42 / Chapter 2.3.2 --- Methods --- p.42 / Chapter 2.3.2.1 --- Experimental Animals and Anesthesia --- p.42 / Chapter 2.3.2.2 --- Transcranial Electrical Motor Evoked Potential Recording --- p.44 / Chapter 2.3.2.3 --- Stimulation Protocol --- p.44 / Chapter 2.3.3 --- Analyses --- p.44 / Chapter 2.3.4 --- Results --- p.45 / Chapter 2.3.5 --- Discussion --- p.52 / Chapter Chapter 2-4 --- Evaluation of the Efficacy of Insulin-like Growth Factor-1 and Growth Hormone in a Porcine Model --- p.54 / Chapter 2.4.1 --- Introduction --- p.54 / Chapter 2.4.2 --- Materials and Methods --- p.54 / Chapter 2.4.2.1 --- Study Design --- p.54 / Chapter 2.4.2.2 --- Intrathecal Injection and Collection of Cerebrospinal Fluid --- p.58 / Chapter 2.4.2.3 --- Measurements --- p.58 / Chapter 2.4.2.3.1 --- Clinical Evaluation --- p.58 / Chapter 2.4.2.3.2 --- Biochemical Assessments --- p.58 / Chapter 2.4.2.3.3 --- Spinal Cord Section, Histological and Immunochemical Staining --- p.63 / Chapter 2.4.2.3.4 --- Western Blot --- p.69 / Chapter 2.4.3 --- Statistical Analysis and Sample Size Calculation --- p.72 / Chapter 2.4.3.1 --- General Analysis --- p.72 / Chapter 2.4.3.2 --- Sample Size --- p.72 / Chapter 2.4.4 --- Results --- p.73 / Chapter 2.4.4.1 --- Changes of TceMEP --- p.73 / Chapter 2.4.4.2 --- Motor Deficit after Spinal Cord Injury at Baseline --- p.75 / Chapter 2.4.4.3 --- Insulin-like Growth Factor-1 and Growth Hormone in Cerebrospinal Fluid --- p.77 / Chapter 2.4.4.4 --- Clinical Assessment --- p.80 / Chapter 2.4.4.5 --- Demyelination, Neuron Survival and Astrocyte Reaction --- p.85 / Chapter 2.4.4.6 --- Apoptosis --- p.89 / Chapter 2.4.5 --- Discussion --- p.93 / Chapter 2.4.5.1 --- Principal Findings --- p.93 / Chapter 2.4.5.2 --- Insulin-like Growth Factor-1 and Neuroprotection after Spinal Cord Injury --- p.93 / Chapter 2.4.5.3 --- Growth Hormone and Neuroprotection after Spinal Cord Injury --- p.95 / Chapter 2.4.5.4 --- Strengths and Limitations of Our Study --- p.96 / Chapter 2.4.5.5 --- Summary --- p.97 / Chapter Part 3 --- Summary and Future Directions --- p.99 / Chapter Chapter 3-1 --- Summary --- p.100 / Chapter Chapter 3-2 --- Future Directions --- p.103 / Chapter Part 4 --- References and appendixes --- p.104 / References --- p.105 / Appendixes --- p.123
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_328494 |
| Date | January 2012 |
| Contributors | Wang, Qinzhou., Chinese University of Hong Kong Graduate School. Division of Anaesthesia and Intensive Care. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography |
| Format | electronic resource, electronic resource, remote, 1 online resource (xx, 128 leaves) : ill. (some col.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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