腦部缺血誘導氧化壓力常伴隨活性含氧物種(ROS)的增加，進而導致神經細胞的退化。星狀膠細胞為中樞神經系統(CNS)中含量最多的膠細胞，調控著神經細胞的成熟、存活與細胞間物質的傳遞。由星狀膠細胞分泌的第一型血小板活化蛋白(TSP-1)為一種具多結構域蛋白結構的胞外糖蛋白，於神經突觸新生、可塑性以及軸突生長扮演重要角色，參與腦部功能的回復。然而，星狀膠細胞TSP-1在氧化壓力下的調控機制目前仍未清楚，所以實驗主要探討星狀膠細胞於氧化壓力下TSP-1基因表現量的變化。在此研究中，利用氯化鈷模擬細胞缺氧狀態，對新生大鼠腦皮質組織培養的星狀膠細胞進行處理，誘導氧化壓力的產生。細胞存活率檢測顯示，0.1 ~ 0.5 mM氯化鈷處理不會引發星狀膠細胞大量死亡；然而星狀膠細胞內ROS的表現量則會隨氯化鈷處理濃度或時間增加，同時也發現以0.3與0.5 mM氯化鈷處理會使對氧化壓力敏感的3-磷酸甘油醛脫氫酶(GAPDH) mRNA表現量增加。另外，因為ROS導致的氧化壓力會誘發c-Jun N-terminal Kinase (JNK)的活化，欲進一步探討氯化鈷對星狀膠細胞中c-Jun磷酸化的影響。由西方點墨法分析得知，氯化鈷處理導致5分鐘時間點磷酸化c-Jun的短暫增加。由以上實驗確認氯化鈷處理會於大鼠星狀膠細胞誘發氧化壓力。接著以定量聚合鏈酶反應分析，顯示氯化鈷處理會導致TSP-1 mRNA表現於2小時微微增加，而後在12、24小時顯著性的降低。另外在2小時氯化鈷處理後，進行細胞回復，則發現TSP-1 mRNA表現於無氯化鈷之細胞回復過程仍持續減低；而GAPDH則在移除氯化鈷後表現量無明顯改變。另外，氯化鈷移除後進行細胞回復，細胞內ROS生成則會回復而與控制組無明顯差異。免疫螢光染色實驗顯示，氯化鈷處理會導致星狀膠細胞內ATF-1向細胞核移動。而電泳遷移率檢測(EMSA)則進一步顯示，氯化鈷處理導致星狀膠細胞內DNA與ATF-1間鍵結活性的增加。綜合以上結果，我們推測氯化鈷會在大鼠星狀膠細胞誘導氧化壓力，並進一步減低TSP-1 mRNA與蛋白質的表現；且氯化鈷所導致的TSP-1 mRNA降低可能為不可逆，而ATF-1可能以負向調控方式參與其中。

Oxidative stress induced by cerebral ischemia along with a mass of the generation of reactive oxygen species (ROS) contribute to neuronal degeneration. Astrocytes, the major glial population in the central nervous system (CNS), mediate neuronal maturation, survival, and transmission. Thrombospondin (TSP)-1, a multidomain glycoprotein, can be secreted by astrocytes and has the role in brain functional repair because of its importance in synaptogenesis, synaptic plasticity and axonal sprouting. However, little was known about the regulation of TSP-1 expression in astrocytes under oxidative stress, so we wanted to figure out that TSP-1 expression in primary rat astrocytes under oxidative stress. In this study, the culture of astrocytes isolated from neonatal rat cortical tissues was exposed to a hypoxic mimetic reagent, cobalt chloride (CoCl2), which is often used as stimulus for chemically induced oxidative stress. Cell viability assay indicated that CoCl2 at the concentrations of 0.1-0.5 mM did not cause significant cell death in astrocytic cultures. However, ROS levels in astrocytes were dose- and time-dependently elevated by CoCl2. Exposure to CoCl2 at 0.3 mM and 0.5 mM also induced an increase in gene expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which is known to be sensitive to oxidative damage. Since ROS-triggered oxidative stress can lead to c-Jun N-terminal Kinase (JNK) activation, we examined whether CoCl2 can induce c-Jun phosphorylation in astrocytes. Indeed, Western Blot analysis showed that treatment with a brief increase in the phosphorylation of c-Jun was observed at 5 min after treatment with CoCl2. Based on these observations, CoCl2-induced oxidative stress in astrocytes was verified. Furthermore, real-time quantitative PCR analysis showed that TSP-1 mRNA expression in astrocytes was slightly upregulated at 2 h after exposure to CoCl2, followed by a significant downregulation at 12 h and at 24 h. After a 2 h-treatment with CoCl2 following cell recovery in the absence of CoCl2, the reduction in TSP-1 mRNA expression was continuously observed. However, GAPDH mRNA expression after cell recovery was increased to a lesser degree than that observed in the culture by a 2-h treatment with CoCl2. It was noticed that no significant difference in the cellular levels of ROS was observed in CoCl2-treated groups after cell recovery when compared to that in controls. Immunofluorescence indicated that treatment with CoCl2 resulted in the nuclear translocation of ATF-1 in astrocytes. Electrophoresis motility shift assay (EMSA) further showed that the DNA binding of ATF-1 was increased in astrocytes after a 2-h treatment with CoCl2. Based on our results, we conclude that CoCl2 induces oxidative stress in astrocytes, and subsequently reduces TSP-1 mRNA expression and its protein production. Moreover, CoCl2-induced inhibition of TSP-1 mRNA is irreversible, and is involved in ATF-1 that could act as the negative regulator for TSP-1 mRNA expression.

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