癲癇是一種常見的神經系統疾病。神經發炎與癲癇的致病機轉相關。組織氧化壓力則是癲癇另一個重要致病因素。雖然神經發炎和腦部氧化壓力這兩個因素均參與癲癇致病機轉；然而，對於這兩個因素在癲癇致病機轉的相互關係，尚未完全了解。在這項研究中，我們研究神經發炎和腦部氧化壓力這兩個因素在癲癇的致病機轉的相互關係以及潛在的分子機制。

在目標1中，我們經由在大鼠的腹膜腔內連續灌注細菌內毒素LPS (2.5 mg/kg/day) 7天或14天，建立經由周邊發炎導致慢性神經發炎的動物模式。此動物模式則呈現在血漿和腦部各處位置（額葉，顳葉，海馬迴，紋狀體，延髓頭端腹外側：RVLM，孤束核：NTS） 均增加促炎性細胞激素 (IL-1β, IL-6, TNF-α)，在腦部各處位置增加活化的小膠質細胞數量，以及對KA (10 mg/kg) 注射誘發的癲癇敏感性增加。在之後的研究，我們主要在海馬迴:人類常見的顳葉癲癇最相關的腦部位置，在慢性神經發炎7天的動物模式中，經由滲透性微型幫浦持續注射治療藥物於側腦室7天，去探討癲癇機轉。

在目標2中，我們將注射環氧合酶-2抑制劑：NS398 (5 μg/μl/h) 於側腦室7天，經由治療神經發炎後，去研究神經發炎和組織氧化壓力在癲癇敏感性之間的相互關係。結果呈現，環氧合酶-2抑制劑會阻斷在海馬迴的活化的小膠質細胞和促炎性細胞因子的增加，以及阻斷在海馬迴的組織氧化壓力的增加（NADPH oxidase subunits 上升），也會減輕在KA誘導的癲癇模式中增加的癲癇敏感性。

在目標3中，我們將注射活性氧化物清除劑：tempol (2.5 μg/μl/h) 於側腦室7天，經由治療氧化壓力後，去研究神經發炎和組織氧化壓力在癲癇敏感性之間的相互關係。結果呈現，活性氧化物清除劑無法阻斷在海馬迴的活化的小膠質細胞和促炎性細胞激素的增加，但是可以阻斷在海馬迴的組織氧化壓力的增加（NADPH oxidase subunits 上升），也會減輕在KA誘導的癲癇模式中增加的癲癇敏感性。

這些結果顯現，周邊發炎會誘發在海馬迴的神經發炎以及之後的氧力壓力，進而導致癲癇敏感性的增加。這些結果更進一步顯現，在周邊發炎後，保護海馬迴免於神經發炎和氧化壓力，對降低癲癇的敏感性具有增益效果。

Epilepsy is a common neurological disorder. Neuroinflammation is involved in the pathophysiology of epilepsy. Tissue oxidative stress is another confounding factor in epilepsy. While both neuroinflammation and brain oxidative stress are involved, relationship between these two factors in epileptogenesis, however, is not fully understood. In this study, I investigated the relationship and the underlying molecular mechanism.

In aim 1, I established a rodent model of chronic neuroinflammation via peripheral inflammation induced by continuous infusion of E. coli lipopolysaccharide (LPS; 2.5 mg/kg/day) in the peritoneum for 7 or 14 days. Results showed an increased proinflammatory cytokines level, including IL-1β, IL-6 and TNF-α in plasma and various areas of brain (frontal lobe, temporal lobe, hippocampus, striatum, rostral ventrolateral medulla (RVLM), nucleus tractus solitarii (NTS)), increased number of the activated microglia in brain and sensitivity to induction of seizure by KA (KA, 10 mg/kg) injection. Based on these findings, I focused my study on the hippocampus, which is associated with temporal lobe epilepsy, a common form of epilepsy in human. Pharmacological agents were delivered via intracerebroventricular infusion with an osmotic minipump in chronic neuroinflammation model for 7 days.

In aim 2, a cycloxygenase-2 inhibitor, NS398 (5 μg/μl/h), was used to study the relationship between neuroinflammation and tissue oxidative stress in seizure susceptibility after the LPS-induced peripheral inflammation. The results showed that NS398 significantly blunted the increase in microglia activation, production of proinflammatory cytokines, and tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus. The same treatment also ameliorated the increase in seizure susceptibility in the KA-induced seizure model.

In aim 3, a reactive oxygen species scavenger, tempol (2.5 μg/μl/h), was used to study the relationship between neuroinflammation and oxidative stress in the increase in seizure susceptibility under peripheral inflammation. The results showed that tempol did not blunt the increase in activated microglia, production of proinflammatory cytokines, but significantly blunted tissue oxidative stress (upregulations of the NADPH oxidase subunits) in the hippocampus and ameliorated the increase in seizure susceptibility in the KA-induced seizure model.

These results indicated that peripheral inflammation evoked neuroinflammation and the subsequent oxidative stress in the hippocampus, resulting in the increase seizure susceptibility. Moreover, protection from neuroinflammation and oxidative stress in the hippocampus exerted beneficial effect on seizure susceptibility following peripheral inflammation.

論文審定書 i
論文公開授權書 ii
誌謝 (Acknowledgement) iii
中文摘要及關鍵詞 (Abstract in Chinese & Keywords) v
英文摘要及關鍵詞 (Abstract in English & Keywords) vii
目錄 (Index) ix
圖次 (Figure Index) xvii
表次 (Table Index) xxii
符號說明 (Abbreviations) xxiii
Chapter 1. General Introduction 1
1.1 Epilepsy 2
1.2 Peripheral inflammation 4
1.3 Neuroinflammation 5
1.4 Oxidative stress 7
1.5 Specific Aims 9
Chapter 2. Establish a rodent model of chronic neuroinflammation induced by peripheral inflammation 10
2.1 Introduction 11
2.2 Materials and Methods 13
2.3 Results 18
2.4 Discussion 20
2.5 Figures and Legends 22
Figure 2-1: Experimental procedures of a rodent model of chronic neuroinflammation induced by peripheral inflammation. 22
Figure 2-2: Intraperitoneal LPS infusion induces peripheral inflammation. 23
Figure 2-3: Intraperitoneal LPS infusion induces neuroinflammation in frontal lobe. 24
Figure 2-4: Intraperitoneal LPS infusion induces neuroinflammation in temporal lobe. 25
Figure 2-5: Intraperitoneal LPS infusion induces neuroinflammation in hippocampus. 26
Figure 2-6: Intraperitoneal LPS infusion induces neuroinflammation in striatum. 27
Figure 2-7: Intraperitoneal LPS infusion induces neuroinflammation in RVLM. 28
Figure 2-8: Intraperitoneal LPS infusion induces neuroinflammation in NTS. 29
Figure 2-9 (A-B): Intraperitoneal LPS infusion induces microglial activation in frontal lobe (A) and temporal lobe (B). 30
Figure 2-9 (C-D): Intraperitoneal LPS infusion induces microglial activation in hippocampus (C) and striatum (D). 31
Figure 2-9 (E-F): Intraperitoneal LPS infusion induces microglial activation in RVLM (E) and NTS (F). 32
Figure 2-10: Increase in seizure susceptibility after intraperitoneal LPS infusion. 33
Figure 2-11: Scheme of the proposed mechanism of a rodent model of chronic neuroinflammation induced by peripheral inflammation. 34
2.6 Tables 35
Table 2-1. No change in body weight, body temperature, daily food or water intake after intraperitoneal LPS infusion. 35
Chapter 3. The role of neuroinflammation in seizure susceptibility under the LPS-induced peripheral inflammation 36
3.1 Introduction 37
3.2 Materials and Methods 39
3.3 Results 46
3.4 Discussion 49
3.5 Figures and Legends 52
Figure 3-1: Experimental procedures of the role of neuroinflammation in seizure susceptibility under the LPS-induced peripheral inflammation. 52
Figure 3-2: Intraperitoneal LPS infusion induces peripheral inflammation which is not affected by intracerebroventricular infusion of NS398. 53
Figure 3-3: Intraperitoneal LPS infusion induces a COX-2-dependent neuroinflammation in the hippocampus. 54
Figure 3-4: Intraperitoneal LPS infusion induces a COX-2-dependent increase in tissue superoxide levels in the hippocampus. 55
Figure 3-5: The COX-2-dependent upregulations of the NADPH oxidase subunits in the hippocampus after intraperitoneal LPS infusion. 56
Figure 3-6: The COX-2-dependent upregulations of antioxidant proteins in the hippocampus after intraperitoneal LPS infusion. 57
Figure 3-7 (A): Intraperitoneal LPS infusion induces a COX-2-dependent microglial activation in the hippocampus. 58
Figure 3-7 (B): Intraperitoneal LPS infusion induces a COX-2-dependent microglial activation in the hippocampus. 59
Figure 3-7 (C): Intraperitoneal LPS infusion induces a COX-2-dependent microglial activation in the hippocampus. 60
Figure 3-7 (D): Intraperitoneal LPS infusion induces a COX-2-dependent microglial activation in the hippocampus. 61
Figure 3-8: COX-2-dependent increase in seizure susceptibility after intraperitoneal LPS infusion. 62
Figure 3-9: Scheme of the proposed mechanism of the role of neuroinflammation in seizure susceptibility under the LPS-induced peripheral inflammation. 63
3.6 Tables 64
Table 3-1. Effect of daily bolus injection of NS398 on the increases in plasma proinflammatory cytokine levels following intraperitoneal infusion of LPS for 7 days. 64
Table 3-2. Effect of daily bolus injection of NS398 on the increases in in tissue proinflammatory cytokine levels in the hippocampus following intraperitoneal infusion of LPS for 7 days. 65
Chapter 4. The relationship between oxidative stress and neuroinflammation in seizure susceptibility under the LPS-induced peripheral inflammation 66
4.1 Introduction 67
4.2 Materials and Methods 68
4.3 Results 74
4.4 Discussion 77
4.5 Figures and Legends 81
Figure 4-1: Experimental procedures of the relationship between neuroinflammation and oxidative stress in seizure susceptibility under the LPS-induced peripheral inflammation. 81
Figure 4-2: Intraperitoneal LPS infusion induces peripheral inflammation which is not affected by intracerebroventricular infusion of tempol. 82
Figure 4-3: Intraperitoneal LPS infusion induces neuroinflammation in the hippocampus. 83
Figure 4-4: Intraperitoneal LPS infusion induces a redox-sensitive increase in tissue superoxide levels in the hippocampus. 84
Figure 4-5: The upregulations of the NADPH oxidase subunits in the hippocampus after intraperitoneal LPS infusion. 85
Figure 4-6: The upregulations of antioxidant proteins in the hippocampus after intraperitoneal LPS infusion. 86
Figure 4-7 (A): Intraperitoneal LPS infusion induces microglial activation in the hippocampus. 87
Figure 4-7 (B): Intraperitoneal LPS infusion induces microglial activation in the hippocampus. 88
Figure 4-7 (C): Intraperitoneal LPS infusion induces microglial activation in the hippocampus. 89
Figure 4-7 (D): Intraperitoneal LPS infusion induces microglial activation in the hippocampus. 90
Figure 4-8: Redox-sensitive increase in seizure susceptibility following peripheral inflammation 91
Figure 4-9: Scheme of the proposed mechanism of the relationship between neuroinflammation and oxidative stress in seizure susceptibility under the LPS-induced peripheral inflammation. 92
Conclusion 93
Limitations and Future Perspectives 94
References 95
Publications 108
Conference Presentation 109

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