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系統識別號 U0026-1208201111543200
論文名稱(中文) 腦低溫術與阿哥馬丁在腦創傷之治療評估
論文名稱(英文) Therapeutic evaluation of brain hypothermia and Agmatine in traumatic brain injury
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 99
學期 2
出版年 100
研究生(中文) 郭進榮
研究生(英文) Jinn-Rung Kuo
學號 s9894105
學位類別 博士
語文別 英文
論文頁數 184頁
口試委員 口試委員-黃朝慶
召集委員-莊季瑛
指導教授-林茂村
指導教授-羅崇杰
口試委員-蔡坤哲
口試委員-林秋烽
中文關鍵字 腦創傷  選擇性腦低溫術  阿哥馬丁  氧化氮化壓力  神經新生  血管新生 
英文關鍵字 Traumatic brain injury  Selective brain cooling  Agmatine  Oxidative and Nitrosative stress  Neurogenesis  Angiogenesis 
學科別分類
中文摘要 在先前研究中我們已發現:選擇性腦低溫術對於由液體衝撞誘發大白鼠腦損傷有治療效果。本論文中,我們將釐清選擇性腦低溫術與一氧化氮合成酶抑制劑–阿哥馬丁(做為正向控制),在腦創傷後氧化、氮化壓力及血管細胞新生、神經細胞新生之影響。在臨床運用上,除了將選擇適合腦低溫術之合適人選外,我們也將評估目前溫度監測器之準確性及腦溫對腦創傷患者之影響。
第一部份基礎研究<一>中,首先我們檢測腦低溫術是否可減輕腦創傷所產生之氧化、氮化壓力傷害。結果發現腦傷後之運動功能障礙及氧化壓力傷害 (較低值的大腦超氧化物歧化酶、麩胺基硫過氧化酶、 麩胺基硫還原酶、過氧化氫酶、及較高值丙二醛),及氮化壓力傷害(較高值之神經性一氧化氮合成酶及3-氮化酪胺酸)可以經由逆行性頸靜脈注射攝氏四度生理食鹽水所造成之腦低溫術,顯著地降低傷害。因此,我們推議腦低溫術可藉由減輕氧化、氮化壓力傷害而促進運動功能進步
其次,我們由螢光染色檢測血管細胞新生及神經細胞新生是否可被腦低溫術所刺激,結果發現 (1).腦低溫術可以減少神經細胞及神經膠細胞凋亡現象 (2). 腦低溫術可以促進神經細胞新生(溴脫氧尿甘正反應之神經細胞)及血管細胞新生(溴脫氧尿甘正反應之血管神經細胞)。我們結論為腦低溫術可以刺激神經細胞及血管細胞新生而減輕腦創傷之損害
第一部份基礎研究<二>中,為正向控制研究,我們以一氧化氮合成酶之抑制劑阿哥馬丁來評估它對腦創傷之影響,結果發現經由給與阿哥馬丁治療可減輕腦創傷後在海馬迴所增加之麩胺酸、含氮氧化物、乳酸/焦葡萄酸鹽比值及甘油濃度,另外因腦創傷所造成大腦栓塞體積及運動感覺功能障礙,也會因給與阿哥馬丁而顯著改善。我們推論阿哥馬丁藉由降低大腦含氮氧化物及麩胺酸堆積而達到腦保護作用,同時我們也証實給與阿哥馬丁治療與腦低術治療一樣也可以促進血管及神經細胞新生
在第二部份人體臨床運用上,我們首先嘗試篩選擇腦創傷後適合接受腦低溫術之合適人選,結果發現接受顱骨切除減壓手術者是一個獨立性的預後決定因子,我們也建議此類患者可作為腦創傷術後接受選低溫術之合適人選。其次在腦溫量測研究中,我們發現目前臨床上實際執行溫度量測方法可能導致臨床醫師低估腦溫數值,同時當腦溫溫度低於體溫溫度,發生逆轉時將是一個不良預後指標。
我們結論為:選擇性腦溫術與給與阿哥馬丁治療,可減輕腦創傷傷害。它們的作用機轉是經由減輕氧化、氮化壓力傷害,細胞凋亡及促進神經細胞、血管細胞新生有關。腦創傷術後接受顱骨切除減壓手術病患可作為接受選低溫術之合適人選。至於在執行選擇性腦溫術時,最恰當之腦溫值及如何評估腦部情況,需進一步去釐清。
英文摘要 Based on previous study, we have found seletive brain cooling had therapeutic effect on fluid percussion induced (FPI) brain injury in rat. In the thesis, we will eluciate the selecive brain cooling and Agmatine (a NO synthese inhibitor as a positive control) effects on oxidative and nitrosative damage, neurogenesis and angiogenesis that occurred during traumatic brain injury (TBI). In the clinical application, beside to select the candidate for brain cooling treatment after TBI, we also try to evaluate the accuracy of temperature monitor and brain temperature effect on TBI patients.
In the first part of basic research I study, first we test whether brain cooling causes attenuation of TBI by reducing brain nitrostative and oxidative damage. We found all the motor deficits and brain oxidative (lower values of cerebral superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, but higher values of cerebral malondialdehyde) and nitrostative damage (higher values of neuronal nitric oxide synthase and 3-nitrotyrosine) was significantly reduced by retrograde perfusion of 4°C saline via the jugular vein. Our data suggest that brain cooling may improve the outcomes of TBI in rats by reducing brain nitrostative and oxidative damage.
Next, we test whether angiogenesis and neurogenesis attenuating TBI could be brain cooling stimulated evaluated by immunofluorescence staining. We found 1. Brain cooling decreased both neuronal and glial apoptosis after FPI. 2. Brain cooling promoted neurogenesis (BrdU/NeuN positive cells) and angiogenesis ([BrdU]/endothelial positive cells) after FPI. We concluded that brain cooling stimulated angiogenesis and neurogenesis attenuateda fluid percussion TBI in rats.
In the basic research 2 study (positive control study), we test the NO synthese inhibitor- agmatine effect on TBI rat. We found Agmatine significantly attenuated the TBI-induced increased hippocampal levels of glutamate, nitric oxide, lactate to pyruvate ratio, and glycerol. In addition, the TBI-induced cerebral infarction, motor and proprioception deficits evaluated 3 days after TBI were significantly attenuated by Agmatine administered. We concluded the agmatine may attenuate TBI by reducing the excessive accumulation of both glutamate and nitric oxide in the brain. We further found that Agmatine-promoted angiogenesis and neurogenesis in TBI rats as found treated with brain cooling.
In the second part of clinical study, we first try to select the candidate for brain cooling treatment after TBI. We found patients underwent decompressive craniectomy was an independent outcome predictor in severe TBI and we recommend these patients could be candidates for selective brain cooling post-operatively . Finally, we measure brain temperature while maintaining brain normothermia in patients with severe TBI. We found the daily practice of temperature measurement may cause doctors to underestimate brain temperature and reversal of the core and brain temperatures could be an early marker of a poor prognosis for patients with severe TBI.
We concluded selective brain cooling and Agmatine had beneficial effects on TBI. Their mechanisms for brain protection were due to attenuate oxidative and nitrosative damage, cell apoptosis, and increase neurogenesis and angiogenesis that occurred during TBI. Patient underwent decompressive craniectomy could be a candidate for selective brain cooling after TBI. The optimal temperature and method to monitor the brain condition need to be clarified if selective brain cooling is to be performed.
論文目次 目錄 頁碼
中文摘要 1
Abstract 4
Acknowledgement 7
Thesis Contents 8
Table list
Basic research 11
Clinical research 11
Figure list
Basic research 13
Clinical research 17
Abbreviations 19
Background 21
Materials and Methods
Basic research 30
Clinical research 39
Results
Basic research 44
Clinical research 53
Discussion
1. Brain cooling effects on nitrosative and oxidative damage 58
2. Brain cooling effects on neuronal loss and apoptosis 60
3. Brain cooling effects on neurogenesis and angiogenesis 61
4. Brain cooling effects on astrogliosis and microgliosis 62
5. Agmatine effect on cell ischemia and damage 63
6. Agmatine effects on nitrosative stress 65
7. Agmatine effects on neuronal loss, neurogenesis and angiogenesis 66
8. Agmatine effects on astrogliosis and microgliosis 68
9. Incline plane device 69
10. Hypothermic retrograde vein flush with 4°C saline in clinical
application 70
11. Age is an independent prognostic predictor in TBI patients 71
12. Pupil reactivity to light stimulus is an independent prognostic
predictor in TBI patients 71
13. The distance of brain CT midline shift is an independent prognostic
predictor in TBI patients 72
14. Injury severity score is an independent prognostic predictor in TBI
patients 72
15. Decompressive craniectomy is an independent prognostic predictor
in TBI patients 73
16. Selective brain cooling via hypothermic retrograde jugular vein
flush versus local brain cooling on the scalp surface of craniectomy
area 74
17. Technique in brain temperature measurement in TBI patients 75
18. Brain temperature changes following TBI 75
19. Brain temperature measurement in TBI patients 76
20. The reversal phenomenon may be an early marker of a poor prognosis
77
21. The incidence and temperature gradient of the reversal phenomenon
in survivors and non-survivors. 78
Conclusion 79
References 80
Tables
Basic research 115
Clinical research 116
Figures
Basic research 120
Clinical research 158
Appendix
1. Figures of the oxidative (ROS) and nitrosative stress (RNS) 166
2. Traumatic brain injury model 167
3. Hypothermic retrograde jugular vein flush (HRJVF) with 4°C normal
saline 168
4. Agmatine structure and mode of action 169
5. Hypothesis I 170
6. Hypothesis II 171
7. Summary of the basic research design 172
8. Summary of the neuroprotective mechanisms of selective brain
cooling in traumatic brain injury 173
9. Summary of the neuroprotective mechanisms of Agmatine in
traumatic brain injury 174
10. Summary of the results of basic and clinical research 175
Publications during 2005-2011
1. Thesis related publications 176
2. Others publications 178
簡歷 184
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