Differential effects of ethanol on the expression of cyclo-oxygenase in cultured cortical astrocytes and neurons
Differential effects of ethanol on the expression of cyclo-oxygenase in cultured cortical astrocytes and neurons
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DOI：
10.1046/j.1471-4159.2001.00129.x
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发表时间：
2001-03-01
影响因子：
4.7
通讯作者：
Miller, MW
中科院分区：
文献类型：
--
作者：
Luo, J;Lindström, CLB;Miller, MW
发育中的中枢神经系统是乙醇毒性的主要靶点。乙醇的致畸作用可能是由于其对甘草素的作用。前列腺素是通过胞浆磷脂酶A（2）（cPLA（2））作用于膜结合磷脂释放花生四烯酸（AA）并通过环加氧酶（考克斯）催化AA转化为前列腺素E-2（PGE（2））而产生的。考克斯以两种同种型表达，组成型COX 1和诱导型COX 2。采用体外培养的未成熟大脑皮质星形胶质细胞和神经元模型，研究乙醇对PGE 2合成的影响。在这两种细胞类型中，cPLA 2的活性和表达均不受乙醇的影响。PGE 2由星形胶质细胞和神经元合成。乙醇（200-400 mg/dL，持续24 h）显著增加了两种细胞类型中PGE 2的产生，并且乙醇诱导的星形胶质细胞中PGE 2积累的增加显著大于神经元中的增加。这些增加是由于乙醇对考克斯的影响。总的考克斯活性上调乙醇在星形胶质细胞和神经元，吲哚美辛，一种非选择性的考克斯阻滞剂，消除了乙醇诱导的增加考克斯活性在两种细胞类型。星形胶质细胞中考克斯活性的增加是由于COX 2表达的增加。NS-398是一种选择性COX 2阻滞剂，可完全抑制乙醇诱导的考克斯活性变化。然而，在神经元中，在考克斯表达没有变化的情况下，乙醇对考克斯活性有直接影响。NS-398仅部分阻断乙醇诱导的神经元考克斯活性增加。因此，星形胶质细胞是乙醇的主要靶点，乙醇诱导的胶质细胞PGE合成增加由考克斯，主要是COX 2介导。乙醇毒性可能是通过PGE 2介导的未成熟的皮质细胞。
The developing central nervous system is a primary target of ethanol toxicity. The teratogenic effect of ethanol may result from its action on prostaglandins. Prostaglandins are generated through the release of arachidonic acid (AA) by the action of cytosolic phospholipase A(2) (cPLA(2)) on membrane-bound phospholipids and the catalytic conversion of AA to prostaglandin E-2 (PGE(2)) by cyclo-oxygenase (COX). COX is expressed in two isoforms, constitutive COX1 and inducible COX2. Cultured astrocytes and neurons from immature cerebral cortex were used as in vitro models to investigate the effect of ethanol on PGE2 synthesis. In both cell types, neither the activity nor the expression of cPLA2 was affected by ethanol. PGE2 was synthesized by astrocytes and neurons. Ethanol (200-400 mg/dL for 24 h) significantly increased PGE2 production in both cell types and the ethanol-induced increase in PGE2 accumulation in astrocytes was significantly greater than in neurons. These increases resulted from the effects of ethanol on COX. Overall COX activity was up-regulated by ethanol in astrocytes and neurons, and indomethacin, a nonselective blocker for COX, eliminated the ethanol-induced increases of COX activity in both cell types. Increased COX activity in astrocytes resulted from an increase in COX2 expression. NS-398, a selective COX2 blocker, completely inhibited ethanol-induced alterations in COX activity. In neurons, however, ethanol had a direct effect on COX activity in the absence of a change in COX expression. NS-398 only partially blocked ethanol-induced increases in neuronal COX activity. Thus, astrocytes are a primary target of ethanol and ethanol-induced increases in glial PGE, synthesis are mediated by COX, principally COX2. Ethanol toxicity may be mediated through PGE2 in immature cortical cells.