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系統識別號 U0026-2903201903091200
論文名稱(中文) 低溫治療為由紫杉醇引起之周邊神經病變的神經保護策略
論文名稱(英文) Preventive Hypothermia as a Neuroprotective Strategy for Paclitaxel-induced Peripheral Neuropathy
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 107
學期 2
出版年 108
研究生(中文) 馬雪婷
研究生(英文) Suet-Theng Beh
學號 S58021145
學位類別 博士
語文別 英文
論文頁數 106頁
口試委員 指導教授-郭余民
召集委員-邱文泰
口試委員-陳家進
口試委員-劉彥青
口試委員-陳慧諴
口試委員-廖倫德
中文關鍵字 化學治療引起的周邊神經病變  低溫治療  神經發炎  神經毒性  光聲  乳癌 
英文關鍵字 Chemotherapy-induced peripheral neuropathy  Therapeutic hypothermia  Neuroinflammation  Neurotoxicity  Photoacoustic  Breast cancer 
學科別分類
中文摘要 化學治療引起的周邊神經病變(chemotherapy-induced peripheral neuropathy, CIPN)為癌症治療中常見的嚴重副作用,目前並沒有有效的預防或治療策略。低溫治療(therapeutic hypothermia)已被證實有效對抗中樞與周邊神經系統的損傷。然而,目前並沒有文獻探討低溫治療對於由化學治療引起的周邊神經病變的療效。我們在已建立的由紫杉醇(paclitaxel)所引起的周邊神經病變的大鼠模式中使用低背低溫治療(lower back hypothermia, LBH),發現當低溫之溫度在坐骨神經(sciatic nerve)達到24度及在給予紫杉醇90分鐘前給予低溫治療,低溫治療會抑制由紫杉醇引起之行為、電生理、與組織上的損傷。低溫治療也抑制了脊髓中的星形膠質細胞(astrocyte)和微小膠質細胞(microglia)的活化、背跟神經節(dorsal root ganglia) 和坐骨神經的巨噬細胞(macrophage)浸潤與神經元損傷以及促炎性细胞因子(pro-inflammatory cytokine)在背跟神經節、坐骨神經和脊髓背角(spinal dorsal horn)的表現與釋放。此外,低溫治療降低了局部血流量及紫杉醇局部組織濃度。最後,我們在由紫杉醇所引起的周邊神經病變的大鼠模式使用單側後肢低溫治療(unilateral hind limb hypothermia),發現低溫治療對接受治療的該側有效但對身體對側沒有效果。更重要的是,當癌細胞接種到接近低溫治療的區域於免疫缺陷小鼠腫瘤模式中,紫杉醇的抗腫瘤生長效果不受低溫治療的影響。綜合以上結果,局部低溫治療的早期介入可減輕由紫杉醇引起的周圍神經病變。低溫治療可作為對抗局部實體腫瘤癌症病患所引起的周邊神經病變之簡單和非藥物預防策略。
英文摘要 Chemotherapy-induced peripheral neuropathy (CIPN) is a severe adverse effect that occurs secondary to chemotherapeutic treatments and has no known preventive or therapeutic strategy. Therapeutic hypothermia has been shown to be effective in protecting against central and peripheral nervous system injuries. However, the effects of therapeutic hypothermia on CIPN have rarely been explored. We induced lower back hypothermia (LBH) in an established paclitaxel-induced CIPN rat model and found that the paclitaxel-induced impairments observed in behavioral, electrophysiological, and histological impairments were inhibited by LBH when applied at an optimal setting of 24°C to the sciatic nerve and initiated 90 minutes before paclitaxel infusion. Lower back hypothermia also inhibited the paclitaxel-induced activation of astroglia and microglia in the spinal cord, macrophage infiltration into and neuronal injury in the dorsal root ganglia and sciatic nerves, as well as the release of pro-inflammatory cytokines in the dorsal root ganglia, sciatic nerves, and spinal dorsal horn. Furthermore, LBH decreased the local blood flow and local tissue concentrations of paclitaxel. Finally, we induced unilateral hind limb hypothermia in paclitaxel-induced CIPN rat model and found that regional cooling is achieved with no effect on the contralateral side. Importantly, in NOD/SCID mice inoculated with cancer cells, the antiproliferative effect of paclitaxel was not affected by the distal application of hypothermia. In conclusion, our findings indicate that early exposure to regional hypothermia alleviates paclitaxel-induced peripheral neuropathy. Therapeutic hypothermia may therefore represent an economical and nonpharmaceutical preventive strategy for CIPN in patients with localized solid tumors.
論文目次 Chinese abstract I
English abstract III
Table of Contents V
List of Tables VIII
List of Figures IX
Abbreviations XI
Introduction 1
1.1 Chemotherapy-induced peripheral neuropathy 1
1.2 Paclitaxel 2
1.3 Pathophysiological mechanisms of paclitaxel-induced peripheral neuropathy 2
1.3.1 Structural changes in peripheral nerves 3
1.3.2 Increased ion channels activity 3
1.3.3 Mitochondrial damage 4
1.3.4 Neuroinflammation and neuronal injury 4
1.4 Therapeutic strategies 5
1.5 Therapeutic hypothermia 6
1.6 Objectives and specific aims 7
Materials and methods 8
2.1 Animals 8
2.2 Paclitaxel infusion protocol 8
2.3 Behavioral assessment 9
2.3.1 Cold-water immersion test 10
2.3.2 Tail-flick test 10
2.3.3 Von Frey test 11
2.3.4 Rotarod performance test 11
2.4 Temperature measurements 12
2.5 Therapeutic hypothermia procedure 13
2.5.1 Lower back hypothermia 13
2.5.2 Unilateral hind limb hypothermia 13
2.6 Preparation of stock solutions, calibration standards, and quality control samples 14
2.7 Sample preparation for UPLC-MS/MS analysis 15
2.8 Ultra-performance liquid choromatography-tandem mass spectrometer analysis 16
2.9 Measurement of electrophysiology parameters 16
2.10 Imaging of vasculature hemodynamics in the rat sciatic nerve 18
2.11 Morphometric measurements of the sciatic and spinal nerves 19
2.12 Tissue processing and immunofluorescence staining 20
2.13 Immunofluorescence image analysis and quantification 21
2.14 Enzyme-linked immunosorbent assay 22
2.15 Cell cultures 22
2.16 Tumor xenograft model 23
2.17 Statistical analysis 23
Results 25
3.1 Paclitaxel disturbs sensory and motor function in rats 25
3.2 Lower back hypothermia alleviates paclitaxel-induced neuropathy in rats 25
3.3 Lower back hypothermia prevents paclitaxel-induced peripheral nerve dysfunction 26
3.4 Lower back hypothermia reduces paclitaxel-induced pathological changes in the sciatic nerve 27
3.5 Paclitaxel treatment causes abnormalities in the axons of dorsal and ventral roots 28
3.6 Lower back hypothermia attenuates paclitaxel-induced glial activation and neuronal injury 28
3.7 Lower back hypothermia ameliorates paclitaxel-induced changes in cytokines expression 30
3.8 Hypothermia decreases local hemodynamics and drug distributions 30
3.9 Unilateral hind limb hypothermia alleviates paclitaxel-induced neuropathy in rats 31
3.10 Unilateral hind limb hypothermia prevents paclitaxel-induced peripheral nerve dysfunction 32
3.11 Unilateral hind limb hypothermia reduces paclitaxel-induced pathological changes in the sciatic nerve 32
3.12 Unilateral hind limb hypothermia ameliorates paclitaxel-induced changes in cytokines expression 32
3.13 Unilateral hind limb hypothermia decreases the toxic accumulation of paclitaxel in the sciatic nerve 33
3.14 Hypothermia does not interfere with the antitumor effect of paclitaxel 34
Discussion 35
Conclusion 40
References 41
Table 54
Figures 56
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