臺灣博碩士論文加值系統

一氧化氮 (Nitric oxide; NO) 在神經系統中兼具毒殺與保護功能，然其在此二種功能間之調控機制，仍待釐清。在中樞神經系統內，多種細胞具製造NO之能力，其中星膠細胞及微膠細胞受發炎訊號刺激後可產生大量之NO。因此在以慢性發炎為一主要病理機序的退化性神經疾病中，NO在腦微環境中可能形成斷續性之高量積累，進而影響腦內細胞之功能。據此假設，本論文擬探討NO對腦內主要免疫細胞─微膠細胞─受不同來源之發炎訊號刺激後的反應之調控機制。
利用小鼠微膠細胞株BV-2為實驗模型，我們發現BV-2細胞可對一種血腦障蔽外之發炎原─細菌內毒素脂多醣 (LPS)─迅速反應而製造大量發炎細胞激素TNF-alpha，然而對於血腦障蔽內衍生之物質如艾茨海默症中常見之乙型澱粉樣蛋白片段 (beta-amyloid peptide fragment 25-35; Abeta25-35) 或甫被證實可引起beta-amyloid peptide凝集之一種受損傷細胞膜衍生物─神經節甘酯 (gangliosides) ─卻反應微弱。但是BV-2微膠細胞若先受NO (來自1 mM之sodium nitroprusside; SNP) 刺激30分鐘，則大幅增強對A25-35及gangliosides之反應，產生相當大量的TNF-alpha；而另一方面，NO卻顯著地抑制微膠細胞對LPS的反應，減少LPS誘發之TNF-alpha釋出。
進一步探討NO調控此二類（血腦障蔽內及血腦障蔽外）代表性刺激原之機制，發現NO可抑制LPS引起之NF-kappaB活化，卻加強beta-amyloid peptide fragment 25-35及gangliosides所引起之NF-kappaB活化。由於NF-kappaB活化與mitogen-activated protein kinase (MAPK)訊息傳導路徑有關，我們乃進一步探討NO對此路徑之影響，結果發現LPS、beta-amyloid peptide fragment 25-35及gangliosides均可不同程度地活化ERK、p38 MAPK及JNK三條路徑，但是NO祇對p38具明顯之調控，亦即NO抑制LPS引發之p38 MAPK活化，卻極明顯地加強了beta-amyloid peptide fragment 25-35及gangliosides所引發之p38 MAPK活化。由於加入p38 MAPK之抑制劑SB203580可以有效抑制LPSbeta25-35及gangliosides以及與NO共同作用所誘發之TNF-alpha產製及NF-kappaB活化，而加入ERK之抑制劑PD98059亦同樣可以阻斷上述藥劑或組合所誘發之TNF-alpha製造及NF-fappaB活化，顯示beta-amyloid peptide fragment 25-35、gangliosides及LPS活化NF-kappaB及引發TNF-alpha合成需要至少p38 MAPK及ERK之同時作用，唯NO之強化或抑制這些刺激原係透過p38 MAPK。至於JNK是否也絕對必要，有待進一步研究。
本研究結果對於NO之細胞毒殺或保護雙重效果，提供一可能之解釋模型，即NO可抑制血腦障蔽外侵入之刺激原，藉此可能保護腦內構造，另一方面卻無法鑑別血腦障蔽內衍生之刺激原的傷害性，而加強此類物質之致發炎反應，進而造成神經損傷。本研究結果若能在人類神經系統得以證實，將對腦部疾病之治療方針具高度參考價值。

Nitric oxide (NO) has been shown to be both neurotoxic and neuroprotective; however, mechanisms governing the switch between the two seemingly distinct effects remain to be elucidated. In the central nervous system, almost all cell types are capable of generating NO. The astroglia and microglia, in particular, can produce large amounts of NO in response to proinflammatory stimulation. Since chronic inflammation is characteristic of numerous neurodegenerative diseases, it is likely that NO may accumulate in pathological microenvironments to levels that can modulate neural cell functions. Therefore, the purpose of this study was to examine the role of NO in the regulation of microglia, the major immune effect cells in the central nervous system, in response to proinflammatory signals derived from various sources.
Using a murine microglia cell line, BV-2, we found that these cells released large amounts of tumor necrosis factor (TNF)-alpha within 6 h of stimulation by lipopolysaccharide (LPS, 1 g/ml), a proinflammatory stimulant from outside of the blood-brain barrier (hence, “extra-BBB”). In contrast, agents of the “intra-BBB” origin, such as Abeta25-35 (20 uM), a toxic beta-amyloid fragment containing amino acid residues 25-35 that is found in the brain of Alzheimer’s disease (AD) patients, and gangliosides (50 ug/ml), plasma membrane derivatives of damaged neurons that may initiate aggregation of Abeta in AD, had minimal effects on TNF-alpha release by BV-2 cells. However, exposure for 30 min of these cells to NO, as liberated by 1 mM sodium nitroprusside (SNP), markedly enhanced TNF-alpha production by BV-2 cells in response to Abeta25-35 or gangliosides stimulation. On the other hand, pre-exposure of SNP/NO significantly inhibited LPS-induced TNF-alpha production in BV-2 microglia cells.
To elucidate the mechanisms for the differential effects of NO on the two classes of stimulants, we measured NF-kappaB activation/translocation by using the electrophoresis mobility shift assay and activation of mitogen-activated protein kinases (MAPKs) by using immunoblotting assays. Parallel to the effects on TNF-alpha release, SNP/NO pretreatment inhibited NF-B translocation induced by LPS but enhanced that induced by Abeta25-35 and Gan. In the activation profile of MAPKs, while LPS, Abeta25-35 and gangliosides could activate, to different extents, phosphorylation of p42/p44 extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK), the modulatory effect of NO was limited to p38 MAPK, i.e., SNP/NO pretreatment inhibited LPS-induced p38 MAPK activation but markedly enhanced Abeta25-35- and gangliosides-induced activation of p38 MAPK. However, SB203580 (an inhibitor of p38 MAPK) could inhibit TNF-alpha release and NF-B activation induced by LPS, Abeta25-35, Gan, and the combinatorial effects with NO and, on the other hand, PD98059 (an inhibitor of MEK1/ERK) could also block all of the above. This means that NF-kappaB activation and TNF-alpha production induced by Abeta25-35, Gan, and LPS required both p38 MAPK and ERK, but NO regulated only p38 MAPK. Our data could not exclude the involvement of JNK without further experiments.
The data presented in this study support a novel model for the mechanisms directing the protective and destructive effects of NO, i.e., NO protects neural cell from “extra-BBB” insults by inhibiting the signaling pathways, yet, on the other hand, may not be able to differentiate the detrimental potential of substances from “intra-BBB” sources thereby enhance the damaging effect. Our model may provide insights to the therapeutic strategy of neurodegenerative diseases given the differential regulatory effects of NO can be demonstrated in the human brain.

中文摘要i
ABSTRACTiii
LIST OF ABBREVIATIONSvi
ACKNOWLEDGEMENTSvii
BIOGRAPHICAL SKETCHix
CHAPTER 1 INTRODUCTION1
1.1The physiologic and pathologic roles of nitric oxide (NO) in the central nervous system1
1.1.1Biosynthesis and the effector functions of NO1
1.1.2Regulatory functions of NO3
1.1.3Dual/Differential effects of NO5
1.2.The role of lipopolysaccharide, -amyloid peptides, and gangliosides in the pathophysiology of the central nervous system8
1.2.1Lipopoplysaccharide (LPS) and brain injury8
1.2.2-Amyloid peptides (A) and Alzheimer's disease9
1.2.3Gangliosides and brain pathology10
1.3The role of microglia activation and MAPK activation in the pathophysiology of the central nervous system11
1.4Purposes and rationales of present research13
CHAPTER 2 MATERIALS AND METHODS14
2.1Reagents14
2.2Cell culture15
2.3Determination of TNF- Release15
2.4Measurement of NF-B Activation by Electrophoresis Mobility Shift Assay and Super-Shift Assay16
2.5Immunoblotting assay for MAPKs17
2.6Statistical Analysis19
CHAPTER 3 RESULTS20
3.1Differential effects of NO on LPS- vs. A25-35- and gangliosides-induced TNF- release from microglia20
3.2Differential effects of NO on NF-B translocation21
3.3Role of mitogen-activated protein kinases (MAPKs) in NO- regulated responses to LSP, A25-35, and gangliosides in microglia cells22
3.4Effect of NAC on NO-upregulated p38 MAPK activation24
CHAPTER 4 DISCUSSION26
4.1A novel model for the dual regulatory effects of NO on inflammatory responses of microglia cells26
4.2NO may differentially alter the pathophysiological roles of LPS, A25-35, and gangliosides in brain disorders27
4.3p38 MAPK serves as an essential target for NO to regulate microglia activation31
4.4Neuroprotective and neurotoxic effects of NO: Ramifications of p38-mediated dual regulatory effects of NO32
APPENDIX 1.ACKNOWLEDGEMENT FOR SPONSORSHIPS AND ASSISTANCE67
APPENDIX 2.COMPOSITION OF BUFFERS USED IN THIS STUDY68
REFERENCES72

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