背景:一氧化碳（CO）是因為含碳質材料的不完全燃燒產生的一種無色，無味的氣體。它經常被忽視或誤診，臨床上治療一氧化碳中毒常常是一個極大的挑戰並且存在許多爭議，如致病機轉, 治療方式等等，尤其是高壓氧治療。因為臨床上對於高壓氧治療在急性中毒後產生的遲發性神經系統後遺症是否有明確的療效仍然是有爭議的。
目的:驗證高壓氧治療是透過增加腦源性神經滋養因子而促進成年的海馬迴神經細胞新生，並進而改善急性一氧化碳中毒引發的遲發性認知功能損害的假設。
材料與方法:成年雄性Sprague-Dawley 大鼠體重介於250〜280公克，隨機分為五組：（1）非一氧化碳處理過的 (原生組) 對照組，（2）急性一氧化碳中毒，（3）急性一氧化碳中毒之後連續7日的高壓氧治療，（4）一氧化碳中毒後施予連續7日高壓氧治療並且經由側腦室輸注酪氨酸激酶受體乙蛋白（TrkB的-Fc）的嵌合體的Fc片段，和（5）急性一氧化碳中毒接著施予側腦室輸注腦源性神經滋養因子。急性一氧化碳中毒是由暴露大鼠於一氧化碳在2500 ppm中40分鐘，隨後一氧化碳增加到3000 ppm 持續20分鐘來進行 (共計一小時)。高壓氧治療（在2.5絕對大氣壓，100％氧氣治療60分鐘），在一氧化碳中毒後持續進行7天。腦內注射組則在一氧化碳中毒後第二天起經由所植入的滲透性微型泵將重組TrkB-Fc嵌合體或腦源性神經滋養因子持續注入側腦室達7天。一氧化碳中毒後將溴脫氧尿苷注入腹腔用以標記海馬迴的有絲分裂細胞。利用免疫組織化學染色或免疫螢光染色來標定溴脫氧尿苷和另外兩個成年神經標誌物，Ki-67和Doublecortin的在海馬迴的分佈情形。海馬迴中的腦源性神經滋養因子的量則利用酶聯免疫吸附測定進行評估。認知行為則是使用的八臂迷宮來評估。
測量和主要結果：急性一氧化碳中毒後在大鼠海馬迴的齒狀回顆粒下區可以發現的 DCX+細胞、Ki-67+細胞，和溴脫氧尿苷陽性細胞的數量明顯減少，意味著一氧化碳中毒會顯著抑制成年海馬迴神經細胞的新生及發育與成熟。這種由一氧化碳中毒引發的抑制會明顯地被早期高壓氧治療緩解。高壓氧治療也促進了海馬迴腦源性神經滋養因子的持續增長。急性一氧化碳中毒後利用重組TrkB-Fc嵌合體的腦室內注射來阻斷海馬迴腦源性神經滋養因子的訊息傳遞會顯著減弱高壓氧治療所帶來的保護作用;而腦源性神經滋養因子側腦室內注射用以模擬高壓氧的作用，則可以在急性一氧化碳中毒後依然保持神經新生的能力。此外，對於急性一氧化碳中毒所導致遲發性的認知功能損害，高壓氧治療則可以明顯地透過腦源性神經滋養因子依賴的方式改善認知功能障礙。
結論：早期高壓氧治療可透過維持海馬迴腦源性神經滋養因子含量增加成年神經細胞新生緩解急性一氧化碳中毒引發的遲發性記憶障礙。

Background: Carbon monoxide (CO) is a colorless, odorless gas produced by incomplete combustion of carbonaceous material. Commonly overlooked or misdiagnosed, CO poisoning often presents a significant challenge, as treatment protocols, especially for hyperbaric oxygen therapy, remain controversial because of a paucity of definitive clinical studies in delayed neurological sequelae after acute poisoning.
Objective: To test the hypothesis that hyperbaric oxygen therapy ameliorates delayed cognitive impairment after acute CO poisoning by promoting neurogenesis through upregulating the brain-derived neurotrophic factor (BDNF) in the hippocampus.
Materials and methods: Adult male Sprague-Dawley rats weighted 250~280 gm were randomly divided into five groups: (1) non–CO-treated Naïve, (2) acute CO poisoning, (3) acute poisoning followed by 7-day hyperbaric oxygen treatment, (4) CO + hyperbaric oxygen with additional intracerebroventricular infusion of Fc fragment of tyrosine kinase receptor B protein (TrkB-Fc) chimera, and (5) acute CO poisoning followed by intracerebroventricular infusion of BDNF. Acute CO poisoning was achieved by exposing the rats to CO at 2,500 ppm for 40 minutes, followed by 3,000 ppm for 20 minutes. Hyperbaric oxygen therapy (at 2.5 atmospheres absolute with 100% oxygen for 60 min) was conducted during the first 7 days after CO poisoning. Recombinant human TrkB-Fc chimera or BDNF was infused into the lateral ventricle via the implanted osmotic mini-pump. For labeling of mitotic cells in the hippocampus, bromodeoxyuridine was injected into the peritoneal cavity. Distribution of bromodeoxyuridine and two additional adult neurogenesis markers, Ki-67 and doublecortin, in the hippocampus was evaluated by immunohistochemistry or immunofluorescence staining. Tissue level of BDNF was assessed by enzyme-linked immunosorbent assay. Cognitive behavior was evaluated by the use of eight-arm radial maze.
Measurements and Main Results: Acute CO poisoning significantly suppressed adult hippocampal neurogenesis evident by the reduction in number of bromodeoxyuridine-positive, Ki-67+, and doublecortin+ cells in the subgranular zone of the dentate gyrus. This suppression of adult neurogenesis by the CO poisoning was appreciably alleviated by early treatment of hyperbaric oxygen. The hyperbaric oxygen treatment also promoted a sustained increase in hippocampal BDNF level. Blockade of hippocampal BDNF signaling with intracerebroventricular infusion of recombinant human TrkB-Fc chimera significantly blunted the protection by the hyperbaric oxygen on hippocampal neurogenesis; whereas intracerebroventricular infusion of BDNF mimicked the action of hyperbaric oxygen and preserved hippocampal neurogenesis after acute CO poisoning. Furthermore, acute CO poisoning resulted in a delayed impairment of cognitive function. The hyperbaric oxygen treatment notably restored the cognitive impairment in a BDNF–dependent manner.
Conclusions: The early hyperbaric oxygen treatment may alleviate delayed memory impairment after acute CO poisoning by preserving adult neurogenesis via an increase in hippocampal BDNF content.

目錄
論文審定書…………………………………………………………i
致謝….…………………………………………………………….. ii
中文摘要…….……………….……………………………………..iv
Abstract….…………………………..………………………….......vi
目錄....................................................................................................ix
Chapter 1 Introduction………………………………………………… 1
1.1 Carbon monoxide poisoning……………………………….. 2
1.2 Neurotoxicology and delayed neuropsychiatric syndrome of
carbon monoxide……………………………………………
4
1.3 Role of hyperbaric oxygen in the treatment of carbon
monoxide poisoning………………………………………...
7
1.4 Adult neurogenesis and hyperbaric oxygen therapy….......... 9
1.5 Hippocampal neurogenesis, brain-derived neurotrophic
factor and memory …………...………………………….....
11
Chapter 2 Rationale…………………………………………………… 14
Chapter 3 Study Design……………………………………………….. 17
Chapter 4 Materials and Methods…………………………................... 21
Chapter 5 Results……………………………………………………… 29
Chapter 6 Discussion……………………………………….................. 34
Chapter 7 Conclusion and Future Work………………………………. 46
Chapter 8 Figures……………………………………………………… 53
References………………………………………………...... 62
Appendix…………………………………………………… 73

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