臺灣博碩士論文加值系統

藥物抑制與基因剔除環氧化合物水解酶(sEH)可以改善動物的缺血性中風，有可能是透過防止有益血管舒張的環氧二十碳三烯酸(EET)被減少代謝，然而其神經保護機制仍不清楚，是否改變缺血後興奮性傳導和神經滋養訊息仍屬未知？在本研究中，成年野生型和sEH剔除（sEH KO）小鼠接受永久性中大腦動脈閉塞（MCAO）術，並且野生型小鼠再接受中風後連續7天的腹膜內注射sEH水解酶抑制劑（AUDA，10mg / kg /天）。我們發現在MCAO後， AUDA組和sEH KO組的小鼠與對照組相比，其腦中的sEH活性和梗塞體積顯著減少，同時顯著改善了其癱瘓上肢的感覺運動功能。我們同時在AUDA組與sEH KO組中的受傷腦半球中發現了磷酸化TrkB的增加；然而兩組在谷氨酸受體的改變則不盡相同。此外對在AUDA組和sEH KO組的免疫組織化學染色進一步揭示在梗塞附近的皮質，神經元的磷酸化TrkB和微血管有顯著增加，暗示著神經血管的增加。再者我們使用海馬迴切片的離體缺血模型來檢驗缺血後區域興奮性的突觸後電位。引人注意的是，在藥物抑制或基因剔除sEH下，會減弱缺血後興奮性的長期增益效應，若給予sEH KO小鼠TrkB拮抗劑ANA12的前處理，則在體外會逆轉被減弱的長期增益效應，也在體內會消弭被減小的梗塞，回到類似野生型小鼠的梗塞大小。藥物抑制與基因剔除sEH的神經保護效果至少有部分是透過增強TrkB的活化訊息來達到減輕缺血後神經的過度興奮及神經的功能缺陷。

Pharmacological inhibition and gene deletion of soluble epoxide hydrolase (sEH) has been suggested to ameliorate infarction in preclinical ischemic stroke by preventing metabolism of beneficial epoxyeicosatrienoic acids. However, it is unclear whether the neuroprotection of sEH inhibition involves alteration of post-ischemic excitatory transmission and neurotrophic signaling. Here, a permanent middle cerebral artery occlusion (MCAO) model was used in adult wild-type and sEH knockout (sEH KO) mice, and wild-type mice were treated with sEH hydrolase inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA, intraperitoneal injection at 10 mg/kg/day) for 7 days after MCAO. We found that sensorimotor recovery of the paretic limbs was significantly enhanced with decreased sEH activity and infarct volume in the brain relative to controls in both AUDA-treated and sEH KO mice after MCAO. TrkB phosphorylation enhancement rather than glutamate receptor alteration was consistently found in the ipsilesional hemisphere by both sEH inhibition and gene deletion. Immunohistochemistry further revealed augmentation of peri-infarct TrkB activation in cortical neurons and the microvasculature in AUDA-treated and sEH KO mice, suggesting a neurovascular enhancement. An ex vivo ischemia model of hippocampal slices was then used to examine post-ischemic field excitatory postsynaptic potentials. Intriguingly, post-ischemic long-term potentiation was attenuated by sEH inhibition or deletion, and TrkB antagonist ANA12 pretreatment eliminated this effect ex vivo and also abolished the infarct reduction by sEH deletion in vivo. The neuroprotective effects of sEH inhibition and gene deletion are both mediated via enhancement of TrkB signaling that attenuates post-ischemic neuroexcitation and neurological deficits.

致謝 I
中文摘要 IV
英文摘要 V
縮寫對照 VI
目錄 VII
第一章 背景 1
第1節 可溶性環氧水解酶(sEH)在腦中風的角色 1
第2節 腦缺血後谷氨酸過量刺激及神經興奮性長期增益效應 4
第3節 sEH抑制或剔除與腦源性神經滋養因子(BDNF)的關聯 6
第二章 目的與假說 8
第三章 方法 9
第1節 小鼠的永久性中大腦動脈阻斷術模型 9
第2節 小鼠的運動感覺行為測試 9
第3節 腦部梗塞體積的測量 10
第4節 水解酶活性及脂肪酸測量 11
第5節 蛋白質測定 11
第6節 基因表現測量 12
第7節 免疫螢光染色 13
第8節 海馬迴切片的缺氧缺糖模型與缺血性長期增益效應(iLTP) 13
第9節 以原肌球蛋白受體激酶B(TrkB)拮抗劑探討神經保護機制 14
第10節 統計分析方法 14
第四章 結果 16
第1節 藥物抑制與基因剔除sEH減少梗塞體積並降低水解酶活性 16
第2節 抑制與剔除sEH改善中風後的運動功能 16
第3節 抑制與剔除sEH減少iLTP的興奮性 17
第4節 抑制與剔除sEH改變損傷腦側谷氨酸受體的表現 17
第5節 抑制與剔除sEH促進TrkB的表現及活化 18
第6節 抑制與剔除sEH對基因的改變 19
第7節 抑制與剔除sEH對梗塞周圍腦皮質組織的影響 19
第8節 抑制TrkB對神經保護機制的影響 20
第五章 結論-抑制或剔除sEH對缺血性傷害的神經保護機制 21
第六章 討論 22
第1節 sEH抑制對生理性及缺血性長期增益效應及神經可塑性的影響 22
第2節 本研究的限制 23
第3節 本研究未來方向 24
參考文獻 25
附表 33
表1. 西方墨點法與免疫組織螢光染色法的使用抗體 33
表2. 即時聚合酶連鎖反應所使用的引子總整理 34
附圖 35
圖1. 實驗設計 35
圖2. 可溶性環氧化物水解酶(sEH)的藥物抑制和基因剔除改善缺血後急性腦梗塞以及感覺運動缺陷 36
圖3. 海馬迴腦片iLTP的區域性興奮性突觸後電位變化 38
圖4. 抑制或剔除sEH對谷氨酸受體蛋白表現量的影響 39
圖5. 抑制或剔除sEH對BDNF及其受體的蛋白質改變 41
圖6. 抑制或剔除剔除sEH對目標基因的影響 42
圖7. 抑制或剔除sEH在腦部梗塞周圍的細胞表現 43
圖8. 專一性的TrkB拮抗劑對基因剔除sEH在體外電生理與體內的腦梗塞之影響 45

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