Luo J, Lindström C L, Donahue A, Miller M W
Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa, USA .
J Neurochem. 2001 Mar;76(5):1354-63. doi: 10.1046/j.1471-4159.2001.00129.x.
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 PGE(2) synthesis. In both cell types, neither the activity nor the expression of cPLA(2) was affected by ethanol. PGE(2) was synthesized by astrocytes and neurons. Ethanol (200-400 mg/dL for 24 h) significantly increased PGE(2) production in both cell types and the ethanol-induced increase in PGE(2) 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(2) synthesis are mediated by COX, principally COX2. Ethanol toxicity may be mediated through PGE(2) in immature cortical cells.
发育中的中枢神经系统是乙醇毒性的主要靶标。乙醇的致畸作用可能源于其对前列腺素的作用。前列腺素是通过胞质磷脂酶A2（cPLA2）作用于膜结合磷脂释放花生四烯酸（AA），以及环氧化酶（COX）将AA催化转化为前列腺素E2（PGE2）而产生的。COX以两种同工型表达，即组成型COX1和诱导型COX2。来自未成熟大脑皮层的培养星形胶质细胞和神经元被用作体外模型，以研究乙醇对PGE2合成的影响。在这两种细胞类型中，乙醇均未影响cPLA2的活性和表达。PGE2由星形胶质细胞和神经元合成。乙醇（200 - 400 mg/dL，作用24小时）显著增加了这两种细胞类型中PGE2的产生，且乙醇诱导的星形胶质细胞中PGE2积累的增加显著大于神经元。这些增加是乙醇对COX作用的结果。总体而言，乙醇上调了星形胶质细胞和神经元中的COX活性，而COX的非选择性阻滞剂吲哚美辛消除了乙醇诱导的这两种细胞类型中COX活性的增加。星形胶质细胞中COX活性的增加是由于COX2表达增加所致。选择性COX2阻滞剂NS - 398完全抑制了乙醇诱导的COX活性改变。然而，在神经元中，乙醇在COX表达未改变的情况下对COX活性有直接作用。NS - 398仅部分阻断了乙醇诱导的神经元COX活性增加。因此，星形胶质细胞是乙醇的主要靶标，乙醇诱导的胶质细胞PGE2合成增加是由COX介导的，主要是COX2。乙醇毒性可能通过未成熟皮层细胞中的PGE2介导。
