缺血性中風 (ischemia stroke)為世界人口死因的前幾名，在中風的病例當中有80% 以上為缺血性中風，中風之後會造成神經功能的缺失與傷害，但目前還尚未找出有效的治療方法，因此近年的研究都在探討如何有效治療大腦的缺血性中風，致力找出腦神經細胞死亡之機制，並期望開發出新的藥物，用以治療缺血性中風所造成的神經細胞死亡；先前的許多研究中已經證實，褪黑激素為一良好的自由基清除劑，並且是一種神經保護劑，能夠減少因缺血性中風所引起的神經細胞死亡。在缺血性中風的機制方面，目前已經證實在中風之後會細胞會產生內質網壓力 (endoplasmic reticulum stress)，抑制細胞合成蛋白質，進而造成神經細胞的傷害與死亡；因此本論文將分為兩個部份探討其相關機制: 第一: 以大白鼠來進行中大腦動脈栓塞 (Middle cerebral artery occlusion，MCAO ) 手術造成暫時性缺血性中風 (transient ischemia stroke)，並於手術後給予褪黑激素 (melatonin, 5 mg/kg)；第二: 以初代神經元培養(primary cortical mixed neuronal culture)在缺氧-缺糖 (Oxygen-glucose deprivation, OGD) 之刺激下，引發內質網壓力，並在事前給予褪黑激素 (melatonin)，以觀察褪黑激素是否能夠減少內質網壓力，進一步達到保護細胞的效果；實驗結果發現大鼠手術後給予褪黑激素治療，並且在缺氧-缺糖刺激前，給予初代神經細胞不同濃度之褪黑激素，皆能夠降低內質網壓力其中RNA dependent protein kinase-like ER kinase (PERK) 途徑 (PERK pathway) 相關蛋白之表現。因此，從實驗結果可以推測，褪黑激素能夠藉由降低內質網壓力，以減少因中風所引起之神經細胞損傷與死亡；可能是經由降低細胞內之自由基 (free radicals)，並活化細胞內抗氧化途徑之相關蛋白，以達到保護神經細胞的作用。

Stroke is a major public health problem in the worldwide. Ischemia stroke accounts for approximately 80% of all strokes and leads to neurologic morbidity and mortality; however, efficient theraputical treatments remain unavailable. Many studies evaluated melatonin is well known to be a potent free radical scavenger and an antioxidant and can decreased neuronal cell death following transient cerebral ischemia. Several recent reports indicate inhibitions of protein synthesis were inducible by endoplasmic reticulum stress under ischemia and that caused neuronal cell death. In the beginning of the experiments, we used Sprague-Dawley rats following transient middle cerebral artery (MCA) occlusion surgery and treat melatonin after surgery. Secondary, we gave an oxygen -glucose deprivation (OGD) stress in primary neuronal culture model and pretreatment of melatonin in different dosages. A series of results indicated melatonin can decrease the expression of phospho-PERK pathway related proteins in the MCAO model. We also found pretreatment of melatonin can decrease the expression of phospho-PERK pathway related proteins in primary neuronal culture under OGD stress. The possible effects of melatonin may scavenge free radical and induce antioxidant responds to decrease endoplasmic reticulum stress that can protect neuronal cells.

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