探討神經性疼痛及神經膠母細胞瘤之治療研究

The studies on treatment of nuropathic pain and glioblastoma multiforme

陳建民(Chien-Min Chen)

指導教授 ： 林中天

國立臺灣大學/獸醫專業學院/獸醫學研究所/博士(2015年)

https://doi.org/10.6342/NTU.2015.11190

摘要

臨床上神經的疼痛是最難處理的問題之一，雖然類固醇常被使用於治療及緩解神經性肌肉的疼痛，但是相關的一些機転並不明確。此外，神經細胞導致的癌症也是相當的難以處理的問題，即便現在有適當的藥物可以治療，但治療效果仍不佳。綜合以上，本論文的目的主要透過基礎及臨床研究，探討在臨床上常遇到的神經學及神經外科學相關問題並希望能藉由一些輔助的藥物能使治療更完善。本論文包含三個實驗性研究及一個臨床研究，分別探討骨穩的使用對於骨質疏鬆患者肺功能及疼痛緩解的影響，皮質醇治療的抗發炎效應，咔唑類衍生物(BC3EE2,9B)對於抑制惡性神經膠質瘤細胞的增殖能力及運用新型的微創手術方法治療犬的椎間盤突出。
研究一為單一醫學中心，量性研究。其目的主要在探究骨穩的使用對於骨質疏鬆患者肺功能及疼痛緩解的影響。共收集37位骨質疏鬆並完成6個月骨穩治療之病患。結果發現，骨穩治療對於骨質疏鬆性脊椎壓迫性骨折的患者，能提升其肺功能並降低疼痛。研究二是運用動物模型之實驗性研究。其目的主要在評估皮質醇合併胰島素治療的抗發炎效應及機轉。在實驗中，我們將56隻大鼠分成7組(每組八隻)，一組對照組，六組實驗組，實驗組則分別採用胰島素或、及皮質醇來治療。結果發現，在單一皮質醇治療的大鼠，不論在靜止或運動狀態下，血清中葡萄糖增加並伴隨著葡萄糖轉運蛋白第4型不活化。然而在皮質醇合併胰島素治療的組別，在運動訓練狀態下，發現透過Akt蛋白質磷酸化能調控葡萄糖轉運蛋白第四型在細胞膜上的表現量。胰島素治療對於葡萄糖轉運蛋白第四型運轉量表達了代償回饋效應。研究三是動物實驗性研究，運用新型的微創手術方法治療犬的椎間盤突出。研究結果發現，透過練習新型的微創手術可達到與傳統椎間盤切除手術一樣的效果，但比起傳統手術新型的微創手術可減少背側肌肉組織及韌帶結構的損傷。研究四是實驗性研究，一般來說犬的腦瘤發病率約十萬分之10-20比人類高希望藉由人類神經膠質瘤細胞，來促進對腦瘤治療的認識，其目的主要在評估咔唑類衍生物(BC3EE2,9B)對於抑制惡性神經膠質瘤細胞(GBM8401及GBM8901細胞株)的增殖能力,。研究結果發現BC3EE2,9B會使此癌細胞分裂週期停滯於G1期，進而抑制癌細胞生長。此外我們發現BC3EE2,9B會誘發自噬作用與temozolomide併用對神經膠質瘤細胞具協同毒殺作用。本研究結果證明BC3EE2,9B可提升化學治療藥temozolomide毒殺抗藥性神經膠質瘤細胞株之分子機轉。

關鍵字

骨穩 ； Akt蛋白質磷酸化 ； 葡萄糖轉運蛋白第4型 ； 皮質醇 ； 咔唑類衍生物 ； 神經膠母細胞瘤 ； 帝盟多

並列摘要

The present thesis report research on neurology and neurosurgery science through basic science and clinical practice. The thesis addresses the effects of clinical treatment for neurological disorders, in particular, neuropathic pain. Four studies were conducted which illustrated the effects of teriparatide on lung function and pain relief, the anti-inflammation effects of hydrocortisone treatment and anti-proliferative effects of a series of synthetic carbazole derivatives in glioblastoma cells. The first study was designed as the quatitative study which used both questionaire and physical examination with 37 participants to evaluate the the effects of teriparatide on lung function and pain relief. All of them completed 6 months treatment. We found that teriparatide treatment improves the lung function and results in diminished pain intensity in women with multiple osteoporotic vertebral compression fractures. The second study used a aminal model to examine the anti-inflammation effects of hydrocortisone treatment in 56 SD rats. Fifty-six SD rats were divided into seven groups, and were treated with insulin or hydrocortisone in sedentary or exercise training groups. The results showed that the serum glucose increased in hydrocortisone treatment accompanied by GLUT4 inactivation in both the sedentary and exercise training rats. In the exercise training groups, GLUT4 was redistributed on the plasma membrane on the co-treatment with insulin and hydrocortisone through Akt phosphorylation. Insulin treatment exerted a compensatory feedback effect on GLUT4 translocation on hydrocortisone cotreatment, which was the cause of GLUT4 inactivation. In the third study aims to design an innovative technique and apply it in dogs with spinal cord dysfunction. The results showed that in experienced hands, such a technique is as effective as traditional lumbar discectomy and decreases traumatizing the normal anatomy of the dorsal musculature and ligamentous structures. The newly developed sheath is inexpensive, disposable, and easy to use, and it can facilitate microscopic surgery. In final study, anti-glioblastoma profiles of a series of synthetic carbazole derivatives were evaluated in vitro. The most promising derivative in this series was BC3EE2,9B, which showed excellent anti-proliferative effects in GBM8401 and GBM8901 cells. BC3EE2,9B also triggered cell-cycle arrest, most prominently at the G1 stage, and suppressed glioblastoma cell invasion and migration. Furthermore, we found that BC3EE2,9B induced autophagy-mediated cell death and synergisticly sensitized GBM cells to temozolomide cytotoxicity. Our results provide molecular evidence for the mode of action governing the ability of BC3EE2,9B to sensitize drug-resistant glioblastoma cells to the chemotherapeutic agent temozolomide.

並列關鍵字

teriparatide ； Akt phosphorylation ； GLUT4 ； hydrocortisone ； carbazole ； glioblastoma ； temozolomide

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