於本研究中，我們發現利用椎管（intrathecal）預先給予海洋天然物11-dehydrosinulariolide至脊髓損傷大白鼠，在受傷後8小時，可以減少因為脊髓損傷所引起的細胞凋亡。其機轉是利用增加抗凋亡蛋白Bcl-2以及增加細胞存活相關蛋白Akt以及ERK的活化。此外給予11-dehydrosinulariolide可以同時促進Bcl-2上游轉譯因子CREB之磷酸化。於受傷後第七天，給予11-dehydrosinulariolide可以減少因脊髓損傷後的發炎反應，減低由於脊髓損傷所增加的發炎相關蛋白：誘發型一氧化氮合成酶（inducible NO synthase）與腫瘤壞死因子α（tumor necrosis factor-α）。給予11-dehydrosinulariolide更可以增加M2微膠細胞的標記arginase-1與CD206。因此，11-dehydrosinulariolide的抗發炎機制或許跟調控微膠細胞的其他活化途徑相關。由於具有神經保護以及抗神經發炎的效果，再加上可以由養殖型珊瑚中大量純化，我們認為11-dehydrosinulariolide可以開發成為一具有潛力的神經保護藥物。除了神經保護與抗發炎的策略，許多學者指出膠質疤（glial scar）會成為脊髓損傷後神經再生的障礙。許多研究也暗示星狀細胞之PI3K/Akt/mTOR路徑的活化與膠質疤的形成相關。在本研究中，我們利用椎管注射一病毒載體（viral vector），在脊髓損傷大鼠過量表現（overexpress）第10號染色體缺失的磷酸酶和張力蛋白的同源基因（tensin homologue deleted on chromosome 10；PTEN）蛋白質。於脊髓損傷後，過量表現PTEN蛋白可以減弱膠質疤的形成、影響硫化軟骨蛋白多醣(chondroitin sulfate proteoglycan, CSPG)的表現、促進神經再生進入受傷區域，導致促進大白鼠行為能力恢復。由於延後（delay）治療組比受傷後立即給予病毒載體的更具有促進恢復行為能力的效果。這個研究的結果或許可以嘉惠一些無法於受傷後立即接受治療的脊髓損傷病患。

In the present study intrathecal pretreatment 11-dehydrosinulariolide attenuated spinal cord injury (SCI)-induced cell apoptosis by upregulating the antiapoptotic protein Bcl-2 and cell survival-related pathway proteins p-Akt and p-ERK, 8 h after SCI. Furthermore, the transcription factor p-CREB, which regulates Bcl-2 expression, was upregulated after 11-dehydrosinulariolide treatment. On day 7 after SCI, 11-dehydrosinulariolide exhibited an anti-inflammatory effect, attenuating SCI-induced upregulation of inducible NO synthase and tumor necrosis factor-α. 11-Dehydrosinulariolide also induced an increase in the expression of arginase-1 and CD206, markers of M2 microglia. Thus, the anti-inflammatory effect of 11-dehydrosinulariolide may be related to the promotion of an alternative pathway of microglia activation. On the basis of its neuroprotective and anti-inflammatory effects and ease of isolation from a coral that can be farmed, 11-dehydrosinulariolide is a potential neuroprotective agent. Besides of neuroprotection and anti-inflammation strategy, several studies suggest that glial scars pose as barriers that limit neurite regeneration after SCI. Evidences suggest that the activation of the PI3K/Akt/mTOR signaling pathway is involved in glial scar formation. In this study, we intrathecally injected a recombinant adenovirus carrying the pten gene to cause overexpression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in rats with SCI. Overexpression of PTEN following SCI attenuated gliosis, affected chondroitin sulfate proteoglycans expression, and improved axon regeneration into the lesion site led to improved locomotor function after SCI. Because delayed treatment with Ad-PTEN enhanced motor function recovery more significantly than immediate treatment with Ad-PTEN after SCI. These findings thus have positive implications for patients who are unable to receive immediate medical attention after SCI.
Key words: marine natural product; 11-dehydrosinulariolide; microglia; neuroprotection; spinal cord injury; anti-inflammation; phosphatase and tensin homologue deleted on chromosome 10; astrocyte; glial scar; chondroitin sulfate proteoglycans.

Table of contents i
List of Figures iv
List of tables vi
Abstract vii
中文摘要 ix
General introduction 1
A new strategy for treatment of SCI is urgently needed 1
Pathophysiological processes following SCI 2
Clinical study of spinal cord injury 3
The experimental drugs to treat secondary injury of SCI 5
Animal models in traumatic spinal cord injury 8
The aim and scope of present study 11
Materials and methods 12
Implantation of intrathecal catheters 12
Preparation of adenovirus vectors 12
Spinal cord contusion injury in rats 13
Drug and viral vectors treatment 13
Behavioral analysis 14
Immunohistochemistry and quantification 15
Western blotting 16
Statistical analysis 17
PART I: A coral-derived compound improves functional recovery after spinal cord injury through its antiapoptotic and anti-inflammatory effects 21
Introduction 22
The roles of glial cells in SCI 22
Glial cells driven neurotrophic factors against SCI 23
Apoptosis plays an important role in the acute stage of spinal cord injury 25
Inflammation contributes substantially to secondary injury in SCI 27
The alternative activated M2 microglia has beneficial effects after SCI 29
The marine-derived natural compounds are good source of potential drugs 30
Background for marine organisms-derived compound 11-dehydrosinulariolide 32
Results 34
11-Dehydrosinulariolide improved locomotor behavior after SCI 34
Antiapoptotic effects of 11-dehydrosinulariolide after SCI 34
Effects of 11-dehydrosinulariolide on the neuroprotection-related signaling pathway 35
11-Dehydrosinulariolide increased the amount of white matter spared after SCI 36
11-Dehydrosinulariolide attenuated SCI-induced inflammatory protein expression 37
11-Dehydrosinulariolide promoted an alternative pathway of microglia activation after SCI 37
11-Dehydrosinulariolide enhanced SCI-induced VEGF-A, GDNF and BDNF expression 38
Discussion 58
PART II: The role of the PI3K/Akt/mTOR pathway in glial scar formation following spinal cord injury 65
Introduction 66
Harmful roles of astrogliosis and glial scar formation in SCI 66
Glial scars are an obstacle to modern SCI treatment: Chondroitin sulfate proteoglycans (CSPGs) are the major components of glial scars inhibiting axonal regeneration 66
The PI3K/PTEN/Akt/mTOR pathway as a novel therapeutic target of CNS injury: Upregulation of PTEN may be beneficial in SCI by inhibiting astrogliosis 69
Results 72
Determining the best time for Ad-PTEN injection by examination of astrocytic Akt activation 72
Time course of exogenous pten gene-induced upregulation of PTEN expression 73
I.t. Ad-PTEN improved locomotor function following SCI 74
Spinal PTEN overexpression attenuated SCI-induced Akt and S6 phosphorylation 75
I.t. Ad-PTEN attenuated SCI-induced gliosis at 7 days after injury 76
PTEN overexpression modulated spinal CPSGs expression after SCI 78
PTEN overexpression attenuated glial scar formation and enhanced neurofilament regeneration across scar 79
Discussion 100
PTEN-regulated astrocytic Akt signaling in SCI 100
I.t. Ad-PTEN overexpressed spinal astrocytic PTEN 101
CSPGs expression after SCI 104
The effects of astrocytic PTEN overexpression in SCI 105
The role of the PI3K/Akt/mTOR pathway in SCI 107
The advantages of PTEN in SCI 109
Summary 111
References 114
Autobiography 160
附錄：發表文章 165

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