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研究生:李欣學
研究生(外文):Hsin-Hsueh Lee
論文名稱:台灣植物多酚類之腦神經保護劑
論文名稱(外文):Polyphenols as Neuroprotectants from Taiwanese Botany
指導教授:楊玲玲楊玲玲引用關係李怡萱李怡萱引用關係
指導教授(外文):Ling-Ling YangYi-Hsuan Lee
學位類別:博士
校院名稱:臺北醫學大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2007
畢業學年度:95
語文別:英文
論文頁數:142
中文關鍵詞:多酚類類黃酮素黃芩素蜜柑黃酮發芽玄米萃取物桂花萃取物自由基脂質過氧化葡萄糖缺乏麩胺酸花生四烯酸六-羥基多巴胺伽傌胺基丁酸神經保護細胞內鈣
外文關鍵詞:polyphenolflavonoidbaicaleintangeretinpre-germinated brown riceOsmanthus fragransfree radicallipid peroxidationglutamateglucose-deprivationarachidonic acid6-hydroxydopamineGABAneuroprotectionintracellular calcium
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腦神經損傷之發生會透過許多不同的機制所調控,損傷初期腦部缺血的結果則會引發一連串與代謝及生化相關之次級訊息傳遞作用。進而造成脂質過氧化產生自由基、興奮性胺基酸的釋出、能量代謝的衰竭、發炎調控因子的釋出、鈣離子失衡以及其他相關影響。過去天然物被用於神經損傷相關疾病(中風、帕金森氏症、阿茲海默症等)已行之多年。加上透過廣泛的化學及藥理研究,許多中草藥陸續被發現具有生理活性,而部份也已應用於臨床治療。在本研究中,我們將分別針對中草藥與台灣原生種藥用植物之萃取物及其活性成分作探討,首先研究具有多酚類之天然物及植物藥材是否對於神經損傷所造成神經興奮性毒性之保護作用及其可能作用之機轉。並利用不同化學物質誘發神經毒性後,觀察由中草藥萃取物或多酚類物質對於其神經毒性之保護評估及可能在中樞神經退化性疾病的神經保護作用。在本次研究由許多藥材材料中發現具有神經保護作用之天然物質。黃芩苷元,萃取自中草藥之黃芩,我們發現能夠抑制由麩胺酸及葡萄糖缺乏所造成的神經興奮性毒性,黃芩苷元本身能降低細胞內鈣並且能降低由麩胺酸所誘導之細胞鈣離子內流,因此其作用機制與降低細胞內鈣而達到神經保護有關。然而蜜柑黃酮,萃取自青皮,能夠抵抗麩胺酸以及葡萄糖缺乏所造成的神經興奮性毒性。蜜柑黃酮在有效作用百分之五十濃度下觀察其神經保護作用,透過共軛雙焦顯微鏡觀察細胞內鈣變化情形,蜜柑黃酮能使細胞短暫地增加鈣離子,然而由蜜柑黃酮增加之內鈣可以被河豚毒素所抑制,此結果與其影響突觸活性有所相關,此外蜜柑黃酮亦可增加伽傌胺基丁酸接受體之活性作用而非透過麩胺酸接受體之相關機制,進而達到降低由麩胺酸所引發之內鈣變化,保護大鼠大腦皮質神經元免於遭受由腦部損傷之神經過度興奮及神經退化性疾病之影響。此外,在發芽玄米萃取物中,我們比較了白米、糙米及發芽玄米之差異,並定量三者伽傌胺基丁酸之含量,其中以發芽玄米乙醇萃取物具有伽傌胺基丁酸成份為最多,為白米的八倍,發芽玄米萃取物中對於花生四烯酸及麩胺酸所誘導神經毒性具有顯著的神經保護之作用,其作用亦與發芽玄米萃取物中所含的伽傌胺基丁酸及多酚類化合物有關,並能增加由麩胺酸所降低之bcl-2與ERK1/2表現。而在我們篩選台灣原生種藥用植物中,桂花具有明顯的自由基清除作用,並在桂花酒精萃取物含有高含量的類黃酮素及多酚類成份,因此能夠對抗麩胺酸及六-羥基多巴胺所誘導的神經毒性,亦調控麩胺酸及六-羥基多巴胺所降低之AKT蛋白質表現,這也是第一次發現桂花具有神經保護、抗自由基及抗氧化的作用。因此具有抗氧化、抗自由基以含多酚類成份之天然物質,這些具有神經保護的天然物,將來亦可以應用於預防特定之神經退化性疾病。
Neuronal injury occurs via various mechanisms, including the initial ischemic insult which in turn initiates a secondary injury cascade of metabolic and biochemical changes. These changes include production of oxygen free radicals with lipid peroxidation, release of excitatory amino acids such as glutamate, failure of energy metabolism, release of inflammatory mediators, disruption of calcium homeostasis, and potentially other unidentified mechanisms. Natural products have been used as medicinal agents for many years. Through a large number of chemical and pharmacological research works, numerous bioactive compounds have been found from Chinese medicinal plants and some of them have been used clinically. The present study was divided into several parts includes Chinese herbal medicine, the extracts of Taiwan folk medicine plant or Taiwan botany, and their active components. The overall goal in this study is to find out the potential natural resources of polyphenols from traditional Chinese Medicine, folk medical plants, and if they can protect neurotoxicity or excitotoxicity in primary cultured cortical neuron. Our experimental design is that polyphenols, specifically found the flavonoids and the medical plant extracts, and to examine their protective effects on the cortical neurons after exposure to different neurotoxic chemicals. In our results, we found four potential candidates with neuroprotective abilities. Baicalein prevents neurotoxicity induced by both glutamate and glucose deprivation via decreasing intracellular calcium. Tangeretin can against glutamate and glucose deprivation. Tangeretin may protect central neurons by increasing the calcium via a synapse activity-dependent manner and might serve as a GABA mimic modulator to protect neurons against overexcitation-related brain injury and neurodegeneration. In addition, in the crude extract of pre-germinated brown rice (PGBR) with high levels of the nutrient GABA and exert a benefit for the prevention on the neurodegenative diseases. The ethanol extract of PGBR exerted the remarkable neuroprotective against glutamate and arachidonic acid-induced neurotoxicity. The ethanol extract of dried flowers Osmanthus fragrans (OFE) contained a high amount of total flavonoid and polyphenol. The neuroprotective activity of OFE was investigated under different insults (glutamate, arachidonic acid, and 6-hydroxydopamine). This is the first demonstration of the neuroprotective, free radical scavenging and anti-oxidative effects of O. fragrans.
Contents

List of chapters, figures, tables, schemes...Ⅰ
Abstract in Chinese...Ⅵ
Abstract in English...Ⅶ
Abbreviation...Ⅸ

Chapter 1
Introduction and Literature Review

1.1 Background...1
1.2 Polyphenols...2
1.3 Neurodegeneration and stroke...3
1.4 Neuroprotective drugs in TCM...3
1.5 Neuroprotective agent...4
1.5.1 Glutamate antagonist...4
1.5.2 Calcium antagonists...6
1.5.3 γ-Aminobutyric acid receptor agent...7
1.5.4 Apoptosis inhibitor ...7
1.5.5 Sodium channel modulator...8
1.5.6 Potassium channel activator...8
1.5.7 Drugs acting on free radical- and nitric oxide-related toxicity...8
1.5.8 Lipoxygenase/Cyclooxygenase inhibitor..9
1.5.9 Other neuroprotective agent...10
1.6 Cerebral ischemic cell signaltansduction...10
1.7 Strategy of this study...12

Chapter 2
Neuroprotective Polyphenols in Cortical Neuron

2.1 Material and method...13
2.1.1 Extraction and isolation of the natural resources...14
2.1.2 Primary cultures of cortical neuron...14
2.1.3 Purification and characterization of test substances...15
2.1.4 Glucose deprivation induced neurotoxicity...15
2.1.5 Glutamate induced neurotoxicity...15
2.1.6 Neuronal survival analysis...16
2.1.7 Cell membrane leakage by lactate dehydrogenase release...16
2.1.8 Calcium imaging of cultured cortical neurons...16
2.1.9 Measurement of intracellular calcium concentration...17
2.1.10 45Calcium influx measurement...17
2.1.11 Statistical analysis...18
2.2 Experimental design...18
2.3 Results...22
2.4 Discussion...30
2.5 References...33



Chapter 3
Neuroprotection of Tangeretin against Excitotoxicty
in Cortical Neuron

3.1 Abstract...41
3.2 Introduction...42
3.3 Material and method...45
3.3.1 Isolation and preparation of tangeretin...45
3.3.2 Chemicals-induced neurotoxicity and protective effects...45
3.3.3 Glutamate and GABA binding assay...46
3.4 Results...47
3.5 Discussion...64
3.6 References...72

Chapter 4
Protective Effects of Oryza sativa on Chemicals Induced Neurotoxicity in Rat Cortical Neuron

4.1 Abstract...77
4.2 Introduction...78
4.3. Material and method...80
4.3.1 Chemicals...80
4.3.2 Plant material...80
4.3.3 Preparation of rice extracts...80
4.3.4 GABA quantitative analysis of rice extracts...81
4.3.5 Neurotoxic and neuroprotective assay...81
4.3.6 Free radical scavenging and anti-oxidative
ability...81
4.3.7 DPPH radical scavenging assay...81
4.3.8 Metal chelating assay...82
4.3.9 Hydroxyl radical inhibitory activity...82
4.3.10 Estimation of the total phenolic contents...82
4.3.11 Western blot...83
4.4 Results...84
4.5 Discussion...93
4.6 References...96

Chapter 5
Neuroprotective and Free Radical Scavenging Effects of O. fragrans

5.1 Abstract...100
5.2 Introduction...101
5.3 Material and method...103
5.3.1 Chemicals...103
5.3.2 Plant material...103
5.3.3 Preparation of O. fragrans...103
5.3.4 Quenching of DPPH by O. fragrans...104
5.3.5 Metal chelating activity of O. fragrans...104
5.3.6 Hydroxyl radical inhibitory activity of O.
fragrans...105
5.3.7 Ferric reducing ability assay of O. fragrans...105
5.3.8 Estimation of the total phenolic contents...105
5.3.9 Estimation of the total flavoninds...106
5.3.10 Chemicals-induced neurotoxicity and protective
effects...106
5.3.11 Determination of lipid peroxidative product of O.
fragrans on rat brain,liver, kidney and heart
tissue...106
5.3.12 Preparation of rat brain, heart, liver, and kidney
mitochondria...106
5.3.13 Protein determination...107
5.3.14 Thiobarbituric acid of reactive substances and
malondialdehyde...107
5.3.15 O. fragrans on AKT expression by western
blotting...107
5.4 Results...108
5.5 Discussion...116
5.6 References...119

Chapter 6
Discussion & Conclusion...122

Chapter 7
Appendix...128


List of Figures

Figure 1 Structures of selected polyphenols in this
study (Ⅰ).....19
Figure 2 Structures of selected polyphenols in this
study (Ⅱ).....20
Figure 3 Effect of baicalein and baicalin on glutamate-
induced 45Ca Influx.....26
Figure 4 Effect of baicalein pre-treatment on glutamate-
induced intracellular calcium.....27
Figure 5 Effect of baicalein post-treatment on glutamate- induced intracellular calcium.....28
Figure 6 Effect of baicalein co-treatment on glutamate- induced intracellular calcium.....29
Figure 7 Effect of baicalein under glucose deprivation
on DNA fragmentation by agarose
electrophoresis.....29
Figure 8 Structure of tangeretin (5, 6, 7, 8, 4''-
pentamethoxyflavone) extracted
from methanol extract of Citri reticulatae
viride pericarpium.....52
Figure 9 Effects of tangeretin with/without neurotoxic
insults in cortical neurons.....53
Figure 10 Effect of tangeretin-induced intracellular
calcium level.....55
Figure 11 Effects of different channel blockers on
tangeretin elevation of [Ca2+]i.....56
Figure 12 Effect of sodium channel blocker on tangeretin
neuroprotection.....58
Figure 13 Effect of tangeretin on glutamate and GABA
receptor binding activity.....59
Figure 14 Effect of GABAA receptor antagonist on
tangeretin neuroprotection.....60
Figure 15 Effect of rice extracts in cortical neuron at
12 DIV.....89
Figure 16 Effects of PGBR on 6-hydroxydopamine,
arachidonic acid, and glutamate-induced
neurotoxicity.....90
Figure 17 PGBR concentration-dependent manner on radical
scavenging activities.....91
Figure 18 Effects of glutamate-induced neurotoxicity on
ERK and bcl-2 expression in primary cortical
neuron cultures by PGBR.....92
Figure 19 Effects of O. fragrans extract on 6-
hydroxydopamine,arachidonic acid, and glutamate-
induced neurotoxicity.....113
Figure 20 Inhibitory effect of O. fragrans extract on
lipid peroxidation in rat tissues mitochodrias
induced by ferrous chloride.....114
Figure 21 Effects of glutamate and 6-OHDA-induced
neurotoxicity on AKT expression in primary
cortical neuron cultures by O. fragrans
extract.....115


List of Tables

Table 1 List of the herbal medicines and folk medicines
in this study.....21
Table 2 Screening test of selected polyphenols by MTT
assay with/without glucose deprivation in
cortical neuron.....23
Table 3 Screening test of selected polyphenols by LDH
releasing assay with/without glucose
deprivation (1h) in cortical neuron....24
Table 4 Screening test of selected polyphenols by LDH
releasing assay with/without glucose
deprivation (24 h)in cortical neuron.....25
Table 5 Effects of tangeretin on free radical scavenging
and antioxidant Activities...61
Table 6 GABA quantitative analysis and anti-radical
investigation of WR, BR,and PGBR extracts.....88
Table 7 Effects of O.fragrans on free radical scavenging
and antioxidant activities.....112

List of Schemes

Scheme 1 Diagram of cerebral ischemic cell signal
transduction.....11
Scheme 2 Proposed pathways of neuroprotection and
potential targets of pharmacologic
intervention.....12
Scheme 3 Flowchart of natural products in this
study.....13
Scheme 4 Morphology of Citri reticulatae viride
pericarpium.....45
Scheme 5 IR spectrum of tangeretin.....62
Scheme 6 NMR spectrum of tangeretin.....63
Scheme 7 Morphology of Oryza sativa.....79
Scheme 8 Morphology of Osmanthus fragrans.....101
Scheme 9 Relationship between glutamate and GABA
receptor.....125
Scheme 10 Disparate environmental and dietary factors
activate common hormetic cellular stress-
response pathways.....126
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