憂鬱症是一種生理失調症狀，目前醫學上可藉著增加體內一種或多種下列神經傳導物質的量來治療：血清素(serotonin)、多巴胺(dopamine)及正腎上腺素(norepinephrine)等。目前抗憂鬱劑有七大類，其中選擇性血清素回收抑制劑(SSRIs)與四環抗憂鬱藥物被廣泛的肯定並視為是治憂鬱症之第一線藥物。但有些選擇性血清素回收抑制劑的生理學上的角色似乎與抑制血清素回收功能無關，如引起不同細胞凋亡的paroxetine隸屬SSRIs，另外maprotiline隸屬於四環抗憂鬱藥物，也曾發現可引起數種細胞株的凋亡，但也有研究也表明maprotiline可以或抑制其它藥物誘發之凋亡，因此這兩種藥對於凋亡的影響尚有爭議。
本研究之主旨，在於探討paroxetine與maprotiline在誘發小鼠神經瘤母細胞及人類骨癌細胞凋亡的作用機轉。首先利用WST-1螢光法測定不同藥劑濃度條件下的細胞存活率及以propidium iodide染色法測定其凋亡的情況。此外，以免疫吸乾法(immunoblotting)偵測凋亡標示蛋白caspase-3的活性是否隨著藥物的處理而有所改變，以及有絲分裂蛋白激酶[mitogen-activated protein kinases (MAPKs)]的磷酸化過程，藉以研究這些抗憂鬱藥物引起細胞凋亡的訊息傳導過程。本研究之結果有助於了解抗憂鬱藥劑對身體重要器官細胞的藥理毒理作用。
研究表明，在24小時內，paroxetine透過增加caspase-3的活化使培養的人類骨癌細胞（MG63）進入細胞凋亡。其次，免疫吸附法表明paroxetine可以活化胞外訊號調節激酶[extracellular signal-regulated kinase (ERK)]，c-Jun氨基末端激酶[c-Jun NH2-terminal kinase (JNK)]與p38有絲分裂蛋白激酶[p38 mitogen-activated protein kinase (p38 MAPK)]的磷酸化表現，但只有SB203580（p38 MAPK的專一性抑制劑）可以部分的避免細胞產生凋亡。其三，細胞內鈣離子的研究發現paroxetine可引起細胞內鈣的濃度上升，但預處理一鈣離子的螯合物BAPTA/AM卻無法避免細胞死亡。這些結果顯示，paroxetine透過誘發與p38 MAPK相關連caspase-3的活化使MG63細胞進入與鈣離子訊號無關的細胞凋亡程序。
在抗憂鬱藥引起老鼠神經瘤母細胞（Neuro-2a）的凋亡研究中，maprotiline也是透過增加caspase-3的活化而導致細胞凋亡的產生。在由maprotiline所造成的Neuro-2a細胞凋亡中，其所引起的JNK磷酸化會幫助caspase-3的活化。因此顯示maprotiline誘發的細胞凋亡是透過依賴JNK/caspase-3的訊息路徑。我們也發現阻斷ERK的活化，可增加caspase-3的活化並造成由maprotiline所誘發的凋亡增加。這結果顯示在Neuro-2a細胞中，ERK為一存活訊號可對抗由maprotiline所引起的凋亡效應。因此，由maprotiline所導致的caspase-3活化似乎依賴JNK的活化與ERK的去活化。maprotiline也會引起細胞內鈣的濃度上升。預處理BAPTA/AM可抑制由maprotiline所誘發的ERK磷酸化，增強caspase-3的活化進一步增加由maprotiline所產生的細胞凋亡。總之，這項研究發現maprotiline在小鼠神經瘤母細胞中所誘發的細胞凋亡是透過與JNK相關連的caspase-3活化這條路徑而造成。Maprotiline同時也會引起與鈣離子訊號和ERK相關的抗細胞凋亡反應。上述的一些結果已發表在Toxicology and Applied Pharmacology與投稿在Toxicology Letters兩本期刊中。

Depression is a physiological disorder that may be treated by increasing the body’s amount of one or a few of the following neurotransmitters: serotonin, dopamine and norepinephrine. Although there are seven distinct classes of antidepressants, selective serotonin reuptake inhibitors (SSRIs) and tetracyclic antidepressants are widely prescribed and generally regarded as the first-line drugs in the treatment of depression. However, many physiological roles of some SSRIs appear to be dissociated with the inhibition of serotonin reuptake. For instance, paroxetine, a member of SSRIs and maprotiline, a member of tetracyclic antidepressant, have been shown to induce apoptosis or to prevent other agents from inducing apoptosis in several cell lines. Thus the effects of these two drugs on the apoptosis are still controversial.
The aim of this study is to investigate the molecular mechanisms of paroxetine and maprotiline in induction of cell death in human osteosarcoma and murine neuroblastoma cells. First, WST-1 reduction assays and propidium iodide-staining assays were used to determine cell viability and apoptosis in the presence of paroxetine and maprotiline. Then immunoblotting was used to measure the activity of apoptotic markers caspase-3 and mitogen-activated protein kinases (MAPKs) to survey the apoptotic pathways induced by these two antidepressants. The experimental results may be helpful to understand the pharmacological and toxicological effects of these two antidepressants in cells from important organs.
Results showed that paroxetine caused apoptosis via the activation of caspase-3 in cultured human osteosarcoma cells (MG63). Although paroxetine could activate the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), only SB203580 (a p38 MAPK inhibitor) partially prevented cells from apoptosis. Paroxetine was also found to induce [Ca2+]i increases but pretreatment with BAPTA/AM, a Ca2+ chelator, prevented paroxetine-induced [Ca2+]i increases, and thus did not protect cells from death. These results suggest that paroxetine caused Ca2+-independent apoptosis via the activation of p38 MAPK-associated caspase-3 in MG63 cells.
Maprotiline was also found to induce apoptosis through increased caspase-3 activation in murine neuroblastoma Neuro-2a cells. Induction of JNK phosphorylation contributed to the activation of caspase-3 resulting in maprotiline-induced Neuro-2a cell apoptosis. Thus, it appears that maprotiline induced apoptosis via JNK/caspase-3-dependent signaling pathways. Blockage of activation of ERK was found to increase the activation of caspase-3 leading to an enhancement of maprotiline-induced apoptosis. These data suggest that ERK was a survival signal to oppose maprotiline-caused apoptotic effect in Neuro-2a cells. Thus the activation of caspase-3 by maprotiline appears to depend on the activation of JNK and the inactivation of ERK. [Ca2+]i measurement in the presence of maprotiline showed that the antidepressant induced [Ca2+]i increases. Interestingly, pretreatment with BAPTA/AM could suppress maprotiline-induced ERK phosphorylation, enhance caspase-3 activation and increase maprotiline-induced apoptosis. In conclusion, this study demonstrates that maprotiline induced apoptosis in murine neuroblastoma cells through activation of JNK-associated caspase-3 pathways. Maprotiline also evoked an anti-apoptotic response that was both Ca2+- and ERK-dependent. This thesis contains some published data in the journal of Toxicology and Applied Pharmacology and some data were submitted in the journal of Toxicology Letters.

摘要 i
ABSTRACT iii
LIST OF ABBREVIATIONS v
CHAPTER 1 INTRODUCTION 1
1. INTRONDUCTION 1
1.1. Monoamine hypothesis and the development of MAOIs and TCAs 1
1.2. Biochemical roles of monoamine neurotransmitter inhibitors 2
1.3. Development of antidepressant drus 2
1.4. Types of antidepressants 5
1.5. The cytotoxicity of antidepressants 8
1.6. The characteristics of apoptosis 9
1.7. The extrinsic pathway of apoptosis 10
1.8. The intrinsic pathway of apoptosis 10
1.9. The role of mitogen-activated protein kinases (MAPKs) in apoptosis 11
1.10. The role of Ca2+ signaling in apoptosis 14
2. AIM 17
3. STUDY STRATEGY 17
CHAPTER 2 MATERIALS AND METHODS 26
2.1. Materials 26
2.2. Cell culture 26
2.3. Solutions 26
2.4. [Ca2+]i measurements 27
2.5. Cell viability assays 28
2.6. Western immunoblotting 29
2.7. Flow cytometry 30
2.8. Statistics 31
CHAPTER 3 THE MOLECULAR MECHANISMS OF PAROXETINE-INDUCED APOPTOSIS IN HUMAN OSTEOSARCOMA CELLS. 32
3.1. INTRODUCTION 32
3.2. RESULTS 35
3.2.1. Effect of paroxetine on the survival of MG63 cells 35
3.2.2. Paroxetine-induced apoptosis in MG63 cells 36
3.2.3. Involvement of MAPKs in paroxetine-induced apoptosis 36
3.2.4. p38 MAPK-regulated caspase-3 activation 37
3.2.5. Effect of paroxetine on [Ca2+]i 38
3.2.6. No effect of chelating Ca2+ with BAPTA on paroxetine-induced cell death 39
3.3. DISCUSSION 40
CHAPTER 4 THR MOLECULAR MECHANISMS OF MAPROTILINE-INDUCED APOPTOSIS IN MURINE NEUROBLASTOMA CELLS 58
4.1. INTRODUCTION 58
4.2. RESULTS 62
4.2.1. Cytotoxic effect of maprotiline on Neuro-2a cells 62
4.2.2. Apoptosis induced by maprotiline 62
4.2.3. Involvement of MAPKs in maprotiline-induced apoptosis 62
4.2.4. JNK-regulated caspase-3 activation 64
4.2.5. Effect of blockade of ERK signaling on maprotiline-induced cell death and apoptosis 64
4.2.6. Blockade of ERK signaling enhances maprotiline-induced caspase-3 activation in Neuro-2a cells 65
4.2.7. Effect of maprotiline on Ca2+ homeostasis 65
4.2.8. Effect of chelating Ca2+ with BAPTA/AM on ERK phosphorylation and maprotiline-induced cell death 66
4.3. DISCUSSION 68
CHAPTER 5 GENERAL CONCLUSION 95
LIST OF FIGURES
Figure 1.1. Selective serotonin reuptake inhibitors (SSRIs). 19
Figure 1.2. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and bupropion. 20
Figure 1.3. Tricyclic antidepressants (TCAs). 21
Figure 1.4. Tetracyclic antidepressants. 22
Figure 1.5. Monoamine oxidase inhibitors (MAOIs). 23
Figure 1.6. New mixed-action agents. 24
Figure 1.7. Mitogen-activated protein kinases signaling cascades. 25

Figure 3.1. Effect of paroxetine on viability of MG63 cells 44
Figure 3.2. Paroxetine-induced apoptosis 46
Figure 3.3. Effect of paroxetine on the phosphorylation of ERK, JNK/SAPK, and p38 MAPK 48
Figure 3.4. Effect of SB203580 on paroxetine-induced apoptosis 49
Figure 3.5. Effect of SB203580 on activation of caspase-3 53
Figure 3.6. Effect of paroxetine on [Ca2+]i 54
Figure 3.7. Independence of paroxetine-induced cell death on preceding [Ca2+]i increases 56

Figure 4.1. Effect of maprotiline on viability of Neuro-2a cells 73
Figure 4.2. Maprotiline induced apoptosis in Neuro-2a cells 75
Figure 4.3. Effect of maprotiline on the phosphorylation of ERK, JNK/SAPK and p38 MAPK 78
Figure 4.4. Effect of SP600125 on maprotiline-induced cell death and apoptosis 79
Figure 4.5. Effect of PD98059 on maprotiline-induced cell death and apoptosis 83
Figure 4.6. Effect of maprotiline on [Ca2+]I 87
Figure 4.7. Interaction of maprotiline-induced cell death, apoptosis and [Ca2+]i increase. 89
Figure 4.8. Effect of BAPTA/AM on maprotiline-induced cell death and apoptosis. 92

Figure 5.1. A novel model for paroxetine-induced apoptosis in MG63 cells. 98
Figure 5.2. A novel model for maprotiline-induced apoptosis in Neuro-2a cells. 99

REFERENCES 100
APPENDIX 1
Paroxetine-induced apoptosis in human osteosarcoma cells: Activation of p38 MAP kinase and caspase-3 pathways without involvement of [Ca2+]i elevation 121
APPENDIX 2
Publications 130

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