臺灣博碩士論文加值系統

可溶性環氧化物水解酶(sEH)屬於同型二聚體酵素，在同一個單體 (monomer) 上具有兩個功能區，分別為C端環氧化物水解酶域 (C-terminal epoxide hydrolase domain)以及 N 端的脂質磷酸域 (N-terminallipidphosphatasedomain)，sEH廣泛分佈於各種組織，也高度表現在腦中，尤其是海馬迴。先前文獻已證實抑制環氧化物水解酶活性可以有效保護因缺血性而造成之腦損傷，但同時也會增加突觸之興奮性傳遞。然而，在興奮性毒性(excitotoxicity)刺激下，環氧化物水解酶抑制劑(sEHI)是否可藉由調控抑制型細胞的存活進而有助於保護記憶功能仍不清楚。在本篇研究中，我們探討在野生型小鼠(WT)中單次腹腔注射紅藻酸(Kainic acid, KA)進而誘發興奮性毒性，接續七天的復原期以此來建立動物模型，而利用鼻腔注射給予環氧化物水解酶抑制劑-TPPU(一天給予0.5mg/kg，連續給予七天)或使用Ephx2基因剔除 (Ephx2-KO)的小鼠對於興奮性毒性之影響為何。研究結果顯示WT小鼠注射紅藻酸後兩小時內癲癇發作，再給予鼻腔注射TPPU可以有效降低
癲癇行為，另外在Ephx2-KO 小鼠中注射KA相較於WT小鼠也顯示有降低癲癇行為。我們也利用海馬迴腦區相關的行為進行測試，發現在WT小鼠中給予KA誘發興奮性毒性會造成非空間之工作記憶的損傷，但在給予鼻腔注射TPPU或是Ephx2-KO小鼠中可以有效達到保護性。相反，在進行空間的學習及記憶測試中則無法恢復KA所造成之損傷。隨後，我們利用神經元特異性蛋白(NeuN)進行免疫螢光染色，發現KA誘發興奮性毒性後會使海馬迴之海馬角(CA1, CA3)以及齒狀迴(DG)的神經細胞都有損傷及減少之情形，但給予TPPU或是Ephx2-KO小鼠皆可有效降低神經細胞的減少。再來，我們利用谷氨酸脫羧酶(glutamic acid decarboxylase 65)(GAD65)進行螢光染色去標定抑制性神經細胞，發現KA誘發興奮性毒性後會使海馬迴之CA1, CA3以及DG的神經細胞損傷及減少，此結果可有效被TPPU減低。接著，我們去檢查抑制性神經細胞的其中一類-parvalbumin (PV) 蛋白所表現之神經細胞(PV+ cell)，結果顯示TPPU可有效減低KA造成的海馬迴 中CA1以及CA3神經細胞損傷之情形。而Ephx2-KO小鼠則可減低KA造成海馬迴 中CA1內PV+抑制型神經細胞損傷之情形。更進一步檢視另一類有calretinin (CR) 蛋白表現之神經細胞(CR+ cell)，發現TPPU或是Ephx2-KO小鼠皆可減低KA造成 海馬迴中的DG內CR+抑制型神經細胞損傷之情形。另外，我們試著使用細胞實驗 去驗證在動物實驗中之現象，我們利用WT出生第零天之小鼠進行初代神經細胞 以及神經膠細胞培養，爾後進行免疫螢光染色發現給予麩胺酸受體亞型N-甲基- D-天冬氨酸(N-methyl-D-aspartate receptor, NMDA)去誘發興奮性毒性，NMDA確 實會造成神經細胞死亡，然而在NMDA之前提前給予TPPU 30分鐘處理可以有效 減少神經細胞的死亡以及樹突之減少。接著，我們利用谷氨酸脫羧酶(glutamic acid decarboxylase 67)(GAD67)進行螢光染色去標定抑制性神經細胞以及進行西 方點墨法測定其蛋白質表現量的變化，發現給予NMDA的處理會促使抑制型細胞 數量以及蛋白質量的減少。而給予TPPU的前處理可有減低GAD67+細胞數量減少 之趨勢。更進一步利用螢光染色及西方點墨法去觀測CR以及PV之變化，TPPU也 可以有效增加CR+抑制性細胞之存活。綜合上述，本篇研究說明了sEH的抑制劑 對於在興奮性毒性引起的認知功能障礙中扮演著重要調控之角色，其機制可能與 增強抑制性神經細胞存活有關。本研究所獲得之資訊，或許可對在興奮性毒性引 起的神經退化性疾病中之病理機制以及其引發之認知及記憶功能障礙與疾病提 供新的治療方向 。

Soluble epoxide hydroxylase (sEH) is a dual activity enzyme with the C-terminal epoxide hydrolase domain and an N-terminal lipid phosphatase domain and is expressed in mammalian brains, especially hippocampus. Inhibition of sEH hydrolase activity has been proven to be protective against ischemic brain injury, but it was also reported to facilitate synaptic plasticity. Synaptic plasticity in the hippocampus is an important role to improve memory function. Also, previous studies demonstrated that inhibition of GABAergic interneuron activity impaired memory function, indicating GABAergic interneuron involved in regulating memory function. However, whether the sEH inhibitor treatment can benefit the recovery of memory function by affecting GABAergic interneurons after excitotoxic insult was unknown. In this study, we examined the post-treatment effect of intranasal delivery (i.n.) of sEH hydrolase inhibitor TPPU (0.5mg/kg once a day for 7 days) on hippocampal damage, with special focus on GABAergic interneurons, and memory impairment 7 days after the intraperitoneal kainic acid (KA) injection, and in comparison with the effect of genetic ablation of Ephx2 (Ephx2-KO). Our results show that the KA-triggered seizure activity 2h after the injection was lower in TPPU-i.n than the vehicle-i.n mice, and also lower in Ephx2-KO than WT mice. Immunohistochemistry staining showed that both Ephx2-KO and TPPU-i.n attenuated KA-induced NeuN+ neuronal loss in hippocampal CA1, CA3 and dentate gyrus (DG). Hippocampus-related pattern separation behavior assessed by the novel object recognition test was impaired by KA, which was ameliorated by TPPU-i.n and also in Ephx2-KO. Another hippocampus-related behavior is the spatial learning memory assessed by the Barnes maze test. The data showed that
TPPU-i.n treatment, not Ephx2 deletion, attenuated KA-induced spatial memory 3 days post-injection. However, this memory-improving effect of TPPU-i.n treatment did not sustain to 7-day post-injection. Notably, the Ephx2-KO mice learn faster than the WT mice to find the target hole during the 4-day training period prior to the drug injection; whereas vehicle-injected Ephx2-KO mice spent more time to find the target hole than the vehicle-injected WT mice 7 days after the training, implying that sEH might be involved in both memory acquisition and consolidation.
Immunohistochemistry study of the GABAergic interneurons as labeled by the GABA synthesizing enzyme glutamic acid decarboxylase 65 (GAD65) show that GAD65 were reduced by KA and rescued by both TPPUi.n and Ephx2-KO in hippocampal subregions. Next, we examined a subset of GABAergic interneurons in the DG hilus region, which expressed a calcium-buffering protein calretinin (CR) to maintain proper neuronal excitability, found that both TPPU and Ephx2-KO could rescue CR+ interneurons in supragranular layer (SG) and hilus of DG after KA insult. Another subtype of GABAergic interneurons, parvalbumin (PV) expressing neurons in the hippocampus, could not be rescued by TPPU treatment after KA-ip insult significantly. Then we tried to confirm this phenomenon in vitro by using primary glia-neuron mix culture treated with glutamate receptor agonist NMDA to induce excitotoxic neuronal death. The results indicated that TPPU pretreatment could ameliorate NMDA-induced loss of NeuN+ neurons and MAP2+ neurons. Next, we examined GABAergic neurons labeled cell cytosol by GAD67, and we found that TPPU pretreatment could not alter NMDA-induced loss of GAD67 protein level or expression. Further examined one type of GABAergic neuron labeled by calretinin, and we found that TPPU pretreatment can significantly ameliorate NMDA-induced reduction of CR+ neurons but not CR protein level. Also, we examined another type of GABAergic neurons labeled by parvalbumin, and the data indicated that TPPU pretreatment cannot alter NMDA-induced the loss of PV+ neurons.
In conclusion, these results suggest that intranasal delivery of sEH inhibitor TPPU and Ephx2 deletion both show moderate protective effects against excitotoxin-induced hippocampal damage and pattern separation deficit accompanied with preservation of CR-expressing GABAergic interneurons in the dentate gyrus. The obtained information may provide clues for the modulation of excitation-inhibition balance in hippocampal circuits.

CONTENTS I
LIST OF FIGURES II
ABBREVIATION IV
中文摘要 V
ABSTRACT VII
INTRODUCTION 1
MATERIALS AND METHODS 13
RESULTS 26
DISCUSSION 39
CONCLUSION 44
REFERENCES 45
FIGURES 55
APPENDIX 83

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